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16. HBV/HCV coinfection
https://t.me/medicina_free
Viral interactions between HBV and HCV
Patients with both HBV and HCV may show a large spectrum of virologic
proiles and diferent viral dominance patterns have been documented. In
most cases, HCV is dominant and suppresses HBV replication (Liaw 2001),
resulting in lower HBV DNA levels and decreased activity of HBV DNA
polymerase (Chu 1998). Moreover, HCV was demonstrated to inhibit HBsAg
production by mechanisms mediated by host immune responses. HBsAg
levels were found even lower compared with HBV-monoinfected patients
undergoing treatment with nucleos(t)ide analogues but comparable to low
replicative HBsAg carriers (Wiegand 2015). Superinfection with HCV in
patients with chronic HBV might even induce seroconversion of HBsAg
(Liaw 1994, Liaw 1991). Most recent clinical indings postulate that HCV
coinfection itself is not associated with seroconversion but a higher ALT
level >80U/L is the major determinant of HBsAg loss in patients with HBV/
HCV coinfection (Yang 2016).
Several authors have reported that HBV can reciprocally inhibit HCV
replication (Sato 1994). HBV DNA replication has been shown to correlate
with decreased HCV RNA levels in coinfected patients (Zarski 1998).
Coinfection with HBV was sometimes associated with a higher spontaneous
HCV clearance (Islam 2016).
Furthermore, patients with coinfection have lower levels of both HBV
DNA and HCV RNA than corresponding monoinfected controls, indicating
that simultaneous suppression of one virus by the other might occur (Jardi
2001). T hus, either HBV or HCV c an play the dominant role, HBV and HCV can
inhibit each other simultaneously and they can alternate their dominance
(Liaw 1995). Both viruses have the ability to induce seroconversion of the
other. The chronology of infection may have a role in determining the
dominant virus.
Interestingly, recent in vitro studies revealed that there is most probably
no direct interference between HBV and HCV replication, making
interindividual diferences in innate and/or adaptive host immune
responses responsible for viral interference observed in coinfected patients
(Bellecave 2009, Eyre 2009). A modulation of human dendritic cells
induced by the combined efects of HBV and HCV core proteins, leads to
an ineicient antigen presentation to CD4+ T cells and thus suppresses the
induction of cellular immune response (Agrawal 2014, Yoshio 2016). These
indings show a possible mechanism by which HBV and HCV synergistically
induce immune tolerance that may be fundamental in establishing chronic,
persistent infection.
Clinical scenarios of HBV and HCV infection
Diferent scenarios of infection have been described with HBV/HCV
coinfection including acute hepatitis with HBV and HCV (Alberti 1995),
occult HBV coinfection of chronic HCV (Sagnelli 2001), and superinfection by
either virus in patients with pre-existing chronic hepatitis due to the other
virus (Figure 1). Frequently the sequence of infection cannot be deined.
Figure 1. Clinical scenarios of HBV/HCV coinfection (modified af ter Crockett 2005)
Acute hepatitis by simultaneous infection of HBV and HCV
Simultaneous coinfection with HBV and HCV is rarely seen, but the
interaction of HBV and HCV appears to be similar to chronic infection.
In acute infection with HBV and HCV, patients showed delayed HBsAg
appearance and a shorter hepatitis B surface antigenaemia compared to those
with acute HBV alone (Mimms 1993). Biphasic alanine aminotransferase
(ALT) elevation was found in some patients, although rates of viral clearance
were similar to those in patients with HBV or HCV monoinfection (Alberti
1995). Simultaneous infection oten has a self-limiting, benign course with
complete recovery from one or both infections (Chen 2007, Chu 1995).
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HCV superinfection
HCV superinfection is frequent in endemic areas of HBV infection, such
as Asia, South America and sub-Saharan Africa (Liaw 2002, Liaw 2004),
which can result in the suppression of HBV replication and termination of
HBsAg carriage. However, long-term follow-up analyses have described a
higher rate of liver cirrhosis and hepatocellular carcinoma (Liaw 2004, Yang
2016). Fulminant hepatic failure was signiicantly higher among patients
with underlying HBV infection than those without (23% vs. 3%) (Chu 1999,
Wu 1994, Chu 1994).
HBV superinfection
HBV superinfection is less common in people living with HCV and
limited data is available. In a case control study, HCV RNA was undetectable
in all observed patients during acute HBV infection, indicating that
superinfection of HBV leads to long lasting suppression of HCV (at one year
71% remained negative, at two years 42%) and in up to 25% of cases even can
lead to permanent clearance of chronic HCV infection, especially in patients
with severe acute HBV infection (Sagnelli 2009, Liaw 2000, Wietzke 1999).
Patients with superinfection and those with HBV monoinfection showed
similar initial HBV viral load and a similar trend of becoming negative for
HBV DNA. HBV superinfection is associated with acute deterioration of liver
function and showed a severe course during acute illness more frequently
(34.5% in superinfection versus 6.9% in HBV monoinfection). The risk of
fulminant hepatitis is increased (Sagnelli 2009, Sagnelli 2002).
Occult HBV infection in patients with HCV infection
Chronic hepatitis in HBV/HCV coinfection
Patients with detectable serum HBV DNA and HCV RNA are at
highest risk of severe liver disease and therefore should be considered for
treatment. Large follow-up studies show that patients with HBV viraemia
are at higher risk for cirrhosis, HCC and overall death than people with
HCV monoinfection (36.8, 6.9, and 41.7 versus 17.4, 3.6, and 31.4 per 1000
person years, respectively) (Kruse 2014, Bini 2014). Active HCV infection
(HCV RNA+) in the setting of inactive HBsAg (HBsAg+/HBV DNA-) is
associated with a clinical course similar to that of HCV monoinfection.
Another possibility is active HBV infection in patients with inactive or prior
HCV infection (HBV DNA+/HCV RNA-/anti-HCV+). This immune proile is
less common, and may indicate HBV suppression of HCV. A longitudinal
study of virologic monitoring of 103 HBV/HCV-coinfected patients revealed
a luctuation in the virologic pattern (Raimondo 2006). Asian ethnicity is
a major independent predictor of HBV dominance, while HCV-dominant
disease is more common in non-Asian individuals (Nguyen 2011). Thus,
careful longitudinal follow-up of levels of serum HBV DNA and HCV RNA is
needed for a correct diagnosis and decision on the most successfu l treatment
strategy. Table 1 shows the immune proiles found in patients with chronic
HBV/HCV infection.
Table 1. Immune profiles in patients with chronic HBV/HCV infection
HBV and HCV
active
HBsAg + – +
HBV DNA + + –
Anti-HCV + + +
HCV RNA + + +
Occult HBV in chronic
active HCV
HCV active in
HBsAg carrier
Occult HBV infection, deined as detectable HBV DNA in liver or
serum and undetectable HBsAg (Ozaslan 2009, Torbenson 2002), has been
identiied in up to 50% of patients with chronic HCV (Matsuoka 2008).
Importantly, a relation to HCV treatment outcomes has been described
(Zignego 1997, Fukuda 2001, Sagnelli 2001). HCV infection with occult HBV
infection has been associated with higher ALT levels, greater histological
activity index and liver disease more oten progressing to liver cirrhosis
(Fukuda 1999, Cacciola 1999, Sagnelli 2001). Occult HBV infection seems
to signiicantly shorten life expectancy compared to HCV monoinfection
(Squadrito 2014, Coppola 2016).
382 383
Cirrhosis
Higher rates of cirrhosis have been shown in people with HBV/HCV
coinfection. In comparison to patients with HBV monoinfection, higher
rates of cirrhosis (44% vs. 21%) and decompensated liver disease (24% vs.
6%) were demonstrated in people with coinfection (Fong 1991). Compared
to HCV monoinfection, a higher rate of cirrhosis (95% vs. 49%) and more
decompensated liver disease (Child-Pugh class C 37% vs. 0%) were found in
people with HBV/HCV coinfection (Mohamed Ael 1997).
16. HBV/HCV coinfection
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Hepatocellular carcinoma
In many studies, coinfection with HBV and HCV is associated with
an increased risk of HCC development, conirmed by three large metaanalyses (Cho 2011, Shi 2005, Donato 1998).
In one longitudinal study, incidence of HCC was 6.4 per 100 person years
in people with HCV/HBV coinfection compared to 2.0 and 3.7 in HBV and
HCV monoinfection, respectively. The cumulative risk of developing HCC
ater 10 years was 45% in HBV/HCV coinfection compared to 16% in HBV
and 28% in HCV monoinfection (Chiaramonte 1999). Possible associated
risk factors for HCC development in coinfection are longer duration of
infection, higher HCV RNA levels, and higher levels of ibrosis (Zampino
2015). Patients with HBV/HCV coinfection should undergo a screening
routine for HCC with liver ultrasound and α fetoprotein levels in serum at
least every six months.
In this context, however, it has to be mentioned that dually infected
patients are an extremely heterogeneous population and most of the
data available does not take into account the diferences in the viruses
(genotypes, main HBV genomic mutations, activity status of one or both
viruses, etc.) or those regarding patients’ characteristics and comorbidities
(presence of diabetes, alcohol intake, etc.) (Huang 2011).
2). Data from a meta-analysis show that the SV achieved in HBV/HCV
coinfection are comparable to those in HCV monoinfection (OR=1.03, 95%
CI: 0.37–2.82 and OR=0.87, 95% CI: 0.62–1.21, respectively) (Liu 2012, Kim
2011, Liu 2009). HCV SV is maintained in 97% in a ive-year follow-up (Yu
2013). Furthermore, HBsAg loss occurs in about 30% within ive years ater
treatment start and there is evidence of an increased possibility of HBeAg
seroconversion during or post-treatment with PEG-INF and ribavirin (Liu
2016, Yu 2013, Liu 2009, Viganò 2009, Yu 2009).
Table 2. PEG-IFN plus ribavirin treatment trials in people with HBV/HCV coinfection
Patients (n) HCV SVR
(%)
19 70 *, 78* * 33 0 31 Potthoff 2008
161 72*, 83** 56 11 35 Liu 2009
17 6 na na na Senturk 2008
50 4 0 *, 75** 100 0 24 Yu 20 09
22 41 86 36 na Viganò 2009
18 60*, 8 8** 12 na na Kim 2011
*HCV GT 1, **HCV GT 2/3, na=not applicable, # HBV DNA negative pre-treatment
HBV DNA
negative (%)
HBsAg
loss (%)
HBV
reactivation
# (%)
Reference
Treatment of HBV and HCV coinfection
Despite the individual clinical importance, solid evidence and wellestablished treatment guidelines for HBV/HCV coinfection are currently
lacking. Generally, treatment guidelines for monoinfection should be
applied to coinfection ater carefully characterising the replicative status of
HBV, HCV and hepatitis delta virus infection. Due to the variety of virologic
proiles in HBV/HCV coinfection it is important to asse ss the dominant virus
prior to initiating therapy. In people with coinfection, treatment should
be initiated when inclusion criteria for standard treatment guidelines of
HBV and HCV monoinfection are met (see Chapter 9 on HBV treatment and
Chapter 12 on HCV treatment). Treating HBV/HCV coinfection leads to a risk
reduction of HCC and improved survival (Liu 2014, Konstantinou 2015). As
with monoinfection, treatment of people with coinfection should be started
before liver decompensation occurs.
Due to loss of viral suppression from the successfully treated dominant
virus, acceleration of liver disease has been reported (Yalcin 2003) and
caution must be exercised upon initiation of therapy.
In coinfection with dominance of HCV infection, PEG-IFN plus ribavirin
is still used because of its proven activity against both viruses (Table
HBV replication may become detectable in up to 60% of patients with
undetectable pre-treatment HBV DNA levels, either during the course of
treatment (38%) or during the treatment follow-up (60%). Reactivation was
only transient in 45% (Liu 2014, Yu 2013, Potthof 2009, Liu 2009). HBV
DNA reactivation was found to be independently associated with younger
age, HCV SV and baseline HBV DNA ≥2000 IU/mL (Hung 2012). Thus, close
monitoring of both viruses is recommended during and ater combination
therapy. In case of HBV reactivation or if HBV replication is detectable at
a signiicant level, concurrent HBV nucleos(t)ide analogue (NA) therapy is
indicated.
Direct acting antivirals (DAA) still need to be further evaluated in people
with HBV/HCV coinfection. IFN-free DAA-based regimes will not be able to
clear HBsAg and simultaneous or on-demand nucleos(t)ide analogues will
be needed if clinically indicated. In the setting of the IFN-free DAA-based
therapies, the possibility of HBV reactivation during HCV treatment is
raised due to viral interferences. Post-marketing cases of HBV reactivation
under diferent combinations of DAAs have been reported (De Monte 2016,
Hayashi 2016, Takayama 2016, Collins 2015). On the other hand, a recent
analysis of 103 previously HBV infected patients showed no evidence of HBV
reactivation under DAA treatment (Sulkowski 2016). Nevertheless, positive
HBsAg status before DAA treatment is a strong risk factor for developing
384 385
16. HBV/HCV coinfection
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hepatitis due to HBV activation during treatment (H 15.0) (Wang 2017).
Due to this potential risk of early HBV reactivation during IFN-free HCV
therapies, it is necessary to closely monitor and preemptively treat HBV
coinfection, regardless its stage (chronic, occult, resolved), whatever HCV
genotype or class of DAA used. Furthermore, in patients receiving tenofovir
as concomitant anti-HBV treatment, the eGF and tubular function should
be monitored during treatment with simeprevir or sofosbuvir/ledipasvir as
tenofovir exposure is signiicantly increased.
In patients with dominant HBV, IFN +/- HBV polymerase inhibitors are
an upcoming option. Data exists from a small cohort of people with HBV/
HCV coinfection treated with lamivudine in combination with standard
interferon for 12 months followed by lamivudine for an additional 6 months
(Marrone 2004). In this study, clearance of HBeAg was found in 3/8, two
patients showed HBeAg seroconversion, and HBV DNA clearance was
observed in 3/8 at the end of therapy. HBV DNA became detectable again in
two patients at the end of follow-up. HCV clearance was achieved in 50%. In
another study, tolerability and eicacy of anti-HBV nucleos(t)ide analogues
(lamivudine plus adefovir [n=10], entecavir [n=7], telbivudine [n=4], tenofovir
disoproxil fumarate [n=3]) were investigated in a cohort of 24 cirrhotic
patients with HBV/HCV coinfection (Coppola 2013). Clearance of HBV DNA
was found in 96% of patients ater 18 months, while HCV reactivation was
low (12.5%). However, while the virologic response was favourable in all
patients and treatment was well tolerated, progression of liver cirrhosis
was seen in up to one-third. Patients who were HCV RNA positive at
baseline deteriorated more frequently. Thus, a favourable clinical impact in
HBV/HCV cirrhotic patients was seen only in patients who were HCV RNA
negative at baseline.
Based on these observations, NA such as tenofovir, adefovir, entecavir
and telbivudine showing a higher genetic barrier in combination with PEGIFN are a possible treatment option. In cirrhotic patients with HBV/HCV
coinfection with detectable HCV RNA, exclusive treatment with NA has
a high risk of clinical deterioration. However, further studies are needed
to estimate the treatment value of these newer drugs in diferent clinical
scenarios.
Interestingly, ibrosis progression rate ater orthotopic liver
transplantation in patients with HBV/HCV coinfection is lower compared
with HCV monoinfection (Taniguchi 2000, Féray 1999). The one- and iveyear patient and grat survival rates were 80% and 70%, respectively. The
ive-year ibrosis progression rate was 0.17 +/- 0.08 units (Manzia 2010).
Conclusion
Coinfection with HBV and HCV is not uncommon, especially within
areas of high hepatitis B prevalence. HBV/HCV coinfection is a challenge
for clinicians due to the complex interactions of HBV and HCV, and the
propensity for developing severe liver disease. No treatment standard
has been established for patients with HBV/HCV coinfection. Treatment
decisions must be made based upon identiication of the dominant virus.
Combination therapy of PEG-IFN plus ribavirin has been shown to be highly
efective in inducing virologic response. Systematic treatment experience
with DAAs in the setting of HBV/HCV coinfection is lacking and decisions
currently have to be made on an individual basis.
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fibrosis and steatosis
Frank Grünhage and Frank Lammert
Introduction
Non-invasive methods for the assessment of liver ibrosis and steatosis
are replacing invasive liver biopsy due to patient wariness and the low
but ever-present morbidity of biopsies. The use of non-invasive markers
is also increasing because clinical questions concerning the presence or
absence of steatosis, ibrosis and cirrhosis as well as treatment monitoring
and follow-up can be suiciently answered by these tests and procedures.
Today, despite the dogma of the biopsy being the gold standard, the use
of non-invasive liver ibrosis detection vastly outnumbers biopsies in
chronic liver diseases. Non-invasive tests have problems in discriminating
accurately between early stages of ibrosis, i.e., F0-F2. Notwithstanding,
non-invasive markers can be used as it primarily relevant to discriminate
between early stages and advanced ibrosis in clinical practice.
In addition, non-invasive tests carry the potential of being used as
screening tools in population-based studies and can detect ibrosis even
in individuals with normal liver function tests. Non-invasive markers
should be able to reliably identify liver cirrhosis in order to initiate further
diagnostic procedures to exclude portal hypertension and to intensify
surveillance strategies. Non-invasive strategies are also warranted
for monitoring the disease while on therapy and ideally document the
regression of ibrosis during follow-up.
Non-invasiveness for the detection of ibrosis has become reality
in clinical practice and has been approved for clinical studies but for
hepatologists ibrosis assessment is only one puzzle piece and more
information is needed. Other endemic conditions such as fatty liver disease
with or without inlammatory changes and or ibrosis increase the need
for other non-invasive tests that also provide information on hepatic fat
contents and inlammation. Whereas ultrasound-based methods such as
the controlled attenuation parameter (CAP) can be used for the rapid and
easy assessment of steatosis, speciic non-invasive test to classify the mode
and extend of inlammation in the liver are still missing.
With most experts agreeing that non-invasive techniques do not
replace liver biopsies completely, they have reduced the number of biopsies
substantially (Leroy 2007, Pinzani 2005, Sebastiani 2006). Hence, the
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clinical question remains: Will the information change my practice or
advice? Recently three major guidelines have been published on the use
of elastography and other methods for non-invasive assessment of liver
ibrosis, which are recommended for further reading:
• http://www.easl.eu/research/our-contributions/clinical-practiceguidelines/detail/non-invasive-tests-for-evaluation-of-liverdisease-severity-and-prognosis
• http://www.efsumb.org/guidelines/guidelines01.asp
• http://www.wfumb.org/reports/
This chapter reviews non-invasive (serum markers and liver stifness
measurement) markers of liver ibrosis as well as fatty liver disease and
aims to illustrate what is relevant in clinical practice.
Mechanisms of liver fibrosis in chronic viral
hepatitis
Liver ibrosis is characterised by the loss of hepatocytes, destruction of
hepatic (micro)architecture, proliferation of hepatic (myo)ibroblasts, and
excess deposition of extracellular matrix (Friedman 2008). The inal stage
of liver ibrosis (cirrhosis) may result in insuicient detoxiication, portal
hypertension, renal and pulmonary failure and hepatocellular carcinoma,
and is associated with excess mortality. Liver cirrhosis is the common endstage of chronic liver diseases such as chronic viral hepatitis, non-alcoholic
and alcoholic liver diseases as well as autoimmune and metabolic liver
diseases. The mechanisms of ibrogenesis in all aetiologies share certain
aspects but difer in detail. Consequently, the non-invasive assessment of
liver ibrosis also varies between diseases.
A key feature of hepatic ibrosis is the activation and proliferation of
ibroblasts and hepatic stellate cells. Chronic liver injury leads to activation
of these cells, which become contractile, produce the extracellular
matrix components and secrete inlammatory and proibrotic cytokines
and chemokines such as transforming growth factor. The activation of
these cells is believed to represent the key event in hepatic ibrogenesis
(Friedman 2008). Hepatic stellate cell activation depends on signalling by
Kupfer cells, endothelial cells, hepatocytes, and platelets. The deposition of
the extracellular matrix is constantly opposed by the degradation of these
proteins. In progressive liver ibrosis, this balance is skewed in favour of
excess extracellular matrix deposition. Matrix metalloproteinases and
their regulators (tissue inhibitors of metalloproteinases, TIMPs) control
matrix deposition and degradation.
Liver biopsy – the “gold standard” for staging of
liver fibrosis
Liver biopsy may be obtained via diferent routes (Table 1). The most
common is the ultrasound-guided percutaneous biopsy.
Table 1. Pros and cons of methods for liver biopsy
Procedure Advantages Disadvantages References
Percutaneous
biopsy
Transiugular
biopsy
(Mini-)
Laparoscopy
Easy to perform
•
• Out-patients
procedure in
selected cases
Applicable in
•
patients with
ascites and
coagulation
deficiencies
•
Higher
detection rates
for cirrhosis
Bleeding can be
•
treated directly
• Low patient acceptance
• Complication rate 0.75–14%
(90% detected within 24 hrs)
Mortality 0.001–0.003%
•
•
Higher complication rates in
advanced fibrosis
Not advised in patients with
•
ascites
• Expensive
•
In-patient procedure
• Smaller biopsies may hamper
fibrosis assessment
Usually inter ventional
•
radiologist required
•
Expensive
• Not available in all centres
The quality and reliability of ibrosis staging via histopathological
assessment of liver biopsy specimens depends largely on the size of the
specimen and the number of portal ields. The biopsy should be at least
20-25 mm long and more than 11 portal tracts should be visible (Bedossa
2003, Chologitas 2006, Rousselet 2005). However, in daily practice these
requirements may not be easy to achieve; and even if a large enough biopsy
is acquired, the specimen only relects about 1/50,000 of the whole liver.
Thus, liver biopsies are particularly prone to sampling errors and may
– like non-invasive markers – have diiculties in discriminating between
adjacent stages of ibrosis (i.e., F1 vs. F2 or F2 vs. F3). Discrepancies of more
than one stage are rare (Regev 2002, Siddique 2003, Skripenova 2007). Intraand inter-observer variability may be unafected by specimen sizes but
can lead to discrepancies in up to 20% of cases, even if one stage diference
between estimates is accepted (Gronbaek 2002, Petz 2003). Standardised
automated staging using deep learning algorithms may improve diagnostic
accuracy (Yu 2018).
Ter j u ng
2003, van
der Poorten
2006, Myers
2008, Chi
2017
Cholongitas
2006,
WolskaKrawczyk
2013
HelmreichBecker 2003,
Denzer 2007
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There is a wide variability in the use of other staging systems in patients
with chronic viral hepatitis. In Germany, current guidelines recommend
the Desmet & Scheuer staging system (Supplementary Table 1) (Batts 1995,
Desmet 1994, French METAVI Cooperative Study Group 1994, Ishak 1995,
Knodell 1981, Schirmacher 2004).
Supplementary Table 1. Commonly used liver fibrosis staging scores
Staging System Fibrosis stages Remarks
METAVIR F0, F1, F2, F3, F4 Best evaluated in
HCV fibrosis
Knodell F0, F1, F3, F4 No interm ediate stage Knodell 1981
Desmet &
Scheuer
Batts & Ludwig Similar to METAVIR Batts 1995
Ishak F0, F1, F2, F3, F4,
Analogous to
METAVIR
F5, F6
Recommended by the
German guidelines
for the assessment of
liver fibrosis
French METAVIR
Cooperative Study
Group 1994
Desmet 1994,
Schirmacher 2004
Ishak 1995
Surrogate markers of liver fibrosis
Liver ibrosis develops as a continuous process rather than in a stepwise
manner. Thus, so-called surrogate markers, which are also continuous
variables, may provide more precise information. Surrogate markers can
be subdivided into two groups (Table 2):
Direct markers relect changes in the content of extracellular matrix
proteins (such as collagen) in the liver.
Indirect markers indicate alterations in hepatic function, increase in
portal hypertension with subsequent splenic enlargement, and/or grade of
hepatic inlammation that may correlate with ibrosis stage.
Direct and indirect markers may be used alone or, more commonly, in
combination (“composite scores”). The calculation of such scores can be
simple (e.g., APRI, FIB-4, FORNS) or based on complicated formulas (e.g.,
Fibrotest, Fibromax, Fibrosure).
Advantages of surrogate markers are (EASL 2015):
• Good reproducibility
• High applicability (95%)
• No cost and wide availability (non-patented)
• Well validated
• Can be performed in the outpatient clinic
Disadvantages of surrogate markers include (EASL 2015):
• Non-speciic of the liver
• Unable to discriminate between intermediate stages of ibrosis
• Performance not as good as elastography for cirrhosis
• Cost and limited availability (proprietary)
• Limitations (haemolysis, Gilbert syndrome, inlammation,
cholestasis, heart failure)
Table 2. Summary of non-proprietary direct and indirect surrogate markers of liver fibrosis
(modified from Pinzani 20 08)
Index Variables Formula for calculation Interpretation
Direct surrogate marker
MP3 PIIINP,
MMP-1
Indirect surrogate markers
Forns Age, plt, γGT,
cholesterol
APRI AS T, pl t ([AST/ULN]/plt [× 10
Fibroindex Plt, AST,
γG T,
Tes t a Plt, spleen
diameter
Fibrosis
probability
index
FIB-4 Plt, AST, ALT,
Bonancini A LT, AST,
Pohl AS T, ALT, plt Positive if: AST/ALT ≥1 and platelet
AgePlatelet
AS T,
cholesterol,
past alcohol
intake,
HOMA, age
age
INR, plt
Plt, age Age score + plt score (0–10 possible
0.5901 (logPIINP[ng/mL]) − 0.1749
(logMMP-1[ng/mL])
7.811 – 3.131 × ln(plt) + 0.781 × ln(γGT)
+ 3.467 × ln(age) − 0.014 (cholesterol)
9
/L]) × 100 >1.5 ≈ Ishak 3–6
9
/L
4
/mm3]) + 0.005
9
/L):
1.738 − 0.064 (plt [× 10
(AST [IU/L]) + 0.463 × (γGT[g/dL])
Plt count/spleen diameter >1750 ≈ Ishak ≤2
x
E
/1 + ex, wherex = −10.929 + (1.827
× ln[AST]) + (0.081 × age) + (0.768 ×
[past alcohol use graded as 0–2]) +
(0.385 × HOMA)
(Ages × AST)/(plt count × <1.45 ≈ Ishak <4–6
Sum (range 0–11) of (plt score) + (ALT/
AST score) + (INR score) plt (× 10
>340 = 0; 280–339 = 1; 220–279 = 2;
160–219 = 3; 10 0–159 = 4; 40–99 = 5;
<40 = 6 ALT/AST ratio: >1.7 = 0; 1.2–1.7
= 1; 0.6–1.19 = 2; <0.6 = 3 INR: \1.4 = 2
count <150 × 10
score) age: <30 = 0; 30–39 = 1; 40–49
= 2; 50–59 = 3; 60–69 = 4; ≥70 = 5.
9
Plt (× 10
175–199 = 2; 150–174 = 3; 125–149 =
4; ≥125 = 5
/L): ≥225 = 0; 200–224 = 1;
<0.3 ≈ F0–2
>0.4 ≈ F3–4
<0.3 ≈ F0–1
>0.4 ≈ F2–4
>6.9 ≈ Scheuer 2–4
<4.2 ≈ Scheuer 0–1
≤0.5 ≈ Ishak 0–2
≤1.25 ≈ F0–F1
≥2.25 ≈ F2–F3
≤1750 ≈ Ishak >2
<0.2 ≈ F0–F1
≥0.8 ≈ F2–F4
>3.25 ≈ Ishak ≥4–6
>8 ≈ Knodell 3–4
Positive ≈ F3–F4
≥6 ≈ F2–F4
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Index Variables Formula for calculation Interpretation
Combined direct and indirect surrogate markers
SH A S TA HA, AST,
albumin
FM plt, PI, AST,
HA, α2-MC,
gender, age
Hepascore HA, α2-MC,
γGT, age,
gender
α2-MC = α2-macroglobulin, HA = hyaluronic acid, MMP-1 = matrix metalloproteinase 1,
PIIINP = aminoterminal peptide of type III procollagen, plt = platelets
−3.84 + 1.70 (1 if HA 41–85 ng/mL, 0
otherwise) + 3.28 (1 if HA >85 ng/mL,
0 otherwise) + 1.58 (1 if HA <3.5 g/dL,
0 otherwise) + 1.78 (1 if AST >60 IU/L,
0 otherwise)
−0.007 plt (G/L) − 0.049 PI (%) + 0.012
AST (IU/L) + 0.005 α2-MC (mg/dL) +
0.021 HA (μg/L) − 0.270 urea (mmol/L)
+ 0.027 age (years) + 3.718
y/1 + y, where y = exp [−4.185818
− (0.0249 × age) + (0.7464 × sex) +
(1.0039 × α2-MC) + (0.0302 × HA) +
(0.0691 × bilirubin) − (0.0012 × γGT)]
>0.8 ≈ Ishak ≥3
<0.3 ≈ Ishak ≤2
≥F2
≥0.5 ≈ F2–F4
<0.5 ≈ F0–F1
Primary endpoints of the studies that evaluated surrogate markers vary
from discrimination of no ibrosis and cirrhosis to the determination of
the stages of ibrosis. With the occurrence of the new antiviral treatment
options for HCV patients that allow the treatment even in decompensated
patients with advanced cirrhosis, the detection of ibrosis in HCV patients
has become a less relevant clinical information. However, in areas with
limited treatment access where treatment is prioritised the determination
of advanced ibrosis stages may guide the decision of whom to treat irst.
In addition patients with liver cirrhosis need continuous monitoring
even ater viral elimination due to an increased risk of the occurrence of
hepatocellular carcinoma.
From the whole range of surrogate markers only a few are in broad
clinical use. The simple APRI score has been widely studied in HBV and
HCV as well as in co-infected patients (Cacoub 2008, Lebensztejn 2005,
Vallet-Pichard 2008, Wai 2006). A comprehensive meta-analysis of the
performance of the APRI test showed that its major strength is the exclusion
of signiicant ibrosis, deined as F2-F4, or cirrhosis with cut-ofs of 0.5 and
1.5, respectively. Importantly, the test performance varied with the quantity
of advanced ibrosis in the diferent patient groups (Shaheen 2007 & 2008).
Fibrotest has also achieved some clinical signiicance. However, this
test may not be available for all patients. Meta-analyses of the predictive
performance of Fibrotest summarise that the reliability for the detection
of advanced ibrosis or cirrhosis is adequate for clinical practice, and a cutof of 0.6 has been suggested (Poynard 2007, Shaheen 2007 & 2008). Of
note, the reliability for the detection of earlier ibrosis stages appears to be
relatively low (Poynard 2007, Shaheen 2008).
It has to be pointed out that the performance of these markers difers
among liver diseases. For instance, a study evaluating indirect markers in
>2,000 patients with chronic liver diseases detected a higher accuracy for
detecting signiicant ibrosis in HCV patients than in NALFD (Sebastian
2011). A comprehensive paper reviewing the diagnostic accuracy of
surrogate markers of ibrosis in HCV patients from 172 studies concluded
that these tests based on diferent biomarkers are equally efective in
diagnosing cirrhosis (Chou 2013). Combinations of diferent scores may be
more efective in avoiding biopsies.
Non-invasive markers have potential value beyond the prediction of
ibrosis. Surrogate markers and in particular elastography techniques
have been evaluated for the prediction of liver-related complications and
mortality. A number of studies aimed to test composite scores in this context
for a variety of liver diseases such as PBC, alcoholic liver disease or HCV
as well as mixed cohorts, describing AUOCs of 0.73 - 0.86 for mortality
prediction (Mayo 2008, Naveau 2009, Parkes 2010, Vergniol 2011).
In summary, surrogate markers may support the clinical decision
making process, but a single surrogate marker or score cannot replace liver
biopsy. On the other hand, attempts have been made to combine diferent
surrogate markers and biopsy in clinical decision algorithms that aim to
reduce the need for liver biopsy.
Ultrasound-based elastography
Several methods for ultrasound-based elastography of the liver have
been developed. These methods can be subdivided into two categories. The
readouts of these measurements are either kPa or m/s, or both. Transient
elastography has been available and evaluated since 2005, whereas the
other technologies have become commercially available thereater. Hence,
transient elastography is the most common elastography method today
but the success in non-invasive evaluation of liver ibrosis obviously has
stimulated others manufacturers of ultrasound machines to promote their
own speciic technology. However, although similar in read-outs, not all
speciic machines have been evaluated in detail.
1. Shear wave speed techniques and readout values*
• Transient elastography (Fibroscan, Echosens)
· kPa
• Point shear wave speed measurement
Virtual touch tissue quantiication (ARFI, Siemens)
· m/s (kPa, calculated)
ElastPQ (Philips)
· kPa
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• Shear wave speed imaging (Supersonic)
· m/s or kPa
2. Strain/displacement techniques
• Strain elastography (colour coded, Hitachi)
Initially elastography was used to assess liver ibrosis stages without
the need for biopsy and to exclude cirrhosis. Over time clinicians and
researchers broadened the application and tried to answer more questions
using elastography:
• Prediction of liver related complications (HCC, portal hypertension,
mortality)
• Monitoring progression or regression of liver disease
• Screening for patients with increased liver stifness in the normal
population
Transient elastography
Transient elastography (TE) is a non-invasive technique to assess
liver ibrosis (Sandrin 1999). TE allows the assessment of liver ibrosis by
calculating the velocity of a low-frequency transient shear wave produced
by a mechanical probe that is placed directly on the skin of the patient. The
velocity of the wave that penetrates the liver tissue depends on the stifness of
the liver, which in turn cor relates with the extent of liver ibrosis. In practice,
a probe is placed in an intercostal space at a position that is comparable to
the position for standard liver biopsy. Ten successful measurements are
usually necessary for the assessment of liver stifness. This can be done in
less than 5 minutes. At present TE machines are exclusively available from
Echosens (FibroScan®). Liver stifness is expressed in kilo Pascal (kPa). The
method is easy to learn and quick, results are available immediately, and a
technical assistant can perform the procedure. In most studies, TE displays
robust intra- and inter-observer variability (Fraquelli 2007) and may be
used in children as well as adults (de Ledinghen 2007).
Normal liver stifness
Evaluation of liver stifness in subjects without apparent liver disease
shows that liver stifness is inluenced by sex and body mass index (BMI).
In general, liver stifness is higher in men than in women (5.8±1.5 vs. 5.2±1.6
kPa) and in obese vs. non-obese (6.5±1.6 vs. 5.3±1.5 kPa). (Roulot 2008).
Interestingly, TE may be used as a screening tool for the general population
to identify patients with unrecognised liver disease (Ginès 2016, Roulot 2011).
Taken together one might say that liver stifness values < 7.5 kPa appear
to relect the normal range, i.e. the absence of advanced liver ibrosis
(Castera 2008, Ferraioli 2015).
Confounding factors
Common sources of false interpretation of results (usually elevated
liver stifness measurements) have been identiied and should be taken
into account when setting up TE measurements in clinical routine (Table3).
Acute liver injury such as acute viral or alcoholic hepatitis, or chronic
viral hepatitis lares can lead to overestimation of liver ibrosis (Arena
2008, Coco 2007, Sagir 2008). Other interfering conditions include cardiac
failure, Valsalva manoeuvre, pulmonary hypertension, amyloidosis,
pregnancy, cholestasis, or steatosis, with the latter being more relevant in
HCV than in HBV (Arena 2008, Fraquelli 2007). Another relevant artefact
is the examination of a patient within 2 hours ater a meal, which increases
resistance by up to 2 kPa (Mederacke 2009). However, this efect was not
observed using CAP for the detection of steatosis (Silva 2019). Special probes
have been developed to overcome problems with measurements in children
and in obese patients (“S-probe”, “XL-probe”) (Engelmann 2011).
Table 3. Reasons and conditions for unreliable TE measurements
Confounder Countermeasure Comment
Obesity
(BMI >30 kg/m
Age >52 years
Steatosis Relevant only in HCV
Non-fas ting Re-measure after 3–6 h fasting
Cardiac failure Reassessment after cardiac
High necroinflammatory
activity (AST/ALT ratio)
Ascites Use other non-invasive
Cholestasis Decompression Stiffness reduction in
2
)
Use XL probe Cut-offs may be slightly
lower with XL probe
patients
period
recompensation
Reassessment after cessation of
inflammatory flare
procedures such as ARFI, SSI or
MR elastography, or re-measure
after complete paracentesis
PSC is incomplete after
stenting, but changes
in stiffness during
long-term follow-up are
associated with severity
of fibrosis and outcomes
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