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17. A ssessment of hepatic fibrosis and steatosis
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Reliability
Common quality criteria applied to certify an acceptable quality of TE
measurements are: 10 successful measurements with >60% successful
measurements and an interquartile range (IQR)/median (M) ratio <0.30.
However, the relevance of these criteria has been questioned, and a threecategory classiication system of reliability has been suggested: “very
reliable” (IQR/M ≤0.10), “reliable” (0.10<IQR/M≤0.30, or IQR/M >0.30 with
median liver stifness <7.1 kPa), and “poorly reliable” (IQR/M >0.30 with
median liver stifness ≥7.1 kPa). Applying these categories to the clinical
endpoint “cirrhosis” leads to the correct classiication of 90.4%, 85.8% and
69.5% patients, respectively (Boursier 2012). In a large overview of 12,000
examinations 4% of measurements with the M-probe were not successful,
and 17% were rated as unreliable (Castera 2010). Multivariate assessment
of factors responsible for failure or unreliability were obesity and limited
operator experience. Interestingly, not BMI in general but a lipohypertrophy
in the thoracic belt in particular was the limiting factor for the success rate.
It is important to note that the applicability of TE is limited to relatively
lean patients (BMI <28 kg/m2), patients without ascites, and “cooperative”
patients. The special “XL-probe” for obese patients has broadened the
applicability of TE and is recommended for patients with a skin-capsule
distance of >2.5 cm (but below 3.5 cm) (Myers 2011). Sequential use of Mand XL-probes show that XL-probes tend to produce higher stifness
measurement values in the same patient as compared to the M-probe, thus
the former probes may overestimate liver stifness in these patients.
Unlike liver histology, no published data is available on the variability
(“sampling error”) of TE results. TE correlates well with other surrogate
markers of liver ibrosis such as APRI and FIB-4 (Vidovic 2010). In patients
with chronic liver disease eligible for TE, liver stifness values correlate
with the stage of ibrosis, irrespective of the underlying disease aetiology.
TE has been evaluated in patients with chronic viral hepatitis, PBC, PSC,
NASH, haemochromatosis, and Wilson disease. Due to high acceptance
by patients, it can easily be used to monitor progression or regression of
ibrosis in patients under observation or on therapy (Wilson 2006, Wong
2011). TE has been evaluated for the detection of liver ibrosis in patients
with acute and chronic viral hepatitis and has also been positively evaluated
for HCV/HIV-coinfected patients and in patients with HCV recurrence
posttransplantation (Carrion 2006, de Ledinghen 2006, Maida 2007).
resulting in moderate negative predictive values. Thus, the assessment of
liver ibrosis by TE alone may result in the underestimation of liver ibrosis
in some patients. Vice versa, if TE predicts signiicant ibrosis, a biopsy will
not be necessary.
An authoritative meta-analysis that evaluated the predictive performance
of TE in patients with chronic liver disease suggested that the optimal cutof value for the diagnosis of signiicant ibrosis is 7.65 kPa and 13.0 kPa for
cirrhosis (Friedrich-ust 2008). For chronic liver diseases other than HCV
the speciic cut-of values for cirrhosis are 11.7 kPa in HBV, 10.3 kPa in nonalcoholic fatty liver disease, 17.9 kPa in biliary liver diseases, and 22.7 kPa
in alcoholic liver disease if drinking and 12.5 kPa if abstinent (Trapper 2015).
A meta-analysis of the performance of TE in patients with alcoholic
liver disease is less enthusiastic about the exactness of TE in this context
and suggests to use both TE and liver biopsy sequentially in some cases to
establish the correct ibrosis stage in all patients; the authors stress the
importance of TE in ruling out cirrhosis or advanced ibrosis rather than
deining exact ibrosis stages (Pavlov 2015).
Apparently diferent diseases have somewhat diferent cut-ofs.
However, rather than using ixed cut-ofs the application of TE in a more
continuous manner and follow-up procedure to assess changes in liver
stifness (Castera 2008). Whereas liver stifness values >12.5 kPa are highly
suggestive for advanced liver ibrosis or cirrhosis, patients with lower
values (<7.5 kPa) are unlikely to sufer from advanced disease. Intermediate
patients may qualify for liver puncture to clarify ibrosis stage if not
answered by other non-invasive procedures.
Since the amount of data for TE and diferent liver disease etiology
is continuously rising, we summarize available cut-ofs and potential
diagnostic consequences for clinicians in Table 4.
Cut-ofs for liver ibrosis
Studies comparing TE with liver biopsy demonstrate both high sensitivity
and speciicity for the detection of advanced ibrosis and cirrhosis. However,
TE performance is less reliable for the detection of ibrosis stages ≥F2 as
compared to more advanced stages of liver ibrosis (sensitivity 56-67%),
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17. A ssessment of hepatic fibrosis and steatosis
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Table 4. Staging of liver fibrosis according to liver stiffness measurements in TE
Disease Cut-of f Diagnosis Consequence /
References
comment
Chronic hepatitis
C virus infection
HI V/HC V
co-infection
Chronic hepatitis
B virus infection
Chronic hepatitis
D virus infection
Non-alcoholic
fatt y liver
disease
Alcohol-related
liver disease
Primary biliary
cholangitis
6.8 - 7.6 kPa Risk of F2 - F4 Antiviral therapy
13.1 kPa F4 Check for portal
≥ 7.1 kPa
≥ 12.5 kPa
6.6 - 8.8 kPa
> 11.7 kPa
> 14.0 kPa Cirrhosis HDV-infected
< 7.9 kPa
≥ 9.3 kPa
14.3 kPa
(M-probe)
16.8 kPa
(XL-pro be)
7.0 kPa
9.0 kPa
12.1 k Pa
18.6 kPa
7.1 k P a
8.8 kPa
10.7 kPa
16.9 kP a
<20 kPa
and platelets
>150,000/
mm
≥ F2
F4
≥ F2
F4
Rules out F3
fibrosis with
90% sensitivity
and specificity
High risk of F3
fibrosis with
90% sensitivity
and specificity
F4 Screen for
≥ F1
≥ F2
≥ F3
F4
≥ F1
≥ F2
≥ F3
F4
No need for
screening for
esophageal
varices
Liver biopsy
hyper tension HCC
screening
TE outperforms APRI
and FT
patients tend to have
higher TE values due
to higher necroinflammatory activity
M-probe with significantly lower cut-offs
than XL-probe
complications
In subjects with F0-F2
fibrosis, the rates of
false-positive LSM
results for F3-F4
fibrosis increased
according to CAP
tertiles (7.2% in lower
versus 16.6% in
middle versus 18.1%
in higher)
12.1 kPa in patient s
with AST < 38 IU/L
and bilirubin < 9
µmol/L
25.9 kPa in patients
with AST > 75 IU/L
and biliurbin > 16
µmol/l
Cut-off of 2.1 kPa
per year was associated with an 8.4-fold
increased risk of liver
decompensation, liver
transplantation, or
death
Talwalkar 2007
Nahon 2008
Friedrich-Rust
2008
Castera 2014
Chon 2012
Xu 2015
Da 2019
Wong 2010
Oeda 2 019
Pet ta 2017
Nguyen-Khac
2018
Corpechot 2012
MoctezumaVelazque 2019
Disease Cut-of f Diagnosis Consequence /
References
comment
Primary sclerosing cholangitis
Autoimmune
hepatitis
Haemochromatosis
Wilson disease ≥ 9.9 - 10.1
Cystic fibrosis
(CF)-associated
liver disesae
Screening 9.1 kPa
Portal
hypertension
HCC > 25 kPa > 45-fold
7.4 kPa
8.6 kPa
9.6 kPa
14.4 kPa
5.8 kPa
10.4 kPa
16.0 kPa
<6.4 kPa Rules out
kPa
≥ 5.2 - 5.95
kPa
9.5 k Pa
> 25 kPa High risk for
≥ F1
≥ F2
≥ F3
= F4
≥ F2
≥ F3
Cirrhosis
significant
fibrosis
Cirrhosis Adult population Paternostro
Suspicion of
CF-associated
liver diseases
≥ F2 in general
population
≥ F2 in
patients at risk
for alcohol-related liver
disease
varices
increase for
risk of developing HCC in
viral hepatitis,
but increased
risk start s at
10.0 kPa
Progression rate > 1.3
kPa per year is associated with decreased
survival
Treatment response
and fibrosis regression may be monitored by TE
Limited prospective
data
Liver stiffness is
higher at diagnosis
and decreases with
treatment
Combination with
APRI may yield higher
diagnostic value
Screening with TE is
cost-effective
Endoscopy screening
for varices
HCC screening Masuzaki 2009
Corpechot 2014
Har tl 2016
Legros 2015
2020
Karlas 2012
Stefanescu 2016
Lam 20 19
Serra-Buriell
2019
Castera 2011
Robic 2012
Fung 2011
Incremental increase of liver stiffness is associated with worse prognosis
Elastography may be used for monitoring stifness changes over time.
Rather than focusing at a given stifness at a certain time point clinicians
may use stifness measurements for monitoring changes in liver stifness.
Studies highlighted that the consecutive increase of liver stifness is related
with higher mortality and liver-related events such as variceal bleeding or
hepatic encephalopathy, especially in patients with liver stifness >12.5kPa
(Perrez-Latorre 2016, Vergiol 2014).
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Monitoring treatment with TE
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TE may be used to monitor changes in liver stifness following either
the natural course or changes in stifness on and ater treatment. Whereas
in the irst scenario prediction of disease progression rates may be useful,
the latter relects the regression of inlammation and/or ibrosis. The
longitudinal monitoring of patients with chronic HBV and HCV infections
but also Wilson disease has documented reduction in liver stifness upon
treatment response (Andersen 2011, Fung 2011, Hezode 2011).
Correlation of liver stiffness with complications and outcome
In addition to the assessment of liver ibrosis stages, TE might be used to
predict the presence of portal hypertension (Rockey 2008). Of note, a cutof value of >25 kPa has been associated with a >45-fold increased risk of
developing HCC in viral hepatitis. However, the risk seems to increase in a
linear fashion start ing from 10 kPa (Fung 2011, Masuzaki 2009). Furthermore,
TE values >21kPa are associated with portal hypertension as well as the risk
of portal hypertension-related complications and indicate that endoscopy
is indicated to assess oesophageal varices as well as the need for primary
prophylaxis with non-selective β-blockers (Castera 2011, Robic 2011).
Combination of non-invasive tests
A combination of non-invasive tests in the form of surrogate markers,
elastography methods or both have the potential of reducing the number
of biopsies, lead priorisation strategies for treatment and surveillance and
predict morbidity and mortality. Despite a number of studies in this ield
we currently do not have a deinite algorithm that is widely accepted in
clinical practice. However, the WHO highlights the combination of APRI,
FIB-4 and TE in order to identify patients at risk and to start treatment in
HCV-infected patients (WHO 2014).
The current EASL guidelines for the use of non-invasive assessment of
liver ibrosis suggest a number of distinct algorithms for diferent liver
disease. The proposed algorithm for HCV patients is shown in Figure 1.
The basic principle is that TE is combined with a serum marker test for
liver ibrosis. Concordant results may reduce the need for biopsy while
inconclusive results may be a reason for biopsy. The experience of the
authors of this chapter is however that for the sake of determining the
stage of liver ibrosis it is hardly ever necessary to perform biopsy unless
other information is needed (e.g., evidence for autoimmune hepatitis);
furthermore, patients are reluctant to undergo biopsy due to the widespread
information on non-invasive alternatives.
17. A ssessment of hepatic fibrosis and steatosis
Figure 1. Assessment of liver fibrosis in chronic hepatitis C (EASL 2015)
Acoustic radiation force imaging (ARFI) and shear wave
imaging (SSI)
Besides TE as the primary tool, shear wave technology to assess liver
ibrosis, ARFI and SSI have now been more intensively studied for the
assessment of ibrosis, cirrhosis and complications. ARFI and SSI both
use a region of interest that can be adapted by the investigator. ARFI is
implemented in Philips and Siemens ultrasound machines. Ideally, the
region of interest (10×5 mm) is set 1-2 cm below the liver capsule. As in TE,
ten sequential measurements are performed and the interquartile range is
used to assess the accuracy of ibrosis evaluation. Although ARFI and SSI
can be used in obese patients and patients with ascites, there is a subgroup
of patients in whom reliable results may not be obtained (Cassinotto 2014),
comprising up to 3% in ARFI cohorts and up to 11% in SSI studies (Cassinotto
2014). A recent meta-analysis reported that the accuracy for the prediction
of ibrosis stages ≥F2, ≥F3 and cirrhosis were 0.87, 0.91 and 0.93, respectively
(Friedrich-ust 2012). A recently published head-to-head analysis
comparing TE with ARFI showed comparable results for both methods
(Colombo 2012). However, ARFI was less prone to methodological failure
than TE. Both methods seem reliable for the detection of advanced ibrosis
(Colombo 2012, Rizzo 2011, Sporea 2012). As with TE, many procedure- and
patient-related factors may inluence test results, in particular increased
stifness during hepatitis lares (Chen 2012, Karlas 2011).
Another shear wave-based technology has recently been introduced
for the diagnosis of liver ibrosis (real-time SSI by Supersonic Imaging),
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17. A ssessment of hepatic fibrosis and steatosis
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combining TE stifness calculations with the possibility of deining regions
of interest as in ARFI. While this method has not yet been widely used, early
studies show a comparable diagnostic accuracy compared to TE (Ferraioli
2012a, Ferraioli 2012b). The comparison of all three methods (ARFI, TE,
SSI) with liver biopsy in patients with fatty liver disease did not reveal
substantial diferences although SSI may be more reliable in the diagnosis
of >F4 ibrosis in these cases but no diferences between SSI and TE or ARFI
and TE have been reported in this context. Interestingly in this patient
cohort the cut-ofs were very close for SSI and TE and substantially lower
than for patients with chronic viral hepatitis (6.3/6.2 kPa for ≥F2, 8.3/8.2 kPa
for ≥F3, and 10.5/9.5 kPa for F4, respectively) (Cassinotto 2015). In principle
these results were conirmed in unselected cases of patients with chronic
liver disease (Gerber 2015).
Concerning data on correlation with histological ibrosis stages,
TE, ARFI and SSI all sufer from the same limitations with overlapping
ranges of stifness results for individual ibrosis stages. However, they
all seem adequate in detecting the presence of ibrosis and cirrhosis.
Numerous comparisons have been made in order to detect an advantage
of one machine over another. In the end none of these studies identiied
substantial diferences for choosing one method over the other. A detailed
critical review on available ultrasound methods with all pros and cons of
each single methods has been published recently and is recommended for
further reading (Ferriaioli 2015).
Computational methods may improve the speciity and sensitivity for
the diagnosis of liver ibrosis stages. For 2D-Shear wave elastography a
neuronal network was applied and predictions were compared to histology
stages. This approach may maximise sen sitivity and speciicity (Wang 2018),
but predictions for lower ibrosis stages were not as markedly improved as
for advanced ibrosis. These techniques highlight the potential of smart
computer algorithms (“artiicial intelligence”) to support non-invasive
assessment of liver phenotypes.
Other imaging techniques for the assessment of liver fibrosis
A number of diferent imaging techniques such as conventional
ultrasound, real-time elastography, portal venous transit time, M imaging
have been used for the assessment of liver ibrosis. None of these methods
has yet achieved an overall clinical acceptance regarding the assessment of
liver ibrosis, either due to low sensitivity and/or speciicity, or high costs.
Clinical decision algorithms
Non-invasive markers for the staging of liver ibrosis are at the edge of
replacing liver histology as the gold standard, at least in hepatitis C. This is
due to the fact that outcome studies with clear endpoints like mortality are
available (Vergniol 2011, Pakres 2010, Naveau 2009, Mayo 2008) or under
investigation (NCT01241227, NCT02037867 and others). The advantages
of these non-invasive tests in comparison to liver biopsy are striking.
In order to overcome test limitations and to beneit from their speciic
advantages, a frequent strategy is to combine diferent non-invasive tests,
using liver biopsy only in case of doubt. However, algorithms vary greatly
in performance and acceptance. Whereas some authors have estimated a
reduction in liver biopsies of 30%, others have estimated reductions of up to
80% (Leroy 2007, Sebastiani 2004, Sebastiani 2006, Sebastiani 2007). New
strategies with sophisticated algorithms may overcome these limitations
and a combination of TE with FibroMeter give results that may be detailed
and reliable on liver ibrosis stage without any need for histology. However,
only one study from France has described this method, which needs to be
cross-validated by independent groups (Boursier 2011a, Boursier 2011b).
Population based screening for advanced liver fibrosis
Patients not being in regular care are diagnosed in late stages when liver
decompensation or liver cancer develops. The diagnosis is rarely made in
early stages-when liver ibrosis is mild to moderate but cirrhosis is not yet
established-because the disease is asy mptomatic. Liver biopsy is not a suitable
procedure for population-based screening for ibrosis and/or fatty liver but
non-invasive methods might be. A comprehensive survey on the frequency
of liver ibrosis in population-based studies revealed progressive disease in
up to 25.7% of participants (Harris 2017). In a population-based screening
study using transient elastography, prevalence estimates of increased liver
stifnesss (≥ 6.8, ≥ 8.0, and 9.0 kPa) were 9.0%, 5.8%, and 3.6%, respectively.
Elastography was more accurate than alanine aminotransferase, NAFLD
ibrosis score, or FIB-4 (Caballería 2018). The minimum acceptable accuracy
of non-invasive tests to diagnose cirrhosis with equivalence to liver biopsy
depends on cirrhosis mortality and prevalence (Majumdar 2019): At 5%
and 20% cirrhosis prevalence, sensitivities and speciicities are 89% and
88%, and 94% and 85%, respectively (if the physician found it acceptable to
subject 20 patients to biopsy to ind one correct case with cirrhosis). Using
these criteria, TE alone and TE plus FibroTest are the only existing tests that
were better than or equal to biopsy at diagnosing cirrhosis at 5% prevalence
(Majumdar 2019). In a recent cost-efectiveness guided approach it could
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17. A ssessment of hepatic fibrosis and steatosis
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be demonstrated that a 9.1 kPa TE cut-of provided the best accuracy for
the diagnosis of signiicant ibrosis (≥ F2) in general population settings,
whereas a threshold of 9.5 kPa was optimal for populations at-risk of
alcohol-related liver disease. TE with the proposed cut-ofs outperformed
ibrosis scores in terms of accuracy. Screening with TE was cost-efective
with mean incremental cost-efectiveness ratios ranging from 2,570 €/
QALY (95% CI 2,456-2,683) for a population at-risk of alcohol-related liver
disease (age ≥45 years) to 6,217 €/QALY (95% CI 5,832-6,601) in the general
population. Overall, there was a 12% chance of TE screening being cost
saving across countries and populations (Serra-Burriel 2019).
Non-alcoholic fatty liver disease
Nowadays virus-induced chronic liver diseases can be efectively
treated by well tolerated antiviral drug regimens, but the epidemic of nonalcoholic fatty liver disease (NAFLD) demonstrates an exponential increase
in burden of disease. The mechanisms contributing to hepatic steatosis
and the development of an inlammatory state with progression to liver
disease are under intense investigation. Patients with NAFLD, in particular
with non-alcoholic steatohepatitis (NASH), sufer from an increased risk of
advancing to progressive liver disease with ibrosis, eventually resulting in
cirrhosis and the need for liver transplantation.
The challenges for the development non-invasive diagnostic strategies
are:
1. to detect steatosis
2. to distinguish an indolent steatotic from the necoinlammatory
state in NASH
3. to determine the stage of damage measured as ibrosis
As for liver ibrosis serological markers either as single markers
or combined in scores are being evaluated in comparison to liver
histopathology. It is debated whether non-invasive tests are comprehensive
for the detection and classiication of disease severity of NAFLD (Bedossa
2018; Castera 2018). It can be expected that non-invasive techniques will
play a more important role in the diagnostic work-up of patients with fatty
liver disease.
Serological markers of steatosis in NAFLD are also being evaluated.
Similarly to the history of non-invasive ibrosis assessment, attempts
are made to established steatosis-speciic markers and scores that aim to
diagnose steatosis by the combination of diferent parameters with more or
less speciicity for steatosis and inlammation in fatty liver disease.
Studies also aim to distinguish the necoinlammatory state, i.e. NASH,
from simple steatosis. A comprehensive review on this topic has been
published by Vilar-Gomez and Chalasani (Vilar-Gomez 2018). Examples of
speciic markers for NAFLD/NASH are cytokeratin 18 and ibroblast growth
factor 21, which are released into the circulation in response to oxidative
stress, hepatocyte apoptosis and inlammation. However, a recent metaanalysis came to the conclusion that current non-invasive tests do not
accurately diferentiate NASH from simple steatosis (Verhaegh 2018).Further
eforts are needed to identify more sensitive and speciic markers and scores.
As for liver ibrosis, several studies aim to increase the diagnostic
accuracy by combining diferent tests in NAFLD. In the case of NAFLDassociated ibrosis, the sequential use of liver stifness measurement, NFS
and FIB-4 has led to an improvement of correct classiication. However, the
best combination and sequence of makers is yet to be deined (Petta 2017). In
the current German guideline, two scores that combine a number of factors
have been included (Table 5). The guideline has also suggested an algorithm
for the diagnostic work up of NAFLD (which needs more evaluation). It
concludes that non-invasive steatosis assessment may be done by applying
the FLI or MRI criteria. For the assessment of advanced ibrosis in NAFLD,
the NFS score is applicable.
https://www.dgvs.de/wissen-kompakt/leitlinien/
leitlinien-der-dgvs/nash/
Whereas the detection of liver ibrosis via TE is hampered by multiple
factors, this may also be the case for serum markers of NAFLD. For instance,
it could be shown that the NAFLD ibrosis score (and the FIB-4 score) is
inaccurate, especially in patients aged 65+ (McPherson 2017). This may
explain the results of a recent meta-analysis (Verhaegh 2018) that showed
that the majority of non-i nvasive markers have no suicient d iagnostic value
to reliably discriminate steatosis and NASH. As in liver ibrosis authors aim
to further increase the diagnostic accuracy by combining diferent tests in
fatty liver disease. In the case of liver ibrosis in NAFLD, the sequential use
of liver stifness measurement, NFS and FIB-4 lead to better classiication.
However, the best combination and sequence of markers is yet to be deined
(Petta 2017).
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17. A ssessment of hepatic fibrosis and steatosis
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Table 5. Non-comprehensive list of serological marker indices of steatosis
Index Variables Formula for calculation Interpretation
Fatty liver
Index (FLI)
NAFLD
fibrosis score
(NFS)
Plt = platelets
BMI, GGT,
triglycerides,
waist
circumference
Age, BMI,
diabetes,
AST, ALT, plt,
albumin
(e
0.953*loge (triglycerides)
+ 0.139*BMI + 0.718*loge
(GGT) + 0.053*waist
circumference - 15.745)
0.953*loge
/ (1 + e
(triglycerides) + 0.139*BMI
+ 0.718*loge (ggt) +
0.053*waist circumference
- 15.745) * 100
−1.675 + 0.037 × age
(years) + 0.094 × BMI (kg/
2
) + 1.13 × IFG/diabetes
m
(yes = 1, no = 0) + 0.99 ×
AST/ALT ratio − 0.013 ×
platelets (×109/l) − 0.66 ×
albumin (g/dL).
Cut off <30: Likelihoodratio (LR) of 0.2 with a
sensitivity of 82% that
no steatosis is present
Cut off had specificity
of 86 % and positive LR
of 4.3 that steatosis is
present
Cut off < -1.455:
Absence of significant
fibrosis (93% certainty)
Cut off > 0.676
Presence of significant
fibrosis (90% certainty)
Can elastography reliably assess ibrosis in these patients and what are
the precautions we need to consider?
Up to date there is no conclusive evidence that increased liver stifness
is a good predictor for the presence and severity of lipid storage in the
liver in patients suspected of NAFLD. In addition, TE and other shear
wave elastography methods can reliably predict cirrhosis (F4: sensitivity
92%, speciicity 92%), but the detection of early ibrosis stages appears to
be limited (Kwok 2014). Finally, elastography is not a reliable tool to detect
necroinlammatory changes in the liver.
Controlled Attenuation Parameter (CAP)
strictly selected patient population deined as a “health check-up” cohort, a
higher upper limit of normal of 288 dB/m was deined, which may be due to
the inclusion of patients with diabetes (Chon 2014). A recent study deined
histopathological categories of liver steatosis (S) grades (S0: ≤10%, S1: 11 – 33%,
S2: 34 – 66%, S3: ≥67%) and correlated these with CAP results. Using receiver
operating statistics, the authors deined cut-ofs with a sensitivity >90% for
all grades of steatosis (215 dB/m for S ≥1, 252 dB/m for S ≥2, 296 dB/m for S3) (de
Ledinghen 2012). In patients with chronic hepatitis C, corresponding cut-of
values of 222 dB/m, 233 dB/m and 29 0 dB/m were identiied for discrim inating
the steatosis grades (Sasso 2012).
As with TE, CAP results are also inluenced by multiple factors and vary
with the cause of the disease (de Ledinghen 2014). A recent meta-analysis
focused on the confounders of high CAP values and found that besides
NAFLD, diabetes and BMI are independently inluencing CAP values. The
authors also point out that the inluence of these confounders may change
according to the prevalence of steatosis in the studied population. According
to their results in 2,735 patients, they determined the following cut-ofs
for >S0, >S1 and >S2: 248, 268, and 280 dB/m, respectively (Karlas 2017).
In contrast to TE, CAP measurements seem not to be inluenced by recent
meals.
Summary
Non-invasive tests have still not completely replaced liver biopsies,
but smart combinations of non-invasive tools avoid this more invasive
procedure in many patients. Whatever the current standard of care, the
patient should be informed about the non-invasive tests, their applicability,
and their limitations. The decision to perform a liver biopsy should
ultimately be made together with the informed patient.
Liver fat content has been historically assessed by ultrasound using
a semi-quantitative estimate or by liver histology. Steatosis is a growing
problem whether in the context of non-alcoholic steatohepatitis or as a
co-factor in the metabolic syndrome and other liver diseases. Until recently
reliable quantitative measures of the degree of steatosis were missing. A novel
tool to overcome this diagnostic gap may be CAP. This analysis is available in
TE machines from Echosens that measure the attenuation of the intensity of
the echo from the ultrasound signal in the liver (available for the M-probe
and the XL-probe). It is calculated only for reliable TE measurements and
does not lengthen the TE procedure. The measurement is expressed in dB/m.
Korean investigators deined a normal upper range of 266 dB/m in potential
liver donors, all with histology proven fat contents <5%. However, in a less
410 411
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18. Diagnosis, prognosis &
https://t.me/medicina_free
therapy of hepatocellular
carcinoma
Ulrich Spengler
Classification of HCC
Tumours are classiied to stratify patients with respect to their survival
prognosis, in order to select and ofer optimised therapeutic options at any
tumour stage. For hepatocellular carcinoma (HCC) the Barcelona Clinic Liver
Cancer (BCLC) clas siication has been adopted as the international standard,
which is recommended by both the American Association for the Study of
Liver Diseases (AASLD) and the European Association for the Study of the
Liver (EASL) (Table 1). The BCLC classiication takes into account several
aspects of the disease: the patient’s general state of health, the severity of
the liver disease as well as the extent of tumour spread (Llovet 1999). Patients
in stages BCLC O and A have a considerably better prognosis than patients
in advanced stages of liver cancer (Mazzaferro 1996). But roughly only 25%
of patients with liver cancer are diagnosed at an early stage. Both EASL
(EASL 2012) and AASLD guidelines provide recommendations regarding
which therapy is best suited to treat patients at each stage of the BCLC
classiication. Unlike classiication schemes in other types of malignancies,
the BCLC classiication is particularly helpful because it is entirely based on
clinical parameters – molecular characteristics are not yet able to reliably
assess individual prognosis of patients with HCC.
The BCLC classiication seems to assess prognosis less accurately in
Asian patients, where hepatitis B is a prevailing cause of liver cancer. An
alternative classiication, the Hong Kong Liver Cancer Staging System
(HKLC), has been proposed recently, which had signiicantly better
ability in Asian patients to distinguish subgroups with speciic overall
survival times (Yau 2014). Importantly HKLC identiied subsets of
patients with intermediate and advanced stages of liver cancer, who might
beneit from more aggressive therapy (resection in intermediate stage,
chemoembolisation in advanced stage). Nevertheless thus far, the HKLC
classiication is based exclusively on retrospective data from Asian patients
in a single centre and still awaits conirmation by prospectively controlled
studies and in non-Asian patients.
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18. Diagnosis, prognosis & therapy of hepatocellular carcinoma
https://t.me/medicina_free
Table 1. Barcelona Clinic Liver Cancer (BCLC) Classification
Tumour stage General state of health Tumour characteristics Child stage
0 Very early Good Single nodule <2 cm A & B
A Early Good Single nodule <5 cm,
3 nodules <3 cm
B Intermediate Good Large, multiple nodules A & B
C Advanced Reduced Vascular invasion,
extrahepatic secondaries
D Terminal Severely reduced Any form C
A & B
A & B
The Cancer of the Liver Italian Program (CLIP) has derived another
widely used prognostic tool for HCC. The CLIP score combines features of
macroscopic tumour morphology (unimodular versus multimodular with
limited extension < 50% versus massive with extension > 50%), serum
alpha-fetoprotein (AFP <400 ng/mL versus > 400 ng/mL), the Child-Pugh
stage, and the presence of portal vein thrombosis to determine a prognostic
score ranging from 0 -6 (Anonymus 2000). Patients with advanced HCC and
low serum levels of vascular endothelial growth factor (VEGF) or high levels
of insulin-like growth factor I (IGF-1) have better survival at each disease
state than those with serum levels in the opposite range. Thus, VEGF and
IGF-1 can been added to the CLIP score as an additional component referred
to as V-CLIP or I-CLIP, respectively (Kaseb 2011a and 2011b).
The latest prognostic classiication combines serum albumin and
bilirubin alone (the ALBI score) and provides an easy-to-use, objective
and discriminatory method for assessing liver functions in patients with
HCC. Its validity has been conirmed in geographically distinct cohorts of
patients with HCC either undergoing liver surgery for localised disease and
sorafenib treatment for advanced disease (Johnson 2015).
Epidemiology
HCC constitutes the ith most frequent form of cancer worldwide, and
it holds the second place in malignancy-related mortality (Jemal 2011).
Incidence and death rates of HCC are steadily rising in most parts of the
world (about 2-3% per year). It occurs two to six times more frequently in
men than in women. The key risk for HCC is liver cirrhosis, approximately
80% of which are related to hepatitis B and C on a global scale.
Chronic hepatitis B is the major risk factor for developing HCC in Africa
and Asia, while in the US, Europe and Japan chronic hepatitis C, alcohol
and non-alcoholic steatohepatitis (NASH) are leading causes of HCC. Eighty
percent of liver cancers are found in cirrhotic livers, which themselves
carry a high risk for HCC. Chronic carriers of hepatitis B virus (HBV) have
a 100-fold increased risk as compared to a non-infected healthy reference
population. Recent reports from Taiwan indicate a direct link between HBV
viral loads and the risk of developing liver cancer within 10 years (Chen
2006, Iloeje 2006). The risk of HCC is signiicantly increased once HBV-DNA
exceeds 2000 IU/mL irrespective of the degree of hepatic inlammation.
Quantitative HBsAg ≥1000 IU/mL is a further biomarker of increased HCC
risk in patients with low or intermediate levels of HBV-DNA (Tseng 2013).
The risk to develop HCC is higher in infection with HBV genotype C than B
and also in infection with genotype D than A. Co-infection with HCV and
HDV and/or exposure to environmental toxins such as alatoxins and the
algal toxin microcystin in drinking water further increase the risk of HCC.
Approximately 70 million people are infected with the hepatitis C virus
worldwide, 20 to 30% of whom will develop liver cirrhosis, which carries a
3-5% annual risk of ultimately progressing to liver cancer. Unlike hepatitis
B, a close relationship between HCV-RNA and the risk of developing HCC
apparently does not exist (Bralet 2000). As a general rule patients will
not develop liver cancer in chronic hepatitis C before their disease has
progressed to advanced ibrosis and cirrhosis (Lok 2009). It appears that
the risk of HCV-induced HCC related to the degree of inlammation and
necrosis, while HBV-related HCC does not correlate well with inlammation
and seems rather to involve activation of speciic oncogenes by the virus.
Consumption of alcohol or tobacco enhances the risk of HCC (Donato
2002, Gelatti 2005). Beyond that, obesity (Calle 2003) and diabetes mellitus
(Davila 2005) must be considered pivotal risk factors that can independently
lead to liver cancer in Western countries and resu lt in 4- to 40-fold increased
HCC rates among patients with chronic viral hepatitis (Starley 2010). In
patients with steatohepatitis, liver cancer can occur before cirrhosis has
developed. Importantly, the risk of HCC is substantially reduced in diabetic
patients who are treated with metformin (Lai 2012).
Finally, certain heriditary diseases such as haemochromatosis
and alpha1-antitrypsin deiciency predispose to HCC. Also genetic
polymorphisms in the adiponutrin gene (rs 738409 C>G), in the KIF1B gene
(rs 17401966), and the MICA gene (rs 2596542) seem to predispose patients
with alcoholic and non-alcoholic fatty liver disease, chronic HBV and HCV
infection, respectively, to develop cirrhosis and HCC (Fallet 2011, Nischalke
2011, Trepo 2013, Zhang 2010, Kumar 2011).
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