Expert Review of Gastroenterology & Hepatology

ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: https://www.tandfonline.com/loi/ierh20

Non-invasive assessment of liver fibrosis and

prognosis: an update on serum and elastography
markers

Uchenna Agbim & Sumeet K. Asrani

To cite this article: Uchenna Agbim & Sumeet K. Asrani (2019): Non-invasive assessment of
liver fibrosis and prognosis: an update on serum and elastography markers, Expert Review of
Gastroenterology & Hepatology, DOI: 10.1080/17474124.2019.1579641

To link to this article: https://doi.org/10.1080/17474124.2019.1579641

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EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY
https://doi.org/10.1080/17474124.2019.1579641

REVIEW

Non-invasive assessment of liver fibrosis and prognosis: an update on serum and

elastography markers
Uchenna Agbima and Sumeet K. Asranib
a
Division of Transplant Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA; bBaylor University
Medical Center, Dallas, TX, USA

ABSTRACT ARTICLE HISTORY

Introduction: Non-invasive assessment of fibrosis is increasingly utilized in clinical practice to diagnose Received 10 August 2018
hepatic fibrosis. Non-invasive assessment of liver fibrosis relies on biologic and/or physical properties to Accepted 4 February 2019
assess tissue fibrosis. Serum markers estimate fibrosis by incorporating markers reflecting hepatic KEYWORDS
function (indirect markers) and/or markers measuring extracellular matrix degradation/fibrogenesis Elastography; hepatitis C;
(direct markers). Radiology based techniques relay the mechanical properties and stiffness of a tissue, hepatitis B; liver fibrosis;
with increased stiffness associated with more advanced fibrosis. liver stiffness; magnetic
Areas covered: In this comprehensive review, the recent literature discussing serum markers and resonance elastography;
elastography-based techniques will be covered. These modalities are also explored in the setting of nonalcoholic fatty liver
various liver diseases. disease; shear wave
Expert opinion: The etiology of liver disease and clinical context should be taken into consideration elastography; vibration-
when non-invasive markers are incorporated in clinical practice. Non-invasive assessment of fibrosis has controlled transient
elastography
been most extensively utilized in hepatitis C, followed by hepatitis B and nonalcoholic fatty liver
disease, but its role remains less developed in other etiologies of liver disease such as alcohol-
associated liver disease and autoimmune liver disease. The role of non-invasive markers in predicting
progression or regression of fibrosis, development of liver-related events and survival needs to be
further explored.

1. Introduction specimen size, sampling error, inter- and intra-observer reliability

Progressive fibrosis of the liver can lead to cirrhosis and compli-
cations of portal hypertension including ascites, variceal hemor-
rhage, portosystemic encephalopathy, as well as hepatocellular
carcinoma (HCC). Evaluation or staging of fibrosis is critical to
monitor the progression of chronic liver disease, determine
prognosis, establish optimal timing for treatment, monitor
response to treatment, and assess the evolution of disease to
mitigate morbidity and mortality associated with the sequelae of
cirrhosis [1]. Long heralded as the gold standard for assessing
fibrosis, liver biopsy is fraught with many limitations [2].
Over the last two decades, there has been significant interest
in the development of non-invasive surrogates of liver fibrosis. In
contrast to liver biopsy, a majority of these tests are simple to
perform, are more accessible and repeatable, rendering them
easier to use at a population level to evaluate fibrosis. The
purpose of this review is to summarize the basic principles of
non-invasive assessment of liver fibrosis and inform the reader
on updates in this field over the last few years.
2. Assessment of liver fibrosis
Liver biopsy is the putative gold standard for diagnosing fibrosis,
but carries notable risk including the potential complications of
pain, bleeding, infection, perforation, and even death [2]. Further,
the quality of liver biopsy may often be limited by small
with histologic assessment [2,3], and decreased level of perfor-
mance for intermediate stages of fibrosis [4]. Thus, there exists
a need for a less-invasive, reproducible, and accurate method to
characterize fibrosis in subjects with chronic liver disease.
2.1. Overview of non-invasive assessment
Non-invasive assessment of liver fibrosis relies on biologic and/or
physical properties to assess tissue fibrosis. Specifically, serum
markers represent biologic properties [5], while the most com-
mon clinically applied radiologic markers utilize physical proper-
ties, that is principles of elastography to indirectly determine
tissue stiffness [5,6].
2.2. Serum tests
In recent years, serum tests have gained widespread use, as they
are readily available, simple to utilize, objective, and cost less as
compared to a liver biopsy. A majority of these tests were devel-
oped in viral hepatitis or nonalcoholic fatty liver disease (NAFLD)
but have been adapted for use in various other liver diseases.
A unifying theme among most serum markers is they have
reasonable negative predictive value (NPV), rendering the mar-
kers useful tests at excluding disease, but fair positive predictive
value (PPV) with many false positives. In general, these tests

CONTACT Sumeet K. Asrani Sumeet.Asrani@baylorhealth.edu Baylor University Medical Center, Dallas, TX, USA
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 U. AGBIM AND S. K. ASRANI
estimate fibrosis by incorporating markers reflecting hepatic
injury and/or complications of portal hypertension (indirect mar-
kers) and/or markers measuring extracellular matrix (ECM) degra-
dation/fibrogenesis (direct markers) [7]. Some tests are
proprietary and available as a send-out test. Others can be
calculated using routine blood work in combination with patient
characteristics. A few examples of serum tests include the NAFLD
Fibrosis Score (NFS), BARD score, FIB-4, aspartate aminotransfer-
ase (AST) to platelet ratio index (APRI), and Enhanced Liver
Fibrosis Score (ELF). The NFS and BARD score are utilized speci-
fically for NAFLD, while the remaining tests were designed for
hepatitis C virus (HCV) but can assess any chronic liver disease.
These, among other tests, are briefly described in Table 1.
Using six common clinical parameters (age, hyperglycemia,
BMI, platelet count, albumin, AST/alanine aspartate [ALT]
ratio), the NFS was developed to detect fibrosis in subjects
with NAFLD with two cut-off scores. The low cut-off score of
<-1.455 can identify stage 3–4 fibrosis (F ≥ 3) using Brunt-
Kleiner staging system with an NPV of 93% and the high cut-
off of >0.696 has a PPV of 90% for detecting F ≥ 3 [15].
In addition to the NFS, another scoring system developed
to stage fibrosis in subjects with NAFLD is the BARD score,
which combines BMI, AST/ALT ratio, and presence of diabetes
to produce a weighted score assessing fibrosis risk. A BARD
score ≥2 indicates advanced fibrosis with an area under the
receiver operating characteristic (AUROC) value of 0.81 and
NPV of 96% [16].
Table 1. Selected serum tests for assessment of fibrosis.
Non-invasive Serum Test Formula/Components
APRI[18] AST/ULN of laboratory AST
Platelets (109/L) X 100
BARD[16] Weighted Sum of: BMI ≥ 28 = 1 point, AST/ALT ≥
0.8 = 2 points, Presence of DM = 1 point
FIB-4[17] Age ([yr] X AST [U/L])
((Platelets [109/L]) X (ALT [U/L]))1/2
NFS[15] −1.675 + 0.037 X age (yr) +0.094 X BMI (kg/m2)
+ 1.13 X IFG/DM
(yes = 1, no = 0) + 0.99 X AST/ALT ratio –
0.013 X platelet (109/L) -
0.66 X albumin (g/dl)
Forns Index[8] 7.811–3.131 X ln(platelet[109/L])
+ 0.781 X ln(GGT[IU/L])
+ 3.467 X ln(age[yr]) – 0.014.(cholesterol[mg/
dL])
GPR[9] GGT
Platelets
Lok Index[10] −5.56–0.0089 X platelet (103/mm3) + 1.26 X AST/
ALT ratio + 5.27 X INR
ELF[26] Age, hyaluronic acid, amino-terminal propeptide
of type III collagen, and tissue inhibitor of
metalloproteinase 1
FibroTest-ActiTest[11] Age, gender, α2-macroglobulin, haptoglobin,
(also referred to as GGT, ALT, apolipoprotein A1
FibroSure in the US)
FibroMeter[12] Age, platelets, PT, AST, α2-macroglobulin,
hyaluronic acid, urea
FibroMeter NAFLD[13] Age, body weight, platelets, AST, ALT, glucose,
ferritin
Hepascore[14] Age, gender, bilirubin, GGT, hyaluronic acid,,
α2-macroglobulin
ALT: alanine aminotransferase; APRI: aspartate aminotransferase to platelet ratio
index; AST: aspartate aminotransferase; BMI: body mass index; DM: diabetes
mellitus; ELF: Enhanced Liver Fibrosis; GGT: gamma-glutamyl transpeptidase;
GPR: gamma-glutamyl transpeptidase to platelet ratio; IFG: impaired fasting
glucose; NAFLD: nonalcoholic fatty liver disease; NFS: nonalcoholic fatty liver
disease fibrosis score; PT: prothrombin time; ULN: upper limit of normal.
The FIB-4 test was originally developed to estimate fibrosis
in subjects co-infected with human immunodeficiency virus
and HCV with two cut-off scores similar to NFS. For the low
cut-off of <1.45, the AUROC value to detect Ishak stage 4–6
(equivalent to Metavir F3–4) was 0.765, the NPV was 90%, and
sensitivity was 70%. For the high cut-off value of >3.25, the
PPV was 65% and specificity was 97% [17]. The pitfall with the
FIB-4 test lies with scores 1.45–3.25, where a test with better
discrimination is needed.
Another serum test is the AST to platelet ratio (APRI) score,
which was also developed in HCV subjects to predict both F ≥
3 and cirrhosis. This score has two cut-off values each for F ≥ 3
and cirrhosis and can identify significant fibrosis in 51% of
subjects and even more accurately identify cirrhosis in 81% of
subjects [18]. Additionally, the use of two cut-off values in the
APRI, FIB-4, and NFS results in an intermediate range where
further testing, including a biopsy, may be needed [19]. Hence,
studies have used a wide range of cut-off values for significant
fibrosis which limits its practical use [20].
Many of the direct markers can be used singularly or incorpo-
rated into panels to assess fibrosis. These direct markers include
amino-terminal propeptide of type III collagen (Pro-C3), hyaluronic
acid, and tissue inhibitor of metalloproteinase-1 (TIMP-1). Pro-C3
measures collagen formation [21] while hyaluronic acid,
a glycosaminoglycan, is highly prevalent in the liver ECM [22].
TIMP-1 is a pivotal regulator in the synthesis and degradation of
the ECM, with its level increasing in parallel with severity of liver
fibrosis [23]. Wisteria floribunda agglutinin-positive Mac-2-binding
protein (WFA(+)-M2BP) is a novel marker involved in ECM adhe-
sion and has shown promising results as a surrogate for fibrosis in
many chronic liver diseases [24,25]. ELF is a proprietary test com-
bining age with direct markers of fibrosis including hyaluronic
acid, Pro-C3, and TIMP-1 [26]. It has three cut-offs scores, but
there are fluctuations in the scores by age and gender raising
questions about the accuracy of the test itself [27]. Other commer-
cially available tests incorporating direct markers are characterized
in Table 1.
2.3. Radiology tests
Over the past two decades, tissue elastography has been used to
diagnose fibrosis, assess response to treatment, and guide man-
agement of patients with chronic liver disease. Elastography
reflects the mechanical properties and stiffness of a tissue, with
increased stiffness correlating with more advanced fibrosis [28].
The current modalities are classified into ultrasound-based elas-
tography or magnetic resonance imaging (MRI)-based elastogra-
phy (MRE). US-based elastography consists of strain-based or
shear-wave based elastography, with the vast majority of com-
monly used techniques using the latter. Strain elastography
utilizes mechanical force (manual compression of tissue) and
has limited applications in assessing liver fibrosis [6,28,29]. Shear-
wave elastography evaluates stiffness by assessing the velocity of
shear waves through tissue; shear waves travel more quickly
through stiff or more fibrotic tissue and slower in soft tissue
[28]. Shear waves are generated either through mechanical vibra-
tion or via acoustic radiation force impulses (ARFI) [28]. MRE
utilizes mechanical vibration to produce waves in the liver,
which subsequently undergo processing using modified phase
 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 3

contrast MRI and are converted to tissue stiffness maps using an
inversion algorithm [28]. Examples of the most common elasto-
graphy modalities include vibration controlled transient elasto-
graphy (VCTE), point-shear wave elastography (pSWE), 2D shear
wave elastography (2D-SWE), and MRE.
In all methods of elastography, subjects should be in the
fasting state [7,28]. Directly comparing values across the tech-
niques is not valid as the shear waves generated by each
technique vary in frequency, thereby influencing shear-wave
speed. Furthermore, techniques also differ in wave duration,
as waves are transient in ultrasound-based elastography ver-
sus continuous in MRE [28]. A comparison of the different
elastography techniques is summarized in Table 2.
2.3.1. VCTE
VCTE, often known as its proprietary name, FibroScan (Echosens)
is the most widely used modality to measure elastography
[7,28,29]. It is a one-dimensional approach and does not evaluate
morphological features of the liver [7,28]. The transducer probe is
placed between the intercostal space over the right lobe of the
liver, delivering short, vibrations, which, in turn, indirectly gen-
erate a shear wave propagating through the liver [28,29]. The
shear waves cause tissue displacement, which is tracked and
measured by the ultrasound transducer probe. Since VCTE does
not display a real-time anatomic or grayscale image, it cannot
show the exact location where stiffness is measured [7,28,29].
Data are displayed in A mode, M mode, and as a shear-wave
propagation graph on the machine [28]. Results are expressed as
Young’s modulus (E) and recorded in kilopascals (kPa), ranging
from 2.5 to 75 kPa. A normal value is approximately 5 kPa [5] and
those indicating stage 2–4 fibrosis (≥F2) and cirrhosis (F4) are >7
kPa and ≥11–14 kPa, respectively, although this depends on the
disease process [7]. Probes are selected by the operator based on
the patient’s habitus; the standard 3.5 MHz M-probe can measure
depths between 25 and 65 mm [28,31], while the 2.5 MHz XL-
probe measures tissue depths between 35 and 75 mm [28]. The
smaller 5 MHz S1 and S2 probes can measure tissue depths
between 15–40 mm and 20–50 mm, respectively [28,32]. The
software determines when measurements are successful and
does not record unsuccessful measurements. Successful read-
ings have at least 10 valid measurements, a success rate (ratio
of valid measurements/total measurements) ≥60%, and have an
interquartile range (value assesses variability of measurements)
of ≤30% of the median value [5,29,31]. Limitations of VCTE
include low reliability in subjects of large body habitus, ascites,
subjects with severe hepatic inflammation, and hepatic conges-
tion, with failure rates ranging from 6% to 23%. However, VCTE’s
utility lies in the ability to serve as a quick, point-of-care test such
as in office settings, its relatively inexpensive cost, and portable
nature [7,28,29].
2.3.2. Point shear wave elastography
In contrast to VCTE which generates shear waves utilizing low-
frequency mechanical vibrations, pSWE (Virtual Touch
Quantification or Acuson S2000 and S3000 systems-Siemens
Healthcare; ElastPQ-Philips Healthcare; Shear Wave
Elastography-GE Healthcare) generates shear waves with high-
frequency ultrasound ‘push pulses’ or ARFI in a region of interest
(ROI) chosen by the operator. Additionally, unlike VCTE, this ROI
can be saved and used at a subsequent time-point for monitor-
ing. After the ultrasound probe is positioned in an appropriate
ROI measuring 10 × 6 mm in the right lobe, acoustic ‘push pulses’

Table 2. Comparison of biopsy and elastography techniques.

Biopsy VCTE pSWE SWE MRE
Example Reference FibroScan Siemens S2000, Virtual Aixplorer, Supersonic Magnetic Resonance
Standard Touch Quantification, Shear Imaging Elastography
ElastPQ
Wave Generation N/A Mechanical ARFI Multiple points using
vibration at 50 Hz ARFI in real time
Mechanical
vibration
at 60 Hz
Dimension N/A 1D 2D 2D 2D or 3D
Associated N/A No associated anatomic image Anatomic imaging via Anatomic imaging via Anatomic imaging via
Imaging ultrasound ultrasound and magnetic resonance
elastograms imaging and
superimposed
elastograms
Limitations Invasive; Technical failure in subjects with ascites, Not as well validated Not as well validated Technical failures in iron
Variability increased abdominal girth, narrow compared to VCTE; compared to VCTE; overload;
with inter- intercostal spaces, congestion, cholestasis, Difficulty controlling Difficulty controlling Claustrophobia;
and intra- hyperemia with food consumption frequency of shear frequency of shear Cost;
observer wave; waves; Availability
reliability Availability Availability
Ease No Yes, Point-of-Care Yes, ultrasound facility Yes, ultrasound facility Advanced radiology
center
Region of 1–2 cm length 10 X 40 mm 10X 6 mm, Operator 20 X 20 mm, Operator Operator dependent
Interest/ dependent location dependent location location of any size
Size or shape
Assessment Yes, with quantification Yes, quantification with Yes, but no quantification Yes, but no quantification
of CAP
steatosis
Yes, quantification with PDFF
ARFI: acoustic radiation force impulse; CAP: controlled attenuation parameter; MRE: magnetic resonance elastography; N/A: not applicable PDFF: proton density fat
fraction; pSWE: point-shear wave elastography; SWE: shear wave elastography; VCTE: vibration controlled transient elastography.
Adapted from Hagan et al. [30].
4 U. AGBIM AND S. K. ASRANI
are transmitted through the liver creating shear waves that travel
perpendicular to the ultrasound beam [5,7,28,33]. Results are
expressed in meters per second at a range of 0.5–5 m/s, with
a variable range between normal and pathologic values reported
in the literature. Unlike VCTE where the vibrations are diminished
by fat, pSWE can detect stiffness in the presence of obesity and
ascites since shear waves are produced inside the liver [7,28].
However, a recent study noted decreased reliability with Virtual
Touch Quantification with abdominal adiposity as measured by
a skin-liver capsule distance of ≥30 mm [34]. An added benefit of
pSWE is that it can be coupled to conventional ultrasound-based
imaging providing further characterization of the liver parench-
yma as well as other abdominal structures, ultimately decreasing
costs [5,7,28,31].
2.3.3. 2D-SWE
In 2D-SWE (Aixplorer or Supersonic Shear Imaging-Supersonic
Imagine), ARFI is used at several depths to create multiple shear
waves in multiple ROIs measuring 20 × 20 mm which are cap-
tured by an ultrasound imaging with a high frame rate (up to
15,000 images per second) [28], allowing for real-time imaging
[5–7,28,31]. This allows for the creation of quantitative maps of
tissue stiffness or elastograms [6,28]. Results are expressed as
meters/second or kilopascals [28]. Compared to point-shear
wave elastography, multiple ROIs can be used with SWE, thereby
reducing sampling variability [7,28]. Limitations include
decreased availability and a lack of studies evaluating its validity
compared to VCTE [5,7,28,31]. An emerging technology, deep
learning Radionomics of elastography (DLRE) utilizes neural net-
works whereby large amounts of images are analyzed to provide
finer detail and may supplement 2D-SWE, thereby increasing its
diagnostic performance [35].
2.3.4. MRI-based imaging
MRE is the most current, accurate non-invasive mode at measur-
ing fibrosis [6,7,28,29,31,36]. Similar to VCTE, MRE uses mechanical
vibrations generated in an active driver to create shear waves,
which are assessed via specialized software producing elasto-
grams. More specifically the active driver, housed in an area out-
side the scanner, activates a passive driver by way of a long
connecting tube. The passive driver is physically positioned over
the largest portion of the patient’s liver and transmits continuous
mechanical acoustic vibrations of 60 Hz [28,36] during four breath
holds. During each breath hold, a sagittal slice of the liver is
assessed. The shear waves are tracked by motion-sensitized MRI
sequences such as gradient recalled echo and processed to create
wave images and elastograms. A confidence map can be created
that shows areas with low reliability. ROI can be placed on the
elastograms avoiding areas with low reliability as well as major
vessels and fissures [7,28,29,31,36]. These techniques allow for
a large area of liver to be sampled (≥250 cm3), which is more
than 5,000 times that of a liver biopsy and 250 times that of VCTE
[6]. Results are expressed as the magnitude of the complex shear
modulus (µ) reported as average stiffness in kPa from 0 to 8 kPa.
An added benefit of MRE is the ability to define lesions such as
HCC with contrast-enhanced MRI, which is often combined with
the test. Limitations of MRI-based techniques include decreased
reliability in iron-overload states, passive congestion, and inflam-
mation as these can increase liver stiffness, thereby confounding
results. Additionally, the inability to use this technique in subjects
with an aversion to confined spaces, availability, and cost has
largely limited MRE to research purposes though this pattern
may be changing [7,28,29,31,36].
Currently, MRE is the best studied MRI-based imaging.
However, other MRI-imaging technology currently under inves-
tigation for the detection of fibrosis includes MRI with diffusion-
weighted imaging (DWI) [7], metabolomic analysis with proton
nuclear magnetic resonance spectroscopy [37], and 3D-MRE [38].
3. Applications of markers to various liver diseases
and complications
The diagnostic accuracy of non-invasive tests is crucial for man-
agement of chronic liver disease. Since the diagnostic para-
meters are often dependent upon the clinical context in which
they are employed, a growing amount of literature has evaluated
the utility of the various modalities in specific disease states. In
the remainder of this evaluation, we review the recent literature
of non-invasive techniques as it pertains to specific liver diseases,
their sequelae, and prognosis. A comparison of clinical utility and
a summary of meta-analysis assessing diagnostic accuracy of
selected noninvasive markers in assessment of fibrosis is shown
in Tables 3 and 4, respectively.
3.1. Nonalcoholic fatty liver disease
Ultrasound alone has a pooled sensitivity of 84.8% and specificity
of 93.8% for detecting ≥20–30% steatosis compared to liver
biopsy [44]. However, fibrosis rather than steatosis is the stron-
gest predictor of mortality [45]. Given the increasing prevalence
of NAFLD (global prevalence 25%) [46], it is impractical to biopsy
everyone. Thus, the use of non-invasive tests to detect fibrosis in
subjects with NAFLD may play a valuable role in long-term
management.
In a study of 452 biopsy-proven NAFLD subjects evaluating
fibrosis by nine serum markers of fibrosis and VCTE, FibroMeter
and VCTE were the most accurate at predicting fibrosis with
AUROC values of 0.79 and 0.84 for detecting F ≥ 2, 0.82 and
0.83 for detecting F ≥ 3, and 0.82, and 0.86 for detecting F4,
respectively. Further, both of these tests showed good discrimi-
native ability for predicting mortality from liver-related complica-
tions in the longitudinal cohort of the study [19]. Petta et al. [47]
found that FIB-4, NFS, and VCTE had the best diagnostic perfor-
mance at diagnosing fibrosis in a study of 761 subjects with
biopsy-proven NAFLD. When VCTE was combined with either
NFS or FIB-4, there was a decreased rate of incorrectly classified
subjects compared to any of these tests alone, but the percen-
tage of discordant results was high, at over 50%. A stepwise
approach (fibrosis assessed initially with either NFS or FIB-4,
followed by VCTE) improved performance particularly in subjects
with intermediate NFS and FIB-4 scores compared to the com-
bined approach. This suggests that a multi-staged or stepwise
approach may be more useful than using a single test to diag-
nose fibrosis non-invasively [47].
When comparing the available ultrasound-based imaging
tests (VCTE, pSWE, and 2D-SWE), all performed well in diagnosing
fibrosis, but 2D-SWE was superior to both (AUROC 0.86–0.89 for
2D-SWE, 0.82–0.87 for VCTE, and 0.77–0.84 for pSWE).
Table 3. Comparison of selected non-invasive markers.
NFS APRI FibroTest FIB-4 VCTE pSWE SWE MRE
Application Developed specifically Developed in context of Developed in Developed in context of Can be applied to any CLD Can be applied Can be applied Can be applied to any CLD
for NAFLD HCV, but can be context of HCV, HIV/HCV, but can be to any CLD to any CLD
applied to any CLD but can be applied to any CLD
applied to any
CLD
Point-of-Care Yes Yes No Yes Yes Yes Yes No
Most + ++ ++ + ++ + + +
clinically
used/
validated
Strength of +++ + + ++ + + + +
validation (NPV >90% for ≥F3 (NPV >90% for ≥F3
in NAFLD and F4) and F4)
Strength of N/A +++ +++ ++ +++ ++ ++ +
validation (HBV<HCV) (HBV<HCV) (HBV<HCV) (HBV = HCV) (HBV<HCV) (HBV<HCV)
in viral overlap of values between
hepatitis adjacent stages of fibrosis; most
accurate non-invasive marker
for detecting cirrhosis
Strength of N/A + ++ + + (elevated LSM in alcoholic + + +
validation hepatitis)
in
alcoholic
liver
disease
Other Two cutoffs result in an Two cutoffs result in an Patented test- not Two cutoffs result in an May need to use XL probe for Difficulty differentiating intermediate
comments intermediate range intermediate range readily available; intermediate range patients with increased stages of fibrosis
where further where further testing Outperforms non- where further testing abdominal girth;
testing is required is required; patented tests for is required; May need to consider
May need to ≥F2 May need to aminotransferase elevation,
consider False positives consider when interpreting results;
aminotransferase occur in setting of aminotransferase NPV > 90% for F4
elevation, when hemolysis or elevation, when
interpreting results Gilbert syndrome interpreting results
Difficulty differentiating Needs more validation
intermediate stages but appears to be
of fibrosis most accurate for
detecting
intermediate stages
of fibrosis in NAFLD
APRI: aspartate aminotransferase to platelet ratio index; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; CLD: chronic liver disease; MRE: magnetic resonance elastography; NAFLD: non-
alcoholic fatty liver disease; NFS: non-alcoholic fatty liver disease fibrosis score; NPV: negative predictive value; pSWE: point-shear wave elastography; SWE: shear wave elastography.
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY
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U. AGBIM AND S. K. ASRANI

Table 4. Summary of meta-analysis assessing diagnostic accuracy of noninvasive markers in fibrosis.

F≥3 F4
Patients Summary AUROC Patients Summary AUROC
Meta-analysis Disease (n of studies), % F ≥ 3 Cutoff (range) Sn (%) Sp (%) NPV (%) PPV (%) value LR+ LR- (n of studies), % F4 Cutoff (range) Sn (%) Sp (%) NPV (%) PPV (%) value LR+ LR-
APRI[56] NAFLD 682 (4) 1.5 32.9 90.5 79.1 55.5 0.77* N/A N/A 790 (5) 0.54–2.00 56.2 83.6 91.7 37.8 0.76* N/A N/A
BARD[56] NAFLD 3057 (14) 2 75.2 61.6 88.7 38.3 0.76* N/A N/A 242 (1) 3 52.2 83.8 94.3 25.3 N/A N/A N/A
FIB-4[56] NAFLD 1910 (6) 2.67 31.9 95.7 85.0 66.0 0.84* N/A N/A 439 (2) 1.92–2.48 76.4 82.4 96.2 39.0 N/A N/A N/A
NFS[56] NAFLD 3896 (14) 0.67–0.676 43.1 88.4 88.5 66.9 0.84* N/A N/A 197 (1) −0.014 80.0 80.8 95.7 42.8 N/A N/A N/A
FibroScan M probe[56] NAFLD 1540 (9) 7.6–8 88.9 77.2 95.5 43.4 0.88* N/A N/A 1362 (9) 10.3–11.3 87.7 86.3 98.0 46.8 0.94* N/A N/A
FibroScan XL probe[56] NAFLD 579 (3) 5.7–9.3 75.3 74.0 88.7 58.7 0.85* N/A N/A 654 (4) 7.2–16 87.8 82.0 97.8 39.8 0.91* N/A N/A
SWE[56] NAFLD 429 (3) 3.02–10.6 89.9 91.8 93.4 88.2 0.95* N/A N/A 181 (1) 3.36 100 85.6 100 55.2 N/A N/A N/A
MRE[56] NAFLD 628 (5) 3.62–4.8 85.7 90.8 93.4 71.0 0.96* N/A N/A 384 (3) 4.15–6.7 86.6 93.4 98.8 53.4 0.97* 13.1 N/A
FibroScan[79] Alcohol 564 (8) 9.5 92 70 N/A N/A 3.1 0.11 330 (7) 12.5 95 71 N/A N/A N/A 3.3 0.07
FIB-4[39] HBV 1473 (6), 33.5 1.45–1.65 68 75 N/A N/A 0.77 2.75 0.42 2105 (10), 20.8 2.9–3.6 42 96 N/A N/A 0.96 13.38 0.3
FibroScan[77] HBV 2437 (9) 9.15 79.0 84.6 N/A N/A 0.893 5.23 0.25 2522 (11) 12.17 80 86.6 N/A N/A 0.905 5.81 0.25
FibroScan[76] HBV (19) 9.4 81.9 86.6 N/A N/A 0.91 N/A N/A (24) 9.0–16.9 86.3 87.5 N/A N/A 0.93 N/A N/A
MRE[77] HBV 1470 (9) 3.62 89.6 93.2 N/A N/A 0.972 10.87 0.09 1470 (9) 4.63 89.5 92 N/A N/A 0.972 10.74 0.10
APRI[40] HCV 441 (13), 28 1.0 61 64 81 40 0.80 N/A N/A 4548 (18), 19 1.0 76 72 69 55 0.83 N/A N/A
2.0 46 91 63 82
FibroScan XL probe [41] All CLD (7) 9.5 66 82 0.83 N/A N/A (6) 12.5 84 78 0.88 N/A N/A
ARFI[42] All CLD 518 (8), 42.6 1.55 86 86 89 82 0.91 N/A N/A 518 (8), 26.6 1.80 92 86 97 71 0.93 N/A N/A
ARFI[43] All CLD (10) 1.43–1.81 81 84 N/A N/A 0.93 5.75 0.13 (13) 1.55–2.25 88 83 N/A N/A 0.94 6.67 0.17
MRE[43] All CLD (11) 3.1–6.47 87 92 N/A N/A 0.96 10.22 0.15 (8) 4–6.47 93 91 N/A N/A 0.97 8.85 0.06

APRI: aspartate aminotransferase to platelet ratio index; ARFI: acoustic radiation force impulse; AUROC: area under the receiver operator characteristic; CLD: chronic liver disease; HBV: hepatitis B virus; HCV: hepatitis C virus; kPa:
kilopascal; LR: likelihood ratio; MRE: magnetic resonance elastography; NAFLD: non-alcoholic fatty liver disease; NFS: non-alcoholic fatty liver disease fibrosis score; NPV: negative predictive value; PPV: positive predictive
value; Sn: Sensitivity; Sp: Specificity; SWE: shear wave elastography.
* Values for all cutoffs.

Interestingly, 2D-SWE and VCTE had very similar cut-off scores at
the various stages of fibrosis, which may facilitate ease of use and
comparability [48].
Comorbidities may attenuate the diagnostic accuracy of non-
invasive tests. Bertot et al. [49] noted decreased ability of
Hepascore, FIB-4, and APRI to differentiate cirrhosis as well as
predict decompensation in NAFLD subjects with diabetes. The
NFS had no difference in differentiating between outcomes
based on the presence of diabetes, likely due to the inclusion
of diabetes in the formula. Additionally, steatosis or obesity
affects the diagnostic performance of serum and imaging tech-
niques to detect fibrosis, as pSWE may be unreliable and 2D-SWE
may have a high degree of failure in obesity [48]. Further, VCTE
overestimates the amount of fibrosis present in the setting of
increased steatosis [48,50,51]. Controlled attenuation parameter
(CAP) is a tool that can be coupled to VCTE to quantify steatosis,
with increasing CAP values signifying more steatosis. However,
a recent secondary analysis of over 2000 subjects noted the use
of CAP only slightly improves the NPV in select situations [51].
Other comorbidities associated with unreliable or failed liver
stiffness measurements (LSM) of VCTE, pSWE, and 2D-SWE
include increased waist circumference, BMI, intercostal wall thick-
ness, and the presence of metabolic syndrome [48].
Analogous to CAP, MRI-based proton density fat fraction
(PDFF) can also quantitatively assess hepatic fat content. MRE
with PDFF performed better than VCTE with CAP using
the M probe in detecting F ≥ 2 (AUROC value of 0.91 vs
0.82) and steatosis grade ≥2 (AUROC value 0.90 vs 0.73) [52].
Most of the studies addressing VCTE’s inadequate reliability in
the setting of obesity utilized the M probe without inclusion of
the XL probe. To address this limitation, a study in the United
States with both the M and XL probe found MRE with PDFF
was significantly better than VCTE with CAP at diagnosing
fibrosis as well as steatosis [53]. For instance, MRE was sig-
nificantly able to detect fibrosis at earlier stages than VCTE,
whereas there were no differences in performance for ≥F2,
≥F3 and F4 [53]. Another study using both the M and XL probe
noted superior MRE performance for ≥F2 and ≥F3 when com-
pared to VCTE on an intention to diagnosis basis (for ≥F3,
AUROC value of 0.92 vs 0.84; p = 0.046), but MRE and VCTE
performed equally in these intermediate stages when exclud-
ing unreliable VCTE examinations (for ≥F3, AUROC value of
0.92 vs. 0.87; p = 0.150) [54].
A growing body of research demonstrates MRE’s superior
ability to detect fibrosis in NAFLD. MRE outperformed pSWE in
determining all stages of fibrosis, particularly in the obese in
a prospective cohort study of 125 biopsy-proven NAFLD patients
[55]. A recent meta-analysis of 64 studies with a total of 13,046
NAFLD subjects demonstrated MRE and SWE had a significantly
greater AUROC value for detecting ≥F3 (0.96 and 0.95, respec-
tively) compared to FibroScan M probe (AUROC value 0.88),
FibroScan XL probe (AUROC value 0.85), NFS (AUROC value
0.84), FIB-4 (AUROC value 0.84), APRI (AUROC value 0.77), and
BARD score (AUROC value 0.76) (p < 0.01). The NPV for excluding
cirrhosis for all the tests was >90% [56]. Despite the evidence of
MRE’s superior discriminative ability in adults, it has not been
well validated in children, as cut-off scores from adults may not
be applicable and further refinement is needed [57]. In terms of
differentiating NASH from normal liver, both MRE and VCTE have
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 7
poor ability to discern NASH from normal liver, although the
AUROC value for MRE at discerning NASH is significantly higher
than VCTE (0.70 vs 0.35; p = 0.0011) [53]. Although these tests
perform well in detecting fibrosis, more investigation is needed
to discern their ability in detecting NASH.
Currently, there is a lack of knowledge regarding cost-
effectiveness of the various modalities for diagnosing NAFLD
as well as markers to distinguish simple steatosis from steato-
hepatitis. One study evaluating cost-effectiveness found that
NFS, followed by the combination of NFS and VCTE is the most
cost-effective strategy to evaluate subjects with NAFLD in the
primary care setting [58].
Non-invasive markers have the ability to predict clinical out-
comes in those with chronic liver disease. Using data from the
National Health and Nutrition Examination Survey, Kim et al. [59]
. were the first to demonstrate increasing mortality with
advanced fibrosis scores. For instance, the adjusted hazard ratio
(HR) for the NFS, APRI, and FIB-4 for subjects with advanced
fibrosis compared to those without any fibrosis was 1.69 (95%
confidence interval [CI] 1.09–2.63), 1.85 (95% CI 1.02–3.37), and
1.44 (95% CI 0.98–2.82), respectively, with most of the mortality
attributed to cardiovascular disease [59]. Similarly, in those with
NAFLD, a recent meta-analysis demonstrated an NFS > 0.676 is
associated with fourfold increased risk of mortality compared to
lower values, with a dose-response effect in mortality with
increases in NFS scores [60]. The FIB-4 and APRI were less effec-
tive at predicting mortality in NAFLD patients compared to NFS
[60]. Further, compared to its performance in other liver disease
etiologies, FibroTest had the highest 10-year prognostic value in
predicting liver-related death in a cohort from France [61]. Non-
invasive tests may also assist in monitoring response to therapy,
but presently, the data are limited. Post-hoc analysis from a trial
evaluating the use of obeticholic acid in NAFLD demonstrated
improvement in histologic fibrosis was associated with improve-
ment in APRI, FIB-4, and NFS compared to baseline scores sug-
gesting serum markers may be useful in monitoring evolution of
treatment [62].
In summary, imaging tests are superior to serum tests in
the non-invasive assessment of fibrosis in NAFLD subjects. The
evaluation of fibrosis by elastography can be challenging in
NAFLD, but the available evidence reveals MRE is the most
accurate modality, particularly in light of failed or unreliable
LSM in the context of obesity with VCTE. Unfortunately, cost
and availability limit the use of MRE. As such, ultrasound-
based modalities are viable contenders, with VCTE being the
most accessible modality.
3.2. Viral hepatitis
3.2.1. Hepatitis C
Non-invasive staging of fibrosis is incorporated in the manage-
ment of chronic HCV in current society guidelines [63,64]. VCTE is
one of the most utilized non-invasive tool evaluating liver fibrosis
in subjects with HCV with better diagnostic accuracy as com-
pared to serum tests [63]. Overall VCTE cut-off values are well-
established for the spectrum of fibrosis stages. However, in
a large US multicenter cohort study of subjects with HCV and
hepatitis B virus (HBV), VCTE could not validate cut-off values for
≥F2 as robustly as ≥F3 and F4 in the validation cohort,
8 U. AGBIM AND S. K. ASRANI
suggesting difficulty in differentiating intermediate stages of
fibrosis [65]. Use of both VCTE and serum biomarkers sequen-
tially, followed by a coupled test if the initial individual tests are
discordant may help with these uncertainties [66]. Additionally,
2D-SWE is equivalent to VCTE in diagnosing fibrosis with similar
diagnostic performance [67].
Evidence suggests longitudinal changes in non-invasive
measures predict prognosis. When evaluating the evolution
of disease in subjects with HCV, those with a baseline LSM
< 7 kPa as measured by VCTE or with an increase in LSM
of ≥1 kPa/year or with ≤0 kPa/year in those with a baseline
LSM ≥ 14 kPa had increased risk of liver-related mortality
[68]. Newer direct antiviral agents have high rates of viral
clearance, improve subjects’ symptoms, and decrease their
need for liver transplantation [69]. While using non-
invasive methods to stage disease in HCV is commonplace,
the role of non-invasive assessment in monitoring fibrosis
regression after achieving a sustained viral response (SVR)
is unclear. HCV viral clearance decreases LSM evaluated by
VCTE [70], FIB-4, APRI, and pSWE [71]. A recent meta-
analysis of 24 studies examining paired LSM prior to and
after achieving an SVR, revealed the decrease in liver stiff-
ness (LS) magnified over time, which they postulate initi-
ally was attributed to the improvement in inflammation
with later declines in LS attributed to fibrosis regression
[70]. However, decrease in liver stiffness is not equated
with resolution of cirrhosis. Hence, despite decline in liver
stiffness, routine management of cirrhosis (e.g. HCC sur-
veillance) after effective HCV therapy should continue.
3.2.2. Hepatitis B
The role of non-invasive testing in patients with HBV is less clear,
though recent society guidelines endorse the use of elastogra-
phy as the preferred test and FIB-4 or FibroTest as alternative
tests [72]. Additionally, the World Health Organization advises
using APRI to stage disease among HBV subjects in resource-
limited settings, whereas VCTE or FibroTest is the preferred test
of choice where cost and/or availability are not barriers [73].
However, APRI has only modest accuracy in detecting fibrosis
among all stages with a summary AUROC value of 0.74 for ≥F2,
0.73 for ≥F3, and 0.73 for F4 [74]. Similarly, FIB-4 had moderate
accuracy in the same study, with a summary AUROC value of
0.78 for ≥F2, 0.82 for ≥F3, and 0.85 for F4 [74]. A new model, the
gamma-glutamyl transpeptidase to platelet ratio (GPR), was
developed in France and Western Africa to evaluate fibrosis in
subjects with HBV, particularly in low-resource settings. The
AUROC value was significantly superior to APRI and FIB-4 at
identifying ≥F2 and ≥F3 in the African training and validation
cohorts [75]. In fact, using the WHO criteria’s APRI cut-off value
of 2 to diagnosis cirrhosis [73], the sensitivity for diagnosis of F4
was 25%, while the sensitivity of GPR was 85% at a cut-off value
of 0.56 [75]. Further studies investigating the role of GPR are
needed.
Similar to other liver diseases, VCTE has been recognized as
a very reliable and accurate tool for detecting fibrosis in subjects
with HBV, with summary AUROC values ranging from 0.80 to 0.88
for ≥F2, 0.89–0.91 for ≥F3, and 0.91–0.93 for F4 [76,77].
Notwithstanding, 2D-SWE and MRE may perform better than
VCTE. In a large-scale analysis of subjects from 13 different
sites, 2D-SWE was superior to VCTE at discriminating among
≥F2, ≥F3, and F4 in HBV subjects [67]. In fact, using the new
DLRE with 2D-SWE, the AUROC value for ≥F3 was 0.98 and F4 was
0.97, which was significantly better than 2D-SWE, APRI, or FIB-4
alone [35]. Further, a meta-analysis has shown MRE is superior to
VCTE for detecting ≥F2 (AUROC value 0.981 vs. 0.796; p < 0.001),
≥F3 (AUROC value 0.972 vs. 0.893; p < 0.001), and F4 (AUROC
value 0.972 vs. 0.905; p < 0.001) [77]. In addition, LSM as mea-
sured by VCTE and FibroTest had the best 5-year prognostic
value for survival compared to APRI, FIB-4, and liver biopsy in
a European cohort of Hepatitis B subjects, even after adjusting
for age, inflammatory activity, viral load, and treatment [78].
3.3. Alcoholic liver disease
In comparison to other chronic liver diseases, there is lack of
literature examining diagnostic and prognostic management in
alcoholic liver disease [79,80], which is needed as a diagnosis of
fibrosis may compel subjects to abstain from alcohol use.
Although VCTE has been the most validated non-invasive test
used in alcoholic liver disease, a recent meta-analysis could not
identify optimal cut-off values for VCTE in alcoholic liver disease,
as there was a paucity of studies included were the sole etiology
of disease was due to alcohol [79]. Nevertheless, studies have
suggested cut-off scores, and VCTE can be used to rule out ≥F3
and cirrhosis with negative likelihood ratios of 0.11 and 0.07,
respectively [79].
In a multicenter prospective study of 217 subjects with heavy
alcohol use, Voican et al. [80] evaluated liver biopsy, VCTE alone,
and VCTE paired with other non-invasive serum markers. At
a cut-off score of ≥12 kPa for ≥F3 and 15 kPa for F4, VCTE had
a sensitivity of 92.2%, specificity of 75.6%, NPV of 84.8%, and
AUROC value of 0.90 for ≥F3, and sensitivity of 85.4%, specificity
of 93.1%, NPV of 98.6%, and AUROC value of 0.93 for F4. The
addition of FibroTest did not add further diagnostic value to
VCTE. The authors attributed the lower specificity of VCTE for
diagnosing ≥F3 and F4 to a high frequency of subjects with
alcoholic hepatitis seen on biopsy. Interestingly, after one
month of alcohol cessation, there was a significant decrease in
LS as measured by VCTE [80]. A similar finding of lower specificity
for pSWE was noted in a prospective study evaluating the diag-
nostic performance of pSWE and paired liver biopsies in 82
alcoholics attending rehabilitation in France [81]. Kiani et al.
[81] noted at a cut-off value of 1.84 m/s for ≥F3 and 1.94 m/s
for F4, pSWE had a sensitivity of 82.4%, specificity of 78.5%, NPV
of 94.4%, and AUROC value of 0.86 for ≥F3, and sensitivity of
92.3%, specificity of 81.6%, NPV of 98.2%, and AUROC value of
0.89 for F4. Evidence is mixed regarding the specificity of non-
invasive assessment of fibrosis in the context of alcoholic liver
disease, as other studies demonstrate non-invasive tests have
high specificities. In the largest study to date of subjects with
heavy alcohol use, Thiele et al. [82] showed VCTE and 2D-SWE
both have very reliable diagnostic accuracy for evaluating
advanced fibrosis (defined as Ishak ≥3) and cirrhosis (defined as
Ishak ≥5) with sensitivities ranging from 82% to 83%, specificities
ranging from 91% to 93%, NPVs of 88%, and AUROC values of
0.94–0.96 for advanced fibrosis, and sensitivities of 94–97%,
specificities of 90–91%, NPVs of 99% and AUROC valued of
0.95–0.96 for cirrhosis. They noted cut-off values for alcoholic

liver disease are higher compared to viral liver disease due to the
different patterns of fibrosis distribution in alcoholic liver disease
[82]. Overall, diagnostic cut-off values for elastography remain to
be defined in the setting of alcoholic liver disease.
3.4. Autoimmune liver diseases
Similar to alcoholic liver disease, non-invasive assessment of
fibrosis has not been rigorously studied in autoimmune liver
disease, likely due to the rare nature of the disease. Studies
reveal serum tests inferior to imaging tests such as VCTE
[83,84] or MRE when evaluating fibrosis in autoimmune hepa-
titis (AIH) [85] or in overlap diseases [86]. After defining opti-
mal cut-off values for VCTE with good diagnostic accuracy for
≥F2, ≥F3, and F4 in AIH, Hartl et al. [87] sought to determine
the impact of immunosuppressive therapy had on perfor-
mance of VCTE. They found a correlation between LSM and
histologic grade (Spearman’s ρ coefficient 0.558; p = 0.001),
not stage (Spearman’s ρ coefficient 0.339; p = 0.19), in patients
who had less than three months of immunosuppressive ther-
apy. Conversely, LSM among subjects with longer treatment
intervals correlated more with stage (Spearman’s ρ coefficient
0.809; p < 0.0001 at 6–18 months after immunosuppression
initiation) as opposed to histologic grade (Spearman’s ρ coef-
ficient 0.404; p < 0.062 at 6–18 months after immunosuppres-
sion initiation). Further, the diagnostic accuracy of VCTE for
staging fibrosis improved with increasing treatment time. As
such, care is advised when interpreting LSM by VCTE in the
months following treatment initiation, as in this study, inflam-
mation had a major impact on LS [87], although this was not
confirmed in another study [84]. Additionally, VCTE may be
used to monitor disease evolution to therapy. When evaluat-
ing the impact of biochemical remission had on LSM in sub-
jects who had not achieved biochemical remission, LSM
strongly correlated with stage (Spearman’s ρ coefficient
0.801; p < 0.001) and weakly correlated with grade
(Spearman’s ρ coefficient 0.312; p = 0.049). The same trend
held true for those who had achieved biochemical remission
[87]. Angiotensin-converting enzyme, a responsible agent in
stellate cell proliferation and inflammation, may predict fibro-
sis stages in AIH with 85.2% sensitivity, 94.8% specificity, and
an AUROC value of 0.91 at a cut-off score of 64 U/l for ≥F3 and
100% sensitivity, 84.4% specificity and an AUROC value of 0.95
at a cut-off value of 68 U/l for F4 [88].
3.4.1. Cholestatic liver disease
Few studies exist evaluating non-invasive assessment in primary
biliary cholangitis (PBC), but Corpechot et al. demonstrated VCTE
outperformed APRI, FIB-4, AST/ALT ratio, hyaluronic acid and the
Mayo risk score in predicting ≥F2, ≥F3, and F4. In fact, they
reported an increase in LSM of 2.1 kPa per year by VCTE was
associated with a 58% rate of morbidity/mortality including liver
decompensation, liver transplantation, or death [89]. Wisteria
floribunda agglutinin-positive Mac-2-binding protein (WFA
(+)-M2BP) was recently introduced as a fibrotic marker for PBC
with an AUROC value ≥0.93 for ≥F2, ≥F3, and F4 [25]. More work
is needed to assess various markers’ role in predicting fibrosis
in PBC.
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 9
When evaluating the role of non-invasive markers in asses-
sing fibrosis in primary sclerosing cholangitis (PSC), Corpechot
et al. [90] noted VCTE had superior diagnostic accuracy to FIB-
4, but similar to APRI and hyaluronic acid. Baseline LSM was
correlated with the risk of clinically significant outcomes such
as hepatic decompensation, liver transplantation, or death.
Additionally, the progression rate of LSM exponentially
increased at ≥F2 and the authors postulate this may be used
to stratify subjects who are at risk for liver-related complica-
tions [90]. Given that cholestatic diseases may have an uneven
geographical distribution throughout the liver, spleen dia-
meter has also been used to assess fibrosis in patients with
PSC [91].
3.5. Post-transplant care
Non-invasive measures of fibrosis have been extensively stu-
died and validated in native livers, but there is growing work
to explore their role in the post-transplant setting, where the
allograft is often more susceptible to recurrent or de novo
disease. Again, much of the available literature in the post-
transplant setting focuses on recipients with recurrent HCV
[92], but there are some data on all etiologies of liver disease
[20] and even in children with biliary atresia [93]. In a meta-
analysis of 24 studies examining FIB-4, APRI, and VCTE in the
post-transplant setting, Bhat et al. [20], noted they all had
good diagnostic accuracy, but the diagnostic accuracy of
VCTE was significantly superior to FIB-4 and APRI. In
a separate study of liver transplant recipients with recurrent
HCV who had achieved a sustained viral response after ther-
apy, VCTE was accurate to diagnose the presence of ≥F3 at
a cut-off value of 14 kPa and exclude ≥F3 at a cut-off value of
10.6 kPa with an AUROC value of 0.902, which outperformed
ELF (0.764; p = 0.002) [92]. Further, baseline and change in
fibrosis scores with serial measurements may be able to pre-
dict death and graft loss [94], as well as response to therapy
[92]. In a unique study in which liver biopsies, hepatic venous
pressure gradient (HVPG), ELF score, and VCTE were measured
at baseline and 12 months after achieving an SVR in liver
transplant recipients with recurrent HCV, Mauro and collea-
gues [92] noted LS was significantly lower in patients who
achieved fibrosis regression (12.6 kPa) than those who did not
achieve regression after antiviral therapy (26 kPa).
Intermediate stages of fibrosis may be challenging to
detect by non-invasive tests. For example, Singh et al. [95]
demonstrated MRE is suitable for detecting cirrhosis in the
post-transplant setting but inferior for detecting ≥F2 or ≥F3.
In a pooled study of 141 liver transplant recipients from six
cohorts, the authors noted the summary AUROC value for
stage 1–4 fibrosis (≥F1), ≥F2, ≥F3, and F4 was 0.73, 0.69,
0.83, and 0.96, respectively [95], which was notably different
from a previous study evaluating fibrosis in native livers where
the AUROC value for ≥F1, ≥F2, ≥F3, and F4 was 0.84, 0.88, 0.93,
and 0.92, respectively [96].
More data are needed to validate the modalities in the
post-transplant population. However, its use may prompt clin-
icians to perform more investigative analysis when uncertain-
ties arise in the post-transplant setting. With more information
10 U. AGBIM AND S. K. ASRANI
regarding the validity, serial measurements could be utilized
in lieu of routine protocol biopsy employed at many centers.
3.6. Portal hypertension
Non-invasive measurements may help identify subjects that
need interventions to prevent portal hypertensive complica-
tions. According to the Baveno VI proceedings [1], two sepa-
rate VCTE measurements of ≥20–25 kPa on different days for
viral-related chronic liver disease is sufficient to rule-in clini-
cally significant portal hypertension as defined by an HVPG
≥10. In fact, the proceedings recommend avoiding screening
endoscopy in any patient with VCTE kPa <20 and platelets
over 150 X 109/L [1]. This has been validated in a subsequent
study of 310 subjects to identify cirrhotics with high-risk
varices, classifying 80% correctly with a sensitivity of 87%,
specificity of 34%, NPV of 96% and AUROC value of 0.76 [97].
Further, in liver transplant recipients with recurrent HCV, VCTE
and ELF measurements were accurate at diagnosing clinically
significant portal hypertension [92]. VCTE and the combination
of liver stiffness-spleen diameter to platelet ratio score may
also predict clinically significant portal hypertension [98].
3.7. Other disease processes and complications
Non-invasive measurements can be used to predict risk of HCC.
In a retrospective study of 986 Korean HBV surface antigen
positive subjects, Suh et al. [99] demonstrated high FIB-4 scores
were more predictive of HCC than traditional ultrasonography
(C-index: 0.775 vs. 0.701; p = 0.0040). This can be attributed to the
use of FIB-4 as marker of fibrosis whereas traditional ultrasono-
graphic methods are not an accurate reflection of fibrosis.
Further, after adjusting for age, sex, BMI, smoking, alcohol use,
and HBV antiviral therapy, compared to subjects with a FIB-4
score, those with a FIB-4 score 1.7–2.4 had adjusted HR of 4.57
(95% CI 1.50–13.92) of incident HCC, while those with a FIB-4
score of ≥2.4 had an HR of 21.34 (95% CI 7.73–58.92) compared
to those with a FIB-4 score <1.25. Similarly, FIB-4 has a higher
predictive value of incident HCC in subjects with moderate to
heavy alcohol use compared to traditional ultrasonography
[100]. Conversely, LS as measured by VCTE was not associated
with HCC development in a cohort of Asian cirrhotics (>50% HBV
prevalence), but was associated with the progression of portal
hypertensive complications [101].
The Fontan procedure is an operation to connect a single
ventricle to the systemic circulation in addition to the ventricle
receiving blood flow from the pulmonary circulation and can
lead to a spectrum of liver complications. A common hepatic
consequence of the Fontan procedure is elevated hepatic
pressures from congestion, which over time can proceed to
fibrosis. Wu et al. [102] report LSM as indicated by VCTE over-
estimated the actual degree of fibrosis when using established
cut-off values in subjects with a Fontan. Serial LSM by MRE in
Fontan subjects correlates with liver disease severity as mea-
sured by the Model for End Stage Liver Disease (MELD) score
and model for end stage liver disease excluding international
normalized ratio (MELD-XI) [103]. Although the use of elasto-
graphy in Fontan related liver disease is evolving, it is unclear
whether elevated values actually represent passive conges-
tion, increased LS, or a combination of long-standing conges-
tion and ischemia from decreased cardiac output leading to
fibrosis [104].
4. Expert opinion
Given the limitations of liver biopsy, alternative strategies are
needed to stage liver disease. Non-invasive serum and imaging
tests are growing in utility, helping to assess fibrosis stage, assist
in prognosis of liver disease, and ultimately guide clinical deci-
sions. Serum markers fill this unmet need, as they are simple,
accessible, reproducible tests with good performance character-
istics. In general, elastography outperforms the serum markers
for detecting cirrhosis. VCTE, the most studied imaging modality,
has good diagnostic accuracy for fibrosis, although its superior
performance diminishes relative to serum markers for advanced
stages of fibrosis. Nevertheless, the utility of VCTE lies in its ability
to provide point-of-care, accurate testing. MRE may outperform
VCTE in intermediate stages, but its accessibility hinders its com-
monplace use. When utilizing non-invasive tests – both serum
and imaging tests, it is imperative to consider the underlying
disease process in the context of the selected tests and results.
Established cut-off values are available for VCTE to stage HCV,
which often guide treatment and surveillance decisions, particu-
larly in advanced disease.
Despite the advances in development of non-invasive tests,
several questions remain. First, it is unclear how to best define
intermediate stages of fibrosis, particularly concerning serum
tests with intermediate ranges, as this is where much uncer-
tainty exists. Second, the appropriate combination of tests,
whether in a deliberate, stepwise or simultaneous fashion
has yet to be defined. For example, using a combination
approach may afford the opportunity to classify cases that
otherwise would have been considered to lie in an intermedi-
ate range when used with a singular test. Again, this will need
to be tailored to individual diseases as the approaches and
tests use may change in the setting of different diseases. Third,
the utilization of these tests in routine management of liver
diseases other than deciding appropriate treatment time for
HCV has not been determined. For instance, the role of non-
invasive tests in longitudinal disease regression, particularly
with treatment of the underlying disease will need to be
explored. Although there is some idea regarding changes in
VCTE with disease regression, it is uncertain how to interpret
improvement in many of the non-invasive serum tests when
disease regression occurs. Similarly, how to utilize serial mea-
surements of non-invasive tests in the clinical monitoring of
progression of liver disease is not entirely clear. Additionally,
relatively little information exists on how to interpret the
magnitude of LSM above the cut-off value of cirrhosis or if
this is significant at all. For example, does an elevated LSM
beyond the cut-off value of cirrhosis for all the non-invasive
modalities translate into elevated HVPG and thereby worsen-
ing portal hypertension? Outside the Baveno VI proceedings,
there is little formal direction on how to interpret LSM in
context of portal hypertension. Understanding how changes
in LSM translate into clinically significant outcomes such as

progression in portal hypertension will guide management
and improve care of patients with liver disease.
With the revolutionary HCV treatment and eradication of
the disease, a shift to investigate NAFLD has occurred, with
more emphasis placed on identifying subjects at risk for
advanced disease. These warrants further refinement to vali-
date imaging tests in NAFLD since obesity and steatosis can
decrease accuracy. As understanding and refinement of tech-
niques improve so will the need to identify and risk-stratify
patients. This means more investigation is warranted to
develop clinical prediction tools and screening algorithms
directing how to employ these tests in the general population
and/or in select patient populations. Ideally, some simple
algorithms could be implemented outside of the gastroenter-
ologists’ or hepatologists’ office and implemented in the pri-
mary care setting with subsequent referral to subspecialty
care.
In general, the goal of these tests is to minimize the need
for routine biopsy. Certainly, this represents an exciting time
for novel approaches exploring the role of non-invasive fibro-
sis staging in liver disease.
5. Five-year view
Non-invasive tests, particularly imaging, will become more rou-
tine in clinical practice with systemic implementation occurring
to guide management of patients. Serum markers such as GTP,
which are simple and easily accessible, will be optimized for use
in low-resource populations and a combination of serial serum
tests and/or imaging tests will be further refined and used to
stage disease. The – omics (e.g. metabolomics, genomics, and
proteomics) are an emerging and simulating area, which will
push the field forward and will continue to be added to our
research and clinical armamentarium. Novel imaging methods
including DWI, gadolinium-based imaging, and 3D-MRI and
other dynamic techniques may be utilized and incorporated
into clinical prediction tools for fibrosis in the future. These
novel imaging methods combined with the -omics should be
particularly salient tools to optimize detection of NAFLD-related
fibrosis.
Future studies will assess accuracy of non-invasive modalities
in children, as this is not a population in which non-invasive tests
have been well characterized or validated. More research will
delve into how to account for the confounding effect of severe
inflammation on LSM (e.g. as in flares of autoimmune disease or
alcoholic hepatitis), and the effect of hepatic congestion from
cardiac etiologies on LSM, as these factors may complicate fibro-
sis assessment. The role of non-invasive markers may evolve to
include prognosis given the advent of effective therapy for liver
disease especially in patients with HCV. In the years to come, liver
biopsy as the reference standard will continue to be challenged
by refinement in these exciting non-invasive tools. Clinical trials
will incorporate non-invasive markers and tests to select partici-
pants, monitor the evolution of disease, and evaluate treatment
response to drugs and interventions, which will make it an
attractive option compared to serial liver biopsies.
An array of highly sensitive and specific diagnostic tests
exist for clinicians to use for fibrosis staging. Overreliance on
EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 11
non-invasive testing, however, should be avoided. Akin to
blood work and other tools, context matters and novel tech-
niques should not replace clinical judgment, physical exam
and the art of medicine.
Funding
This paper was funded by a Baylor Foundation Grant.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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