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Review Article
The non-invasive assessment of hepatic
fibrosis
Gina Gheorghe
a
, Simona Bung
au
b
, Gabriela Ceobanu
c
,
M
ad
alina Ilie
a
, Nicolae Bacalbas
‚a
d
, Ovidiu Gabriel Bratu
e
,
Cosmin Mihai Vesa
f
, Mihnea-Alexandru G
aman
g,h,
*,
Camelia Cristina Diaconu
c,i
a
Department of Gastroenterology, University of Medicine and Pharmacy “Carol Davila”, 050474
Bucharest, Romania
b
Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea,
Romania
c
Department of Internal Medicine, Clinical Emergency Hospital of Bucharest, 014461 Bucharest,
Romania
d
Department of Obstetrics and Gynecology, University of Medicine and Pharmacy “Carol Davila”,
050474 Bucharest, Romania
e
Department of Urology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest,
Romania
f
Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea,
410028, Oradea, Romania
g
University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
h
Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni
Clinical Institute, Bucharest 022328, Romania
i
Department of Internal Medicine, University of Medicine and Pharmacy “Carol Davila”, 050474
Bucharest, Romania
Received 18 May 2020; received in revised form 30 June 2020; accepted 10 August 2020
KEYWORDS
Acoustic radiation
force impulse
imaging;
Chronic liver disease;
Hepatic disease accounts for approximately 2 million deaths/year worldwide. Liver fibrosis, as
the last stage of numerous chronic liver diseases, is one of the most relevant prognostic fac-
tors. The liver biopsy with the histopathological examination is considered to be the “gold
standard” for the identification and staging of the hepatic fibrosis. However, liver biopsy is
known as an invasive investigation that has multiple limitations. Research studies conducted
* Corresponding author. Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute,
022328 Bucharest, Romania.
E-mail addresses: gheorghe_gina2000@yahoo.com (G. Gheorghe), simonabungau@gmail.com (S. Bung
au), gabriela.ceobanu@ymail.com
(G. Ceobanu), drmadalina@gmail.com (M. Ilie), nicolae_bacalbasa@yahoo.ro (N. Bacalbas
‚a), ovi78doc@yahoo.com (O.G. Bratu),
vcosmin2020@gmail.com (C.M. Vesa), mihneagaman@yahoo.com (M.-A. G
aman), drcameliadiaconu@gmail.com (C.C. Diaconu).
https://doi.org/10.1016/j.jfma.2020.08.019
0929-6646/Copyright ª2020, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.jfma-online.com
Journal of the Formosan Medical Association (2021) 120, 794e803
Elastography;
FibroTest;
HepaScore
in the last few years focused on identifying non-invasive type methods for the evaluation of
hepatic fibrosis; usually, there are 2 categories of such investigations: serologic tests and im-
aging techniques. This narrative review presents the non-invasive investigation methods used
in the liver fibrosis evaluation. New molecular perspectives on fibrogenesis and fibrosis regres-
sion, as well as the appearance of therapeutic antifibrotic agents, justify the necessity of non-
invasive tools to detect and grade liver fibrosis.
Copyright ª2020, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Introduction
Chronic liver disease is one of the main causes of morbidity/
mortality and it accounts for 2 million deaths worldwide each
year.
1
The most prevalent etiologies of chronic liver disease
consist of infections with hepatitis B/C viruses, alcohol-
related liver disease, and non-alcoholic fatty liver disease
(NAFLD).
1e3
Liver fibrosis is a response induced by chronic
liver injury, as it is in the viral hepatitis case, alcoholic liver
disease, autoimmune hepatitis, NAFLD, non-alcoholic stea-
tohepatitis (NASH) and cholestatic liver diseases.
4,5
Hepatic
fibrosis represents a serious health problem, as it may induce
and lead to advanced liver cirrhosis and hepatocellular car-
cinoma.
6
There is a strong relationship between liver fibrosis
and hepatocellular carcinoma (HCC). On one hand, the
presence of advanced liver fibrosis in patients with HCC may
increase the risk of complications of antineoplastic therapy
or even death (due to liver failure); on the other hand, he-
patic fibrosis is a risk factor for the recurrence of hepato-
cellular carcinoma after curative therapy.
7
Therefore,
detecting and staging liver fibrosis is essential in guiding the
management of patients diagnosed with HCC. A timely and
correct diagnosis of liver fibrosis is of paramount importance,
as current data show that it can be delayed if it is diagnosed in
an incipient stage.
6,7
The actual methods of diagnosis of liver
fibrosis consist of non-invasive tests which include serolog-
ical and imaging investigations, and liver biopsy, an invasive
method.
Pathophysiology of liver fibrosis
As already stated, liver fibrosis is considered as being the final
stage of hepatic chronic diseases.
8
The major factors involved
in fibrogenesis areinflammation and hepatocellular necrosis.
Massive necrosis and stromal collapse lead to the formation of
fibrous bands and nodules of regenerating hepatocytes,which
are usually large and irregular.
9
The development of regen-
erative nodules is a compensation mechanism aimed to
replace destroyed or non-functional hepatocytes.
9
Hepatic
fibrogenesis is based on the excessive synthesis of collagen
fibres. Under normal conditions, the synthesis of the extra-
cellular matrix is provided by hepatocytes, endothelial cells
and lipid-storing cells. In pathological circumstances, there is
a rise in the number of cells involved in collagen production,
an increase in the quantity of collagen produced by each cell
and also a change in extracellular matrix constituents, with
increased formation of mature type I collagen, laminin,
fibronectin and glycoproteins.
9
Of great importance in the development and progression
of hepatic fibrosis are the fibroblasts and Ito cells, also
named stellate cells, that change their phenotypic
expression and differentiate into myofibroblasts, which
have a main function in the collagenisation process of the
Disse space.
9
Hepatic fibrogenesis is conditioned, on one
hand, by the imbalance between cytokines that stimulate
hepatocyte regeneration (TGF-aetransforming growth
factor-a, EGF eepidermal growth factor, HGF ehepato-
cyte growth factor) and cytokines that inhibit regeneration
and stimulate fibrogenesis (TGF-beta1 etransforming
growth factor-beta1, HBGF eheparin-binding growth fac-
tor) and, on the other hand, by the disproportion between
the tissue inhibitors of metalloproteinases (TIMP) and the
matrix metalloproteinases (MMP).
9
In consequence, there will be a reduction in the activity
of MMP, which has anti-fibrotic and resorptive properties
and an intensification in the activity of TIMP.
9
The catabolic
of collagen fibres and the reversibility of fibrosis may be
possible when the levels of collagen are low, collagen fibres
have developed recently or when there is an increase of
MMP associated with a reduction of TIMP.
9,10
Advanced
fibrosis and formation of regenerating nodules are however
irreversible processes.
9,10
A schematic view of the patho-
physiology of liver fibrosis is presented in Fig. 1.
Assessment of liver fibrosis
Liver biopsy and histopathological examination is confirmed
as the gold standard in the case of the hepatic fibrosis eval-
uation and grading. The first percutaneous liver biopsy was
performed in 1883, in Germany, by Paul Ehrlich.
10
Over the
years, the evolution of liver puncture was obvious; nowadays,
there are many alternative procedures used in obtaining
samples of liver tissue: unguided biopsy, ultrasound-guided
biopsy, CT-guided biopsy, trans-jugular liver biopsy, laparo-
scopic biopsy or via laparotomy.
11
Despite significant prog-
ress, as clinical and experimental studies show, the liver
biopsy remains an invasive procedure that can be associated
with serious complications
12
such as: pain,
13
intraperitoneal
haemorrhage, intrahepatic and/or subcapsular haemor-
rhage, haemobilia, biliary peritonitis,abscesses, bacteremia,
sepsis,
14e16
pneumothorax, hemothorax, pleurisy, arterio-
venous fistulae, subcutaneous emphysema, side effects of
anesthesia, injury to other organs (lung, gall bladder, kidney,
colon),
17e19
or even death.
12,20
The contraindications of the liver biopsy are divided into
absolute contraindications and relative contraindications.
The absolute contraindications are as follows: significant
coagulopathy or thrombocytopenia; nonsteroidal anti-
inflammatory drugs use within last 7e10 days; patient’
impossibility to provide blood transfusion support or
Non-invasive assessment of hepatic fibrosis 795
decline blood transfusion; patient’ inability to cooperate
with the procedure; extrahepatic biliary obstruction;
vascular tumor/echinococcal cyst; suspected hemangioma;
incapacity to find an adequate biopsy site by ultrasound
and/or percussion. The relative contraindications of the
liver biopsy are hemophilia, ascites, morbid obesity,
amyloidosis, infection within the right pleural cavity or
infection below the right hemidiaphragm.
21
Furthermore,
because it evaluates only small segments of the liver and
not the whole hepatic structure, there can be
falseenegative errors. These limitations of liver biopsy led
to the emergence and development of some non-invasive
tools, very useful in liver fibrosis evaluation (e.g. serolog-
ical tests and imaging techniques).
22
Non-invasive tests aim to identify and stratify the level of
hepatic fibrosis by referencing certain histological scores,
such as the METAVIR score. This particular score was spe-
cifically coined for patients infected with hepatitis C virus
(HCV) and it evaluates the fibrosis level on a 5 points scale
23
(F0 eno fibrosis, F1 eportal fibrosis without septa, F2 e
few septa, F3 enumerous septa without cirrhosis, and F4 e
cirrhosis). The level of fibrosis is significant if the METAVIR
score F2.
23
Non-invasive tests can also be utilized to
monitor patients who are undergoing treatment with drugs
that induce hepatic lesions, such as methotrexate.
Fig. 2 shows the methods, generally available and
emerging, for evaluating liver fibrosis.
Serological tests
To evaluate the level of hepatic fibrosis, a variety of sero-
logical tests has been identified. Panels that utilize sero-
logical markers have been designed to increase the
predictive capacity.
These non-invasive tests require validation against liver
biopsy, which is the present gold standard for the diagnosis;
their diagnostic accuracy is evaluated using the area under
the receiver operator characteristic (AUROC), which com-
bines the sensitivity and specificity of the liver fibrosis
marker.
24
The most utilized panels at the moment are as fol-
lows
22,25
: aminotransferase-to-platelet ratio index (APRI),
FibroTest/FibroSure, Hepascore, and FibroSpect. Other
panels of serological tests which can be used in the evalu-
ation of liver fibrosis are: ActiTest, FIB-4 index, NAFLD
fibrosis score, PGA index, Fibro Index, Forns index, Fibro-
meter, BARD score, ELF, ALBI grade, Lok index, GUCI,
Bonacini-index (CDS), King’s score, Pohl index, VITRO score,
Zeng index.
26
These serological tests can differentiate be-
tween patients with or without significant fibrosis. The
main disadvantage is that they cannot accurately differ-
entiate between the particular levels of fibrosis.
27,28
So far,
none of the panels may be considered the standard
Figure 1 Schematic view of the pathophysiology of liver fibrosis.
Figure 2 Methods, generally available and emerging, for
evaluating liver fibrosis. Color figures are clearly marked as
being intended for: (II) color reproduction on the Web (free of
charge) and in grayscale in print (free of charge). Grayscale
versions of the figures are also supplied for printing purposes.
796 G. Gheorghe et al.
evaluation of hepatic fibrosis. Their usage depends on local
availability.
Serological tests may be classified into two
categories
22,27,28
:
Indirect tests reflect the changes in the hepatic func-
tion, but they do not allow the directly reflection of the
extracellular matrix metabolism (Table 1).
Direct tests reflect directly the extracellular matrix
metabolism. These fall under 3 subcategories: markers
associated with matrix deposition, markers associated
with matrix degradation and cytokines and chemokines
associated with fibrogenesis (Table 2).
Both quantitative and qualitative modifications of the
extracellular matrix pertain to hepatic fibrosis. Potential
biomarkers for the identification and stratification of he-
patic fibrosis include as follows: synthesis/degradation
products of collagen; enzymes which are involved in
biosynthesis/degradation matrix; proteoglycans/glycos-
aminoglycans; extracellular matrix glycoproteins.
22,28
He-
patic fibrosis evaluation markers were combined in
different panels to increase the predictive capacity of
these histopathological modifications.
19
APRI is a hepatic fibrosis evaluation score that was pri-
marily studied in HCV infected patients, human immuno-
deficiency virus (HIV) and HCV coinfected patients, and
patients with alcoholic liver disease/NAFLD.
29e33
According
to data from the literature, APRI sensitivity in detecting
hepatic fibrosis is 77%, while its specificity is 72%.
22
APRI
score is calculated using the following formula:
APRI Z[(AST∕AST
ULN
)/platelet count]100, where AST
ULN
is the superior limit of the normal value of AST.
34
A meta-analysis that included 40 studies and 8739 pa-
tients with chronic hepatitis C showed that APRI had an
AUROC of 0.77, 0.80 and 0.83 for the diagnosis of significant
fibrosis (F2), severe fibrosis (F3) and cirrhosis, respec-
tively.
34
Another meta-analysis including 22 studies showed
similar results, with an AUROC of 0.76 for significant fibrosis
and 0.82 for cirrhosis.
35
FibroTest and FibroSure represent the same test which
has been commercialized under many names in the USA and
Europe. These tests require the age and sex of the patient,
but also values such as a-2-macroglobulin, a-2-globulin, g-
globulin, apolipoprotein A1, GGT, and total bilirubin.
36
ActiTest is a variant of FibroTest which further utilizes
ALT, thus reflecting hepatic fibrosis and necro-inflammatory
activity.
37
FibroTest sensitivity in detecting hepatic fibrosis
is 60e75%, while its specificity is 80e90%.
38
A meta-analysis
of 8 studies showed that FibroTest had a median AUROC of
0.84 for the diagnosis of advanced fibrosis and concluded
that FibroTest is an effective alternative to biopsy in pa-
tients diagnosed with chronic hepatitis C and B, ALD and
NAFLD.
39
HepaScore utilizes values such as bilirubin, g-glutamyl
transferase (GGT), hyaluronic acid, a-2-macroglobulin, sex
and age. This score has been tested in patients with alco-
holic liver disease, though it was not more accurate than
FibroTest.
40
It has proven to be accurate in patients with
HCV infection.
41
The AUROC for HepaScore was 0.85 for
significant fibrosis, 0.96 for advanced fibrosis and 0.94 for
cirrhosis.
42
FibroSpect II uses values of serum hyaluronic acid, a-2-
macroglobulin and tissue inhibitor of metalloproteinase-1
(TIMP-1). This score has proven useful in differentiating
Table 1 Indirect markers used in the liver fibrosis
evaluation.
Individual markers Serological panels
Serum aminotransferase levels
Platelet count coagulation parameters
GGT
Total bilirubin
A-2-macroglobulin
A-2-globulin (haptoglobin)
Proteomics and glycemic
APRI
FibroTest/FibroSure
ActiTest
Hepascore
FIB-4 index
NAFLD fibrosis score
PGA index
Fibro Index
Forns index
Fibro-meter
BARD score
Fibrospect II
ELF
ALBI grade
Lok index
GUCI
Bonacini-index
(CDS)
King’s score
Pohl index
VITRO score
Zeng index
GGT egamma-glutamyl transferase; APRI eaminotransferase-
to-platelet ratio index; FIB-4 efibrosis-4 index; NAFLD fibrosis
enon-alcoholic fatty liver disease; PGA eprothrombin time,
GGT, apolipoprotein A1; BARD eBMI, AST/ALT ratio, diabetes
mellitus; GUCI eGo
¨teborg University Cirrhosis Index.
Table 2 Direct markers used in the liver fibrosis
evaluation.
Markers
associated with
matrix
deposition
Markers
associated with
matrix
degradation
Cytokine and
chemokines associated
with hepatic fibrosis
PICP
PIIINP
Type I and IV
collagen
Laminin
Hyaluronic acid
YKL-40 (CHI3L1)
MMPs
TIMP-1 and TIMP-
2
TGF-a
TGF-b
PDGF
PICP eprocollagen type I carboxy-terminal peptide; PIIINP e
procollagen type III amino-terminal peptide; YKL-40 (inflam-
matory glycoprotein), also known as CHI3L1 echitinase-3-like
protein 1; MMP ematrix metalloproteinases; TIMP etissue in-
hibitors of metalloproteinases; TGF etransforming growth
factor; PDGF eplatelet-derived growth factor.
Non-invasive assessment of hepatic fibrosis 797
chronic HCV patients with moderate/severe fibrosis from
those with mild/no fibrosis.
43
The European Liver Fibrosis panel (ELF) utilizes hyal-
uronic acid level, amino-terminal pro-peptide of type III
collagen level and TIMP-1. The specificity of this score can
reach 95%.
44
Table 3 presents panels of serological tests
(and their components) utilized in the hepatic fibrosis
evaluation.
22
Regarding the correlation between liver fibrosis and HCC,
data from the literature suggest that serological tests cannot
determine the exact extent of liver fibrosis and therefore
cannot accurately stage it. However, a study of 464 patients
with surgically-treated HCC showed that the serological tests
which correlated best with the severity of liver fibrosis were
CDS and Lok’s index in hepatitis B virus-associated hepato-
cellular carcinoma, and FIB-4 and Lok’s index in hepatitis C
virus-associated HCC.
7
The best predictor for liver cirrhosis
was CDS.
7
The independent indicators of advanced liver
fibrosis included: multiple tumours, hepatitis C, low platelet
count and prolonged prothrombin time.
7
Imaging tests
Imaging tests are non-invasive investigation tools used to
detect and stage liver fibrosis.
45,46
They include conven-
tional investigations eultrasound (US), computed tomog-
raphy (CT), magnetic resonance imaging (MRI), as well as
newer techniques of imaging (ultrasound elastography and
magnetic resonance elastography).
22
Morphologic assessment of liver fibrosis can be per-
formed using conventional US, CT and MRI. However, these
investigations are characterized by unreliability and low
sensitivity, as the morphologic features they describe are
usually absent in the early stages of fibrosis.
47
Imaging signs
of liver fibrosis include morphological changes of the liver
(nodular hepatic surface, caudal lobe hypertrophy, het-
erogeneous parenchyma, changes in liver size), increase in
diameter and tortuosity of the hepatic artery, reduction of
hepatic vein diameter, and dilated venous system, as well
as the dilation of portal, splenic and superior mesenteric
veins, and spleen modification (splenomegaly).
48
The
development of gastro-esophageal, para-esophageal, left
and short gastric, umbilical and abdominal wall varices,
splenorenal and retroperitoneal shunts are also signing of
advanced hepatic disease. Because these are imaging
changes seen merely in end-stage liver fibrosis, conven-
tional investigations demonstrate their inaccuracy for
staging liver fibrosis over its entire spectrum of severity.
49
Another limitation of conventional imaging is due to the
fact that many morphologic features are subjective, lead-
ing to differences of opinion between observers as found
within studies.
50
An emerging imaging technique is positron emission to-
mography (PET), the most commonly used radiopharma-
ceutical for PET examination being F-fluoro-2-deoxy-D-
glucose (F-FDG). Having a superior spatial resolution, F-FDG
PET/CT can assess liver fibrosis by quantification of hepatic
glucose metabolism, as concluded by a study published by
Verloh et al.
51
Elastography is a newer technology. There are two types
of ultrasound elastography: shear wave elastography (SWE)
and strain elastography (SE), also named real time elastog-
raphy (Hi-RTE). SWE provides a quantitative measure of
stiffness by using acoustic/mechanical pulses induced by the
ultrasound machine.
22
Among SWE methods: ultrasound e
transient elastography (TE), acoustic radiation force impulse
imaging (ARFI), two-dimensional (2D) shear wave elastog-
raphy (SWE). The first SWE system was Transient elastog-
raphy (Fibroscan) and it is considered the most widely SWE-
based technique in the non-invasive liver fibrosis diagnosis.
49
However, TE does not offer morphologic imaging guidance,
as the ultrasound detector is one-dimensional (1D).
Compared to transient elastography, both ARFI and 2D-SWE
Table 3 Panels of indirect serologic tests used in the
hepatic fibrosis evaluation.
Serological
test
Components
APRI AST, platelet count
FibroTest/
FibroSure
a-2-macroglobulin, a-2-globulin
(haptoglobin), g-globulin, apolipoprotein
A1, GGT, total bilirubin
ActiTest ALT, a-2-macroglobulin, a-2-globulin
(haptoglobin), gglobulin, apolipoprotein
A1, GGT, total bilirubin
HepaScore Bilirubin, GGT, hyaluronic acid, a-2-
macroglobulin, age, gender
FIB-4 index Platelet count, ALT, AST, age
NAFLD fibrosis
score
BMI, blood glucose levels, aminotransferase
levels, platelet count, albumin, age
PGA index Prothrombin index, GGT, apolipoprotein A1
FibroIndex Platelet count, AST, gglobulin
FornsIndex GGT, cholesterol, platelet count, age
Fibrometer Platelet count, prothrombin index, AST, a-2-
macroglobulin, hyaluronic acid, blood urea
nitrogen, age
BARD score BMI, AST/ALT ratio, DM presence
FibroSpect II Serum hyaluronic acid, tissue inhibitor of
metalloproteinase-1 (TIMP-1) and a-2-
macroglobulin
ELF Hyaluronic acid level, amino-terminal pro-
peptide of type III collagen level, and TIMP-1
ALBI grade Bilirubin, albumin
Lok index Platelet count, AST, ALT, INR
GUCI Platelet count, AST, prothrombin index
Bonacini-
index (CDS)
ALT/AST ratio, INR, platelet count
King’s score Age, platelet count, AST, INR
Pohl index Platelet count, AST, ALT
VITRO score Platelet count, von Willebrand factor
antigen
Zeng index Age, a-2-Macroglobulin, GGT, and
hyaluronic acid levels
AST easpartate aminotransferase; GGT egamma-glutamyl
transferase; ALT ealanine aminotransferase; BMI ebody mass
index; TIMP-1 etissue inhibitor of metalloproteinase-1; APRI e
aminotransferase-to-platelet ratio index; FIB-4 efibrosis-4;
NAFLD enon-alcoholic fatty liver disease; PGA eprothrombin
time, GGT, apolipoprotein A1; BARD eBMI, AST/ALT ratio,
diabetes mellitus; DM ediabetes mellitus; ELF eEuropean Liver
Fibrosis panel; CDS ecirrhosis discriminant score, GUCI e
Go
¨teborg University Cirrhosis Index.
798 G. Gheorghe et al.
are imaging techniques incorporated in US scanners. ARFI
method can be done in real-time imaging, so that the larger
blood vessels and masses can be distinguished and avoided.
45
2D-SWE technique is currently the newest SWE-based
method; its concrete role in monitoring and staging liver
fibrosis needs to be demonstrated through further studies.
48
Both ARFI and 2D-SWE are technologic advancements over
TE, with lower failure rates; nevertheless, a real benefit in
the diagnostic accuracy of one technique over the others for
liver fibrosis staging has not been clearly established yet.
Comparison between different types of shear wave elas-
tography is depicted in Table 4 .
50e60
Hi-RTE is technically different from SWE methods; in this
case, the evaluation of the tissue stiffness is obtained after
manual compression. In a study conducted by Tatsumi, 119
patients with chronic liver disease underwent Hi-RTE; the
results were compared with TE and serum markers. Hi-RTE
showed a negative correlation with stages of fibrosis and TE
findings, thus suggesting RTE’s superior performance
compared to TE.
61
Another study, conducted by Colombo
et al., evaluated 45 patients with chronic liver disease and
27 normal subjects and compared three elastographic
methods: TE, ARFI, and Hi-RTE. The AUROCs for predicting
significant fibrosis (F2) for TE, RTE, and ARFI were 0.89,
0.75, and 0.81, respectively. In this study, TE was superior to
RTE, with no significant difference between TE and ARFI nor
between ARFI and RTE. The AUROC values for predicting
liver cirrhosis (FZ4) for TE, RTE, and ARFI showed similar
values (0.92, 0.85, and 0.93, respectively).
62
MRE (magnetic resonance elastography) is a non-invasive
procedure used to measure the liver viscoelastic proper-
ties.
63
As a consequence of hepatic fibrosis, liver stiffness
increases, and it can be evaluated using the propagation of
mechanical waves measurement. MRE has proven its supe-
riority to transient elastography through the capacity to
scan the entire organ and also because it can be performed
in patients with ascites or obesity. Multiple studies have
shown that the diagnostic performance of MRE is higher to
that of ARFI and TE, one major characteristic being its
possibility to diagnose accurately mild fibrosis.
64,65
In a
meta-analysis which included 12 studies, MRE was proven to
have a high accuracy for the diagnosis of significant or
advanced fibrosis and cirrhosis, independent of the BMI and
the etiology of chronic liver disease.
63
Because MRE as-
sesses the whole liver, sampling errors are limited and
interobserver variability is reduced. Also, MRE allows the
regional distribution characterization of the hepatic
fibrosis, a fact that may be useful in underlying and diag-
nosis of liver disease (e.g. primary sclerosing cholangitis).
There are some limitations of MRE, such as high cost,
restricted availability, long time of examination and its
reliance on patient’ cooperation for breath-holds.
63e65
Sequential algorithms
Evidence provided by a clinical study conducted on 183
subjects suffering from chronic hepatitis C has shown that
Table 4 Comparison of the different types of shear wave elastography.
46e55
Transient elastography (TE) Acoustic radiation force impulse
imaging (ARFI)
2D shear wave elastography (2D-
SWE)
Mechanism Uses shear wave imaging to estimate
liver stiffness
Uses conventional hepatic
Ultrasonography to assess liver
stiffness
- Combines ultrasound images with
radiation force induced into the
liver
- Measure shear waves propagation
in real time
Advantages - Accurately diagnoses cirrhosis
(fibrosis stage 4)
- Distinguishes advanced fibrosis from
minimal or no fibrosis
- TE can be used by physicians at the
bedside
- Inexpensive
- Portable
- Short procedure time (<5 min)
- Immediate results
- Reproducible
- Accurately diagnoses early liver
fibrosis in chronic liver disease
patients
- It is performed in real-time
imaging
- Ability to select the area to be
assessed, avoiding large vessels or
ribs
- Can be applied in patients with
obesity and/or ascites
- High accuracy and precision
- Low failure rate
- Good applicability
- Adjustable location of interest
depending on the operator
- Failure rate is significantly lower
than that of TE
Disadvantages - The exact measurement locations are
not recorded
- Cannot evaluate liver parenchyma for
hepatic disease or masses
- Less reliable in patients with obesity,
narrow intercostal spaces, and/or
ascites
- High technical failure rate (6e23%)
- Requirement for patient fasting
- Requirement for patient fasting
- Relatively high expense for
deploying at multiple sites
- More expensive
- Less available and validated by
current studies compared with TE
- Requires more expertise to
perform
- More expensive
- Requires more operator expertise
- Restricted availability
- Insufficient evidence concerning
the diagnostic performance
Non-invasive assessment of hepatic fibrosis 799
an association of TE and biochemical tests offered favour-
able diagnostic results in identifying advanced fibrosis and
clinically significant fibrosis.
66
In the case of concordance
between FibroScan and FibroTest, the obtained results
revealed a favourable ratio of liver biopsy for significant
fibrosis (F2) in 84% of cases, an excellent ratio for severe
fibrosis (F3) in 95% of cases and for liver cirrhosis in 94% of
cases.
66
Based on the findings of a clinical research carried
out on 235 patients suffering from chronic hepatitis C, was
designed the Fibropaca algorithm that included APRI,
FibroTest and the Forns Index.
67
The association of the
three tests allowed the proper classification for 81.3% of
the subjects included in the research.
67
A set of three algorithms, Sequential algorithms for
fibrosis evaluation (SAFE) biopsy, comprising Fibrotest and
APRI, was designed by Sebastiani et al.
68
The algorithms
were applied in assessing the F2 stage for subjects with
normal or high values of liver transaminases as well as for
diagnosing F4. Using SAFE biopsy influenced the decrease in
the necessity for liver biopsy with 50%.
68
A captivating al-
gorithm in examining great numbers of people is a serum
non-invasive assay as the first examination test, succeeded
by shear wave elastography.
69
Combining transient elas-
tography and blood fibrosis assays offers the potential for a
precise diagnostic of advanced liver fibrosis. A new algo-
rithm was designed
70
comprising an imaging procedure
FibroMeterVCTE and a serum assay, easy liver fibrosis test
(eLIFT). The eLIFT is a score that integrates age, gender,
AST, prothrombin time, gamma-glutamyl transferase and
platelets, being designed to identify advanced cirrhosis.
The FibroMeterVCTE represents a procedure of vibration
controlled transient elastography (VCTE). In the research,
eLIFT was carried out first, succeeded by FibroMeterVCTE if
eLIFT did not identify advanced fibrosis. The association of
FibroMeterVCTE and eLIFT presented a sensitivity of 76.1%
in identifying advanced fibrosis and for identifying cirrhosis
a sensitivity of 92.1%.
70
Emerging technologies egenetic and
microbiome signature scores
Genetic differences among people determine distinctive
predisposition for the occurrence of liver fibrosis, ac-
counting approximately half of the phenotypic variation in
a chronic liver disease like NAFLD.
69
High risk of fibrosis or
steatosis is connected with particular gene polymorphisms.
A research performed on 515 subjects suffering from NAFLD
revealed an association of steatosis with variations of
TM6SF2 and PNPLA3 genes.
70
The TM6SF2, PNPLA3 and
MBOAT7 gene variations can be associated with hepatocyte
lesions as demonstrated by the research findings.
70,71
The
MBOAT7 polymorphism was correlated to liver fibrosis while
TM6SF2 variant was correlated to fat accumulation. High
risk of steatosis and fibrosis was connected with the PNPLA3
polymorphism. The discovery of a genetic signature
comprising 7 predictive (single nucleotide polymorphisms)
SNPs able to detect Caucasian subjects suffering from
chronic hepatitis C presenting high risk of cirrhosis deter-
mined the establishing of a cirrhosis risk score using genetic
variants.
72
Other developing procedures comprise the
usage of microRNAs, fragments of RNA that adjust gene
expression; miRNA122 being correlated in NAFLD subjects
with liver fibrosis.
69
Imaging techniques are evolving, of
them three-dimensional (3D) MRE has the potential to
determine shear wave propagation in several plans, thus
keeping away from mathematical suppositions character-
istic to 3D methods.
69,70
It was noticed that particular gut flora was connected to
an increased risk of liver cirrhosis.
73
The risk of developing
obesity, NAFLD and gastrointestinal malignancies is corre-
lated with the presence of a dysbiotic microbiome.
74e78
Moreover, particular gut bacteria may transform choline
in trimethylamine, accentuating the risk of evolution to
non-alcoholic steatohepatitis (NASH).
74
A team of re-
searchers set a microbiome or gut bacteria signature score
comprising 37 bacterial species that had promising poten-
tial in differentiating mild/moderate NAFLD from severe
NAFLD.
74
Conclusions
Non-invasive liver fibrosis evaluation is an important topic
of recent research. Since needle liver biopsy is usually
associated with significant risks/limitations, different
scores (based on various biochemical markers or hepatic
tissue stiffness) were elaborated. Non-invasive serologic
tests are classified into direct tests (which, as the name
implies, directly evaluate the metabolism of the extracel-
lular matrix) and indirect tests that reflect the changes in
liver function, caused by liver fibrosis. With a sensitivity
and specificity that can reach up to 95%, serological tests
may be useful non-invasive methods in detecting liver
fibrosis.
22
As well, non-invasive imaging tests include con-
ventional morphologic investigations (US, CT or MRI) and
newer imaging techniques (US/MRI elastography). Both
these non-invasive types of tests have the advantage of
being more accessible and avoiding complications that may
occur after liver biopsy. They are also recommended to be
performed in patients for whom liver biopsy is contra-
indicated. Sequential algorithms may be efficient for
detecting advanced fibrosis, using a combination of elas-
tography methods with direct or indirect serum tests. New
methods related to genetic signature scores appear, based
on combinations of microbiome signature scores or SNPs,
characteristic for dysbiotic gut flora, having right differ-
entiating capacity in determining/anticipating liver
fibrosis.
Author contributions
Conceptualization: Gina Gheorghe and Gabriela Ceobanu.
Data curation: M
ad
alina Ilie. Formal Analysis: Cosmin Mihai
Vesa. Investigation: Gabriela Ceobanu, M
ad
alina Ilie, Nic-
olae Bacalbas
‚a and Camelia Cristina Diaconu. Methodology:
Simona Bung
au and Ovidiu Gabriel Bratu. Software: Cosmin
Mihai Vesa. Supervision: Simona Bung
au and Camelia Cris-
tina Diaconu. Validation: Gina Gheorghe and Camelia Cris-
tina Diaconu. Visualization: Ovidiu Gabriel Bratu and
Cosmin Mihai Vesa. Writingdoriginal draft: Gina Gheorghe,
Simona Bung
au and Cosmin Mihai Vesa. Writingdreview
and editing: Simona Bung
au, Mihnea-Alexandru G
aman
and Camelia Cristina Diaconu. All authors have read and
800 G. Gheorghe et al.
agreed to the published version of the manuscript. Gina
Gheorghe, Camelia Cristina Diaconu, Simona Bung
au, Nic-
olae Bacalbas
‚a and Cosmin Mihai Vesa contributed equally
to the writing of this paper and share first authorship. All
authors approved the submission of the final version of the
manuscript.
Declaration of competing interest
The authors have no conflicts of interest relevant to this
article.
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