Book on hepatitis from page 328 to 337

Book on hepatitis from page 328 to 337

328  Hepatology 2012
patient procedures, since >90% of complications are detected within the first 24
hours (Piccinino 1986).
Transjugular puncture of the liver via cannulation of a hepatic vein is an
alternative, which can be performed in patients with severe coagulation deficiencies.
It is resource intensive and carries a risk of intrahepatic hemorrhage or capsule
perforation with intraabdominal bleeding. Complication rates are lower as compared
to percutaneous biopsies and range from 2.5% (Mammen 2008) to 6.5% with a
reported mortality rate of up to 0.09% in high-risk groups (Kalambokis 2007).
However, the quality of specimens from transjugular biopsies may be lower because
of the higher fragmentation of specimens and the lower numbers of portal fields in
transjugular biopsies (Cholongitas 2006).
Laparoscopy and mini-laparoscopy are even more invasive procedures  for
obtaining liver biopsies. A recent randomized trial showed a higher detection rate of
liver cirrhosis as compared to percutaneous biopsies with lower complication rates
for laparoscopy (Denzer 2007). No data is available for detection of lesser fibrosis
stages. Thus, we recommend this procedure only in selected cases if the results will
have an impact on the clinical management of the patient (Helmreich-Becker 2003).
The quality and reliability of fibrosis staging via histopathological assessment of
liver biopsy specimens depends largely on the size of the specimen and the number
of portal fields. The biopsy should be 20-25 mm long and more than 11 portal tracts
should be visible (Bedossa 2003, Cholongitas 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 reflects about 1/50,000 of the whole
liver. Thus, liver biopsies are particularly prone to sampling errors and may – like
non-invasive markers – have difficulties in discriminating between adjacent stages
of fibrosis (i.e., F1 vs. F2 or F2 vs. F3). Recent studies report up to one stage
difference between specimens from the right and the left lobe in up to 38% of
biopsies (Regev 2002, Siddique 2003). Discrepancies of more than one stage are
rare (Regev 2002,  Siddique 2003,  Skripenova 2007). Intra-  and inter-observer
variability may be unaffected by specimen sizes but can lead to discrepancies in up
to 20% of cases, even if one stage difference between estimates is accepted
(Gronbaek 2002, Petz 2003). Standardized automatic staging via image analysis
may improve interobserver variability (Hui 2004, Calvaruso 2009).
All staging systems for liver fibrosis are based on the definition of categorical
stages of liver fibrosis that describe the increase of deposition of collagen and the
progressive destruction of liver architecture ranging from no fibrosis to cirrhosis
with a variable number of intermediate stages (Table 1). The use of categories
decreases interobserver variation, but also results in a loss of information that may
be covered by more detailed scoring systems (Standish 2006).
Whereas the METAVIR score is considered best in HCV fibrosis, there is a wide
variability in the use of other staging systems in patients with chronic viral hepatitis.
In Germany, current guidelines recommend the staging system defined by Desmet
& Scheuer (Table 1) (Batts 1995,  Desmet 1994,  Ishak 1995,  Knodell 1981,
Schirmacher 2004, French Cooperative Study Group 1994).
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  329
Table 1. Commonly used liver fibrosis staging scores.
Staging System  Fibrosis stages  Remark
METAVIR Score  F0, F1, F2, F3, F4 Best evaluated in
HCV fibrosis
(The French METAVIR
Cooperative Study Group
1994)
Knodell Score  F0, F1, F3, F4  No intermediate
stage
(Knodell 1981)
Desmet
& Scheuer
Analogous to
METAVIR
Recommended by
German
guidelines for the
assessment of
liver fibrosis
(Desmet 1994, Schirmacher
2004)
Batts & Ludwig  Similar to METAVIR    (Batts 1995)
Ishak Score  F0, F1, F2, F3, F4,
F5, F6
(Ishak 1995)
Surrogate markers of liver fibrosis in chronic viral
hepatitis
Liver fibrosis 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 makers can be subdivided into direct and
indirect markers. Direct markers reflect changes in the content of extracellular
matrix proteins (such as collagen) in the liver. In contrast, indirect markers reflect
alterations in hepatic function, increase in portal hypertension with subsequent
splenic enlargement, and/or grade of hepatic inflammation that may correlate with
liver fibrosis stage (Table 2)  (see http://hepatologytextbook.com/link.php?id=7).
Direct and indirect markers may be used alone or -  more commonly -  in
combination (“composite scores”). The calculation of such scores can be simple or
based on complicated formulas (e.g., Fibrotest/Fibrosure) (Table 2). Most studies of
non-invasive markers were performed in HCV patients, while studies in HBV or
coinfected cohorts are sparse (Pinzani 2008). Primary endpoints of the studies that
evaluated surrogate markers vary from discrimination of no fibrosis and cirrhosis to
the determination  of fibrosis stages. However, for the clinical management of
patients with chronic viral hepatitis both are needed. Whereas the former is needed
to identify patients in need of urgent treatment, the latter may separate those patients
with an indication for antiviral treatment due to significant fibrosis from those with
no or minor fibrosis in whom treatment may be postponed.
From the whole range of surrogate markers only a few are in clinical use. The
simple APRI score has been widely studied in HCV and HBV  as well as in
coinfected patients (Cacoub 2008, Lebensztejn 2005, Vallet-Pichard 2008, Wai
2006). A recent comprehensive meta-analysis of the performance of the APRI test
showed that its major strength is the exclusion of significant fibrosis, defined as F2-F4, or cirrhosis with cut-offs of 0.5 and 1.0, respectively. However, the authors
conclude that using this marker alone, only about one third of all biopsies can be
avoided. Importantly, the test performance varied with the quantity of advanced
fibrosis in the different patient groups (Shaheen 2007, Shaheen 2008). Fibrotest has
also achieved some clinical significance. However, this test may not be available for
all patients. Recent meta-analyses of the predictive performance of Fibrotest
330  Hepatology 2012
summarize that the reliability for the detection of advanced fibrosis or cirrhosis is
adequate for clinical practice, and a cut-off of 0.6 has been suggested (Poynard
2007, Shaheen 2008, Shaheen 2007). Of note, the reliability for the detection of
earlier fibrosis stages appears to be relatively low (Poynard 2007, Shaheen 2008). In
summary, surrogate markers may support the clinical decision making process, but a
single surrogate marker or score cannot replace the liver biopsy. On the other hand,
attempts have been made to combine different surrogate markers and biopsy in
clinical decision algorithms that aim to reduce the need for liver punctures (Table
2). Increasingly efforts are made to combine surrogate markers with transient
elastography, and it seems that some progress can be expected in precise prediction
of different fibrosis stages, which may eventually replace liver biopsy for fibrosis
staging.
Transient elastography
Transient elastography (TE) is a non-invasive technique to assess liver fibrosis
(Sandrin 1999). TE allows the assessment of liver fibrosis 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 actual stiffness of the liver, which in turn
correlates with the extent of liver fibrosis. 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 stiffness. This can be done in less than 5 minutes. At present TE machines are
exclusively available from Echosense (FibroScan
®
). Liver stiffness is expressed in
kilo Pascal (kPa). The method is easy to learn, quick, results are available
immediately, and a technical assistant can perform the procedure. TE displays
robust intra- and inter-observer variability (Fraquelli 2007) and may be applied in
children and adults (de Ledinghen 2007). Recently a special S probe for testing
children and patients with small intercostals spaces was introduced, and normal
reference values for different ages were defined (Engelmann 2011).
Evaluation of liver stiffness in subjects without apparent liver disease shows that
liver stiffness is influenced by gender and body mass index (BMI). In general, liver
stiffness is higher in men than in women (5.81±1.54 vs. 5.23±1.59 kPa) (Roulot
2008). Interestingly, TE may be used as a screening tool for the general population
to identify patients with unrecognized liver disease (Roulot 2011).
It is important to note that the applicability of TE is limited to relatively lean
patients (BMI <28 kg/m
2
), patients without ascites, and “cooperative” patients. A
special probe for obese patients has recently broadened the applicability of TE and
is recommended for patients with a skin-caspular distance of >2.5 cm but below 3.5
cm (Myers 2011). In addition, TE is hampered in those with acute liver injury such
as acute viral or alcoholic hepatitis, or chronic viral hepatitis flares, which may lead
to an overestimation of liver fibrosis (Arena 2008, Coco 2007, Sagir 2008). 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 fibrosis such
as APRI and FIB-4 (Vidovic 2010). In patients with chronic liver disease eligible
for TE, liver stiffness values correlate well with the stage of fibrosis, irrespective of
the underlying disease etiology. TE has been evaluated in patients with chronic viral
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  331
hepatitis, PBC, PSC, and NASH. Due to high acceptance by patients, it can easily
be used to monitor progression or regression of fibrosis in patients under
observation or on therapy (Wilson 2006, Wong 2011). TE has been evaluated for
the detection of liver fibrosis in patients with acute and chronic viral hepatitis and
has also been positively evaluated for HIV/HCV-coinfected patients and in patients
with HCV reccurrence post-transplantation (Carrion 2006,  de Ledinghen 2006,
Maida 2007). In chronic viral hepatitis, it is unknown whether there is a difference
in TE results between patients with chronic HBV, HCV, and/or HIV/HCV-coinfected patients.
In some clinical situations, e.g., older patients or patients with risk factors for
therapy, a positive decision for treatment of chronic hepatitis B and C is guided by
the diagnosis of significant fibrosis. The presence of F2 fibrosis indicates significant
liver fibrosis, which justifies treatment according to treatment guidelines for chronic
hepatitis B, C and coinfected patients (Sarrazin 2010).
Recent studies comparing TE with liver biopsy demonstrate both high sensitivity
and specificity for the detection of advanced fibrosis and cirrhosis. However, TE
performance is less reliable for the detection of fibrosis stages ≥2 as compared to
more advanced stages of liver fibrosis (sensitivity 56-67%), resulting in moderate
negative predictive values. Thus, assessment of liver fibrosis by TE alone may
result in the underestimation of liver fibrosis in some patients. Vice versa, if TE
predicts significant fibrosis, a biopsy will not be necessary. One drawback in
clinical practice is that the different TE studies suggest slightly different cut-off
values (Table 3). A recent meta-analysis that evaluated the predictive performance
of TE in patients with chronic liver disease suggested that the optimal cut-off value
for the diagnosis of significant fibrosis is 7.65 kPa and 13.01 kPa for cirrhosis
(Friedrich-Rust 2008). This cut-off proved to be robust, especially in patients with
chronic HCV infection.
In addition to the assessment of liver fibrosis stages, TE may also be used to
predict the presence of portal hypertension and thus the need to evaluate the patient
for the presence of esophageal varices (Rockey 2008). Whether TE is reliable
enough to predict the stage of cirrhosis is still debatable and needs further studies
(Foucher 2006).
Increasing knowledge from studies on transient elastography also revealed a
number of conditions that may produce false positive results the user should be
aware of. These conditions include acute and chronic cardiac failure, valsalva
maneuver, hepatitis flair, pulmonary hypertension, amyloidosis, cholestasis,
pregnancy and steatosis, with the latter being more relevant for HCV than for HBV-infected patients (Fraquelli 2007, Arena 2008).
Another relevant artifact is the examination of a patient within 2 hours after a
meal, which may increase resistance by up to 2 kPa (Mederacke 2009).
The spectrum of interpretation of elevated TE results has been broadened
recently. For instance, a cut-off value of >25 kPa has been associated with >45-fold
increased risk to develop HCC in viral hepatitis. However, the risk seems  to
increase in a linear fashion starting from a cut-off of 10 kPa (Fung 2011, Masuzaki
2009). Furthermore, TE values >21.1 are associated with portal hypertension as well
as the risk of portal hypertension-related complications and suggest endoscopy to
confirm or exclude esophageal varices and to initiate or decline the need for primary
prophylaxis with propranolol (Castera 2011, Robic 2011).
332  Hepatology 2012
Table 3. Cut-off values for transient elastography in different study populations.
Study  Population  Cut off (kPa)
F=0  F≥1  F≥2  F≥3  F=4
Castera  HCV
N=183
n.d.  n.d.  7.1
Se: 0.67
Sp: 0.95
PPV: 0.95
NPV: 0.48
9.5
Se: 0.73
Sp: 0.91
PPV: 0.87
NPV: 0.81
12.5
Se: 0.87
Sp: 0.91
PPV: 0.77
NPV: 0.97
Ziol  HCV
N=327
n.d.  n.d.  8.8  9.6  14.6
n.d.  n.d.
Se: 0.56
Sp: 0.91
PPV: 0.88
NPV: 0.56
Se: 0.86
Sp: 0.85
PPV: 0.71
NPV: 0.93
Se: 0.86
Sp: 0.96
PPV: 0.78
NPV: 0.97
Foucher  HCV / HBV
N=711
n.d.  n.d.  7.2
Se: 0.64
Sp: 0.85
PPV: 0.90
NPV: 0.52
12.5
Se: 0.65
Sp: 0.95
PPV: 0.90
NPV: 0.80
17.6
Se: 0.77
Sp: 0.97
PPV: 0.91
NPV: 0.92
Ogawa  HCV / HBV
N=229
3.5  6.4  9.5
Se: 0.67
Sp: 0.95
PPV: .95
NPV: .48
11.4
Se: 0.67
Sp: 0.95
PPV: .95
NPV: .48
15.4
Se: 0.67
Sp: 0.95
PPV: .95
NPV: .48
6.3  6.7  9.1
Se: 0.67
Sp: 0.95
PPV: 0.95
NPV: 0.48
13.7
Se: 0.67
Sp: 0.95
PPV: 0.95
NPV: 0.48
26.4
Se: 0.67
Sp: 0.95
PPV: 0.95
NPV: 0.48
Arena  HCV
N=150
7.8
Se: 0.83
Sp: 0.82
PPV: 0.83
NPV: 0.79
10.8
Se: 0.91
Sp: 0.94
PPV: 0.89
NPV: 0.95
14.8
Se: 0.94
Sp: 0.92
PPV: 0.73
NPV: 0.98
De
Ledinghen
HIV/HCV
N=72
n.d.  n.d.  4.5
Se: 0.93
Sp: 0.18
PPV: n.d.
NPV: n.d.
n.d.  11.8
Se: 1.0
Sp: 0.93
PPV: n.d.
NPV: n.d.
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  333
Other imaging techniques for the
assessment of liver fibrosis
A number of different imaging techniques such as conventional ultrasound, real-time elastography, acoustic radiation force imaging (ARFI), portal venous transit
time, NMR imaging and CT have been used for the assessment of liver fibrosis.
None of these methods has yet achieved an overall clinical acceptance regarding the
detection of early liver fibrosis, either due to low sensitivity and/or specificity, or
high costs. The most promising candidate for everyday usability may be the ARFI
technique that has been integrated in high-end ultrasound machines. This technique
allows the measurement of liver fibrosis in an area of interest rather than a global
assessment as with the transient elastography method. This may be an advantage as
different regions of the liver may be studied separately but may – like histology –
also be a source of “sampling bias” and low reproducability. Compared to transient
elastography the available data from large populations is sparse. A recent meta-analysis managed to combine data from 518 individuals. Nevertheless, in this
analysis the overall accuracy for the prediction of fibrosis stage ≥F2, ≥F3 and
cirrhosis as determined by ROC analysis were 0.87, 0.91. 0.93, respectively
(Friedrich-Rust 2012).
Clinical decision algorithms
Until now, no non-invasive marker for the staging of liver fibrosis has been able to
replace the liver histology as the gold standard. This is largely due to the fact that
outcome studies with clear endpoints like mortality have not been performed and
that a clear differentiation of fibrosis stage by non-invasive strategies has been
unreliable. But the advantages of these non-invasive tests in comparison to liver
biopsy are striking. In order to overcome test limitations and to benefit from their
specific advantages, a frequent strategy is to combine different noninvasive tests,
thereby using liver biopsy only in case of doubt. However, former algorithms vary
greatly in performance and acceptance. Whereas some authors have calculated 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 all these limitations and combination
of TE with FibroMeter achieved results that may give detailed and reliable
information on liver fibrosis 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).
334  Hepatology 2012
Figure 1. Potential clinical decision algorithm for safer liver biopsies in patients
with chronic viral hepatitis.
Summary
Non-invasive tests have not replaced liver biopsies today, but smart combinations of
non-invasive tools can save many patients from the more invasive procedure.
Whatever the current standard of care, the patient should be informed about the non-invasive tests, their applicability and their limitations. The decision to biopsy should
ultimately be made together with the informed patient.
References
Arena U. Acute viral hepatitis increases liver stiffness values measured by transient
elastography. Hepatology 2008;47:380-4.
Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg
Pathol 1995;19:1409-17. (Abstract)
Bedossa P, Carrat F. Liver biopsy: the best, not the gold standard. J Hepatol 2009;50:1-3.
(Abstract)
Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C.
Hepatology 2003;38:1449-57. (Abstract)
Boursier J, de Ledinghen V, Zarski JP, Fouchard-Hubert I, Gallois Y, Oberti F, Cales P.
Comparison of 8 diagnostic algorithms for liver fibrosis in hepatitis C: New algorithms
are more precise and entirely non-invasive. Hepatology 2011a. Epub ahead of print.
Boursier J, de Ledinghen V, Zarski JP, Rousselet MC, Sturm N, Foucher J, et al. A new
combination of blood test and fibroscan for accurate non-invasive diagnosis of liver
fibrosis stages in chronic hepatitis C. Am J Gastroenterol 2011b;106:1255-63.
(Abstract)
Cacoub P, Carrat F, Bedossa P, Lambert J, Penaranda G, Perronne C, et al. Comparison of
non-invasive liver fibrosis biomarkers in HIV/HCV co-infected patients: The fibrovic
study - ANRS HC02. J Hepatol 2008;48:765-73. (Abstract)
Calvaruso V, Burroughs AK, Standish R, Manousou P, Grillo F, Leandro G, et al. Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic
venous pressure gradient. Hepatology 2009;49:1236-44. (Abstract)
Carrion JA, Navasa M, Bosch J, Bruguera M, Gilabert R, Forns X. Transient elastography for
diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C
recurrence after liver transplantation. Liver Transpl 2006;12:1791-8. (Abstract)
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  335
Castera L, Pinzani M, Bosch J. Non Invasive Evaluation of Portal Hypertension Using Transient
Elastography. J Hepatol 2011. Epub ahead of print. (Abstract)
Cholongitas E, Senzolo M, Standish R, Marelli L, Quaglia A, Patch D, et al. A systematic review
of the quality of liver biopsy specimens. Am J Clin Pathol 2006;125:710-21. (Abstract)
Coco B, Oliveri F, Maina AM, Ciccorossi P, Sacco R, Colombatto P, et al. Transient
elastography: a new surrogate marker of liver fibrosis influenced by major changes of
transaminases. J Viral Hepat 2007;14:360-9. (Abstract)
de Ledinghen V. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in
HIV/hepatitis C virus co-infected patients. J Acquir Immune Defic Syndr 2006;41:175-9. (Abstract)
de Ledinghen V, Le Bail B, Rebouissoux L, Fournier C, Foucher J, Miette V, et al. Liver
stiffness measurement in children using FibroScan: feasibility study and comparison
with Fibrotest, aspartate transaminase to platelets ratio index, and liver biopsy. J
Pediatr Gastroenterol Nutr 2007;45:443-50. (Abstract)
Denzer U, Arnoldy A, Kanzler S, Galle PR, Dienes HP, Lohse AW. Prospective randomized
comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis
and complications. J Clin Gastroenterol 2007;41:103-10. (Abstract)
Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis:
diagnosis, grading and staging. Hepatology 1994;19:1513-20. (Abstract)
DiMichele DM, Mirani G, Wilfredo Canchis P, Trost DW, Talal AH. Transjugular liver biopsy is
safe and diagnostic for patients with congenital bleeding disorders and hepatitis C
infection. Haemophilia 2003;9:613-8. (Abstract)
Engelmann G, Gebhardt C, Wenning D, Wuhl E, Hoffmann GF, Selmi B, et al. Feasibility study
and control values of transient elastography in healthy children. Eur J Pediatr 2011.
(Abstract)
Foucher J, Chanteloup E, Vergniol J, Castera L, Le Bail B, Adhoute X, et al. Diagnosis of
cirrhosis by transient elastography (FibroScan): a prospective study. Gut
2006;55:403-8. (Abstract)
Fraquelli M, Rigamonti C, Casazza G, Conte D, Donato MF, Ronchi G, Colombo M.
Reproducibility of transient elastography in the evaluation of liver fibrosis in patients
with chronic liver disease. Gut 2007;56:968-73. (Abstract)
Fraquelli M, Rigamonti C, Casazza G, Donato MF, Ronchi G, Conte D, et al. Etiology-related
determinants of liver stiffness values in chronic viral hepatitis B or C. J Hepatol
2011;54:621-8. (Abstract)
Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.
Physiol Rev 2008;88:125-72. (Abstract)
Friedman SL, Rockey DC, Bissell DM. Hepatic fibrosis 2006: report of the Third AASLD Single
Topic Conference. Hepatology 2007;45:242-9. (Abstract)
Friedrich-Rust M, Nierhoff J, Lupsor M, Sporea I, Fierbinteanu-Braticevici C, Strobel D, et al.
Performance of Acoustic Radiation Force Impulse imaging for the staging of liver
fibrosis: a pooled meta-analysis. J Viral Hepat 2012;19:e212-e9. (Abstract)
Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, Herrmann E.
Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134:960-74. (Abstract)
Fung J, Lai CL, Seto WK, Wong DK, Yuen MF. Prognostic significance of liver stiffness for
hepatocellular carcinoma and mortality in HBeAg-negative chronic hepatitis B. J Viral
Hepat 2011;18:738-44. (Abstract)
Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver
diseases. J Hepatol 2007;47:598-607. (Abstract)
Gronbaek K, Christensen PB, Hamilton-Dutoit S, Federspiel BH, Hage E, Jensen OJ, Vyberg
M. Interobserver variation in interpretation of serial liver biopsies from patients with
chronic hepatitis C. J Viral Hepat 2002;9:443-9. (Abstract)
Helmreich-Becker I, Schirmacher P, Denzer U, Hensel A, Meyer zum Buschenfelde KH, Lohse
AW. Minilaparoscopy in the diagnosis of cirrhosis: superiority in patients with Child-Pugh A and macronodular disease. Endoscopy 2003;35:55-60. (Abstract)
Hui AY, Liew CT, Go MY, Chim AM, Chan HL, Leung NW, Sung JJ. Quantitative assessment of
fibrosis in liver biopsies from patients with chronic hepatitis B. Liver Int 2004;24:611-8. (Abstract)
Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F,, et al. Histological grading and
staging of chronic hepatitis. J Hepatol 1995;22:696-9. (Abstract)
336  Hepatology 2012
Kalambokis G, Manousou P, Vibhakorn S, Marelli L, Cholongitas E, Senzolo M, et al.
Transjugular liver biopsy--indications, adequacy, quality of specimens, and
complications--a systematic review. J Hepatol 2007;47:284-94. (Abstract)
Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and
application of a numerical scoring system for assessing histological activity in
asymptomatic chronic active hepatitis. Hepatology 1981;1:431-5.
Lebensztejn DM, Skiba E, Sobaniec-Lotowska M, Kaczmarski M. A simple noninvasive index
(APRI) predicts advanced liver fibrosis in children with chronic hepatitis B.
Hepatology 2005;41:1434-5. (Abstract)
Leroy V. Prospective comparison of six non-invasive scores for the diagnosis of liver fibrosis in
chronic hepatitis C. J Hepatol 2007;46:775-82. (Abstract)
Maida I, Soriano V, Barreiro P, Rivas P, Labarga P, Nunez M. Liver fibrosis stage and HCV
genotype distribution in HIV-HCV coinfected patients with persistently normal
transaminases. AIDS Res Hum Retroviruses 2007;23:801-4. (Abstract)
Mammen T, Keshava SN, Eapen CE, Raghuram L, Moses V, Gopi K, et al. Transjugular liver
biopsy: a retrospective analysis of 601 cases. J Vasc Interv Radiol 2008;19:351-8.
(Abstract)
Masuzaki R, Tateishi R, Yoshida H, Goto E, Sato T, Ohki T, et al. Prospective risk assessment
for hepatocellular carcinoma development in patients with chronic hepatitis C by
transient elastography. Hepatology 2009;49:1954-61. (Abstract)
Mederacke I, Wursthorn K, Kirschner J, Rifai K, Manns MP, Wedemeyer H, Bahr MJ. Food
intake increases liver stiffness in patients with chronic or resolved hepatitis C virus
infection. Liver Int 2009;29:1500-6. (Abstract)
Myers RP, Fong A, Shaheen AA. Utilization rates, complications and costs of percutaneous
liver biopsy: a population-based study including 4275 biopsies. Liver Int 2008;28:705-12. (Abstract)
Myers RP, Pomier-Layrargues G, Kirsch R, Pollett A, Duarte-Rojo A, Wong D, Beaton M,
Levstik M, Crotty P, Elkashab M. Feasibility and diagnostic performance of the
fibroscan xl probe for liver stiffness measurement in overweight and obese patients.
Hepatology 2011. Epub ahead of print.
Petz D, Klauck S, Rohl FW, Malfertheiner P, Roessner A, Rocken C. Feasibility of histological
grading and staging of chronic viral hepatitis using specimens obtained by thin-needle biopsy. Virchows Arch 2003;442:238-44. (Abstract)
Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver
biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol 1986;2:165-73. (Abstract)
Pinzani M. Fibrosis in chronic liver diseases: diagnosis and management. J Hepatol
2005;42:S22-36. (Abstract)
Pinzani M, Vizzutti F, Arena U, Marra F. Technology Insight: noninvasive assessment of liver
fibrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol
Hepatol 2008;5:95-106. (Abstract)
Poynard T, Morra R, Halfon P, Castera L, Ratziu V, Imbert-Bismut F, et al. Meta-analyses of
FibroTest diagnostic value in chronic liver disease. BMC Gastroenterol 2007;7:40.
(Abstract)
Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error
and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J
Gastroenterol 2002;97:2614-8. (Abstract)
Robic MA, Procopet B, Metivier S, Peron JM, Selves J, Vinel JP, Bureau C. Liver stiffness
accurately predicts portal hypertension related complications in patients with chronic
liver disease: A prospective study. J Hepatol 2011. (Abstract)
Rockey DC. Noninvasive assessment of liver fibrosis and portal hypertension with transient
elastography. Gastroenterology 2008;134:8-14. (Abstract)
Roulot D, Costes JL, Buyck JF, Warzocha U, Gambier N, Czernichow S, et al. Transient
elastography as a screening tool for liver fibrosis and cirrhosis in a community-based
population aged over 45 years. Gut 2011;60:977-84. (Abstract)
Roulot D, Czernichow S, Le Clesiau H, Costes JL, Vergnaud AC, Beaugrand M. Liver stiffness
values in apparently healthy subjects: Influence of gender and metabolic syndrome. J
Hepatol 2008;48:606-13. (Abstract)
Rousselet MC, Michalak S, Dupre F, Croue A, Bedossa P, Saint-Andre JP, Cales P. Sources of
variability in histological scoring of chronic viral hepatitis. Hepatology 2005;41:257-64. (Abstract)
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  337
Sagir A, Erhardt A, Schmitt M, Haussinger D. Transient elastography is unreliable for detection
of cirrhosis in patients with acute liver damage. Hepatology 2008;47:592-5. (Abstract)
Sandrin L, Catheline S, Tanter M, Hennequin X, Fink M. Time-resolved pulsed elastography
with ultrafast ultrasonic imaging. Ultrason Imaging 1999;21:259-72. (Abstract)
Sarrazin C, Berg T, Ross RS, Schirmacher P, Wedemeyer H, Neumann U, et al. [Prophylaxis,
diagnosis and therapy of hepatitis C virus (HCV) infection: the German guidelines on
the management of HCV infection]. Z Gastroenterol;48:289-351. (Abstract)
Schirmacher P, Fleig WE, Dienes HP. [Biopsy diagnosis of chronic hepatitis]. Z Gastroenterol
2004;42:175-85. (Abstract)
Schwarz KB, Zellos A, Stamato L, Boitnott J, Perlman E, Chong S, Casella JF. Percutaneous
liver biopsy in hemophiliac children with chronic hepatitis C virus infection. J Pediatr
Gastroenterol Nutr 2008;46:423-8.
Sebastiani G. Stepwise combination of algorithms of non-invasive markers to diagnose
significant fibrosis in chronic hepatitis C. J Hepatol 2004;44:686-93. (Abstract)
Sebastiani G, Alberti A. Non invasive fibrosis biomarkers reduce but not substitute the need for
liver biopsy. World J Gastroenterol 2006;12:3682-94. (Abstract)
Sebastiani G, Vario A, Guido M, Alberti A. Sequential algorithms combining non-invasive
markers and biopsy for the assessment of liver fibrosis in chronic hepatitis B. World J
Gastroenterol 2007;13:525-31. (Abstract)
Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio
index for the prediction of hepatitis C-related fibrosis: a systematic review.
Hepatology 2007;46:912-21. (Abstract)
Shaheen AA, Myers RP. Systematic Review and Meta-Analysis of the Diagnostic Accuracy of
Fibrosis Marker Panels in Patients with HIV/Hepatitis C Coinfection. HIV Clin Trials
2008;9:43-51. (Abstract)
Shaheen AA, Wan AF, Myers RP. FibroTest and FibroScan for the prediction of hepatitis C-related fibrosis: a systematic review of diagnostic test accuracy. Am J Gastroenterol
2007;102:2589-600. (Abstract)
Siddique I, El-Naga HA, Madda JP, Memon A, Hasan F. Sampling variability on percutaneous
liver biopsy in patients with chronic hepatitis C virus infection. Scand J Gastroenterol
2003;38:427-32. (Abstract)
Skripenova S, Trainer TD, Krawitt EL, Blaszyk H. Variability of grade and stage in simultaneous
paired liver biopsies in patients with hepatitis C. J Clin Pathol 2007;60:321-4.
(Abstract)
Standish RA, Cholongitas E, Dhillon A, Burroughs AK, Dhillon AP. An appraisal of the
histopathological assessment of liver fibrosis. Gut 2006;55:569-78. (Abstract)
Terjung B, Lemnitzer I, Dumoulin FL, Effenberger W, Brackmann HH, Sauerbruch T, Spengler
U. Bleeding complications after percutaneous liver biopsy. An analysis of risk factors.
Digestion 2003;67:138-45. (Abstract)
TFMCSG. Intraobserver and interobserver variations in liver biopsy interpretation in patients
with chronic hepatitis C. The French METAVIR Cooperative Study Group.
Hepatology 1994;20:15-20. (Abstract)
Vallet-Pichard A, Mallet V, Pol S. Predictive value of FIB-4 versus fibrotest, APRI,
FIBROINDEX and FORNS to noninvasively estimate fibrosis in hepatitis C.
Hepatology 2008;47:762-3. (Abstract)
van der Poorten D, Kwok A, Lam T, Ridley L, Jones DB, Ngu MC, Lee AU. Twenty-year audit of
percutaneous liver biopsy in a major Australian teaching hospital. Intern Med J
2006;36:692-9. (Abstract)
Vidovic N, Lochowsky RS, Goldmann G, Rockstroh J, Wasmuth JC, Spengler U, et al.
Correlation of transient elastography with APRI and FIB-4 in a cohort of patients with
congenital bleeding disorders and HCV or HIV/HCV coinfection. Haemophilia
2010;16:778-85. (Abstract)
Wai CT, Cheng CL, Wee A, Dan YY, Chan E, Chua W, et al. Non-invasive models for
predicting histology in patients with chronic hepatitis B. Liver Int 2006;26:666-72.
(Abstract)
Wilson LE, Torbenson M, Astemborski J, Faruki H, Spoler C, Rai R, et al. Progression of liver
fibrosis among injection drug users with chronic hepatitis C. Hepatology 2006;43:788-95. (Abstract)
Wong GL, Wong VW, Choi PC, Chan AW, Chim AM, Yiu KK, et al. On-treatment monitoring of
liver fibrosis with transient elastography in chronic hepatitis B patients. Antivir Ther
2011;16:165-72. (Abstract)