With further research, these and other non-invasive
imaging techniques may reduce the need for
biopsies--procedures done to obtain a tissue sample--to
determine the presence and severity of fibrosis and
cirrhosis.
Two of the three new papers evaluated
techniques of elastography--tests that evaluate
reactions to ultrasound vibrations or energy waves as a
means of measuring the elasticity or stiffness of the
liver tissue. Lower elasticity (or higher stiffness)
corresponds to increased fibrosis or scarring. When
fibrosis becomes severe, it signals the presence of
cirrhosis
Dr. Jayant A. Talwalkar and colleagues of Mayo Clinic
College of Medicine, Rochester, Minn., analyzed the
current evidence on ultrasound-based transient
elastography--the approach that has received the most
research attention to date. Based on data from 18
previous studies, the ultrasound test was highly
accurate in identifying patients with cirrhosis, defined
as severe (stage IV) fibrosis of the liver. About 90
percent of patients with cirrhosis were correctly
identified by ultrasound-based transient elastography.
The test was somewhat less accurate in detecting
less-severe fibrosis.
Because the studies used
differing cutoff points, the analysis could not
establish the true accuracy of this emerging technology.
The researchers highlight the need for additional
high-quality studies including patients with liver
fibrosis ranging from mild to severe.
Dr. Meng Yin and colleagues, also of Mayo Clinic
College of Medicine, evaluated a different approach to
measuring liver elasticity/stiffness: MR elastography.
Although the principle is the same as with the
ultrasound technique, MR elastography measures reactions
to mechanical shear waves, rather than ultrasound
vibrations.
The researchers performed MR elastography in 50
patients with chronic liver disease and 35 normal
volunteers. The test was nearly 100 percent accurate in
identifying patients with any degree of liver fibrosis,
including those with mild fibrosis. With further study,
Dr. Yin and colleagues believe MR elastography could be
a useful initial test for fibrosis--avoiding the
discomfort and risks of liver biopsy for many patients,
while potentially increasing the reliability of
diagnosis.
Dr. Chen-Hua Liu and colleagues of National Taiwan
University Hospital, Taipei, evaluated a different
ultrasound technique for measuring fibrosis. Using
widely available duplex Doppler ultrasound equipment,
they measured the characteristics of blood flow in the
vessels in and around the liver in patients with chronic
hepatitis C--an increasingly important cause of fibrosis
and cirrhosis.
The results showed that a specific measure of blood
flow in the spleen--the splenic artery pulsatility index
(SAPI)--was highly accurate in identifying fibrosis and
cirrhosis. The authors believe that, with further study,
the SAPI could also be a useful indicator of
fibrosis/cirrhosis in other groups of patients with
kidney disease.
Cirrhosis and related complications are responsible
for over 40,000 deaths per year in the United States,
with direct health care costs of more than $1 billion.
Several trends are likely to produce further increases
in death and disease from cirrhosis, including the aging
of the population; the epidemic of obesity, which leads
to nonalcoholic fatty liver diseases; and the emergence
of liver disease among patients with chronic hepatitis
C.
Traditionally, liver biopsy has been the "gold
standard" technique for diagnosing fibrosis and
cirrhosis. However, in addition to pain and a risk of
bleeding and other complications, liver biopsy is a
costly technique that is prone to sampling errors. The
new non-invasive imaging techniques may provide a useful
new set of tools not only for diagnosing liver fibrosis
and cirrhosis, but also for evaluating the effectiveness
of new treatments for early-stage fibrosis.
"Application of current imaging modalities may help
to define the presence of cirrhosis and even fibrosis in
patients with suspected liver disease," commented Dr. C.
Mel Wilcox, Editor of CGH. "Using Doppler ultrasound and
MRI, these investigators found these modalities to be
accurate and reproducible in detecting fibrosis and
cirrhosis. Look for more studies using these
non-invasive imaging studies, and perhaps others in the
future."
Adapted from materials provided by
Elsevier, via
EurekAlert!, a service of AAAS.
http://www.sciencedaily.com/releases/2007/10/071001092211.htm
New Index for Assessing Liver Fibrosis
By Liz Highleyman
A study of
non-invasive alternatives to
liver biopsy for assessing
fibrosis has concluded that a series of simple blood tests can
accurately diagnose the condition, according to a report in the February
2007 issue of Hepatology.
Fibrosis, the
formation of fibrous scar tissue in the liver, typically indicates
progressive damage, and can progress to
liver cirrhosis. Determining the stage of fibrosis is important for
people with chronic hepatitis C since it can help guide decisions about
treatment. While liver biopsy is considered the "gold standard" for
assessing
liver disease, it is uncomfortable and expensive, prompting
researchers to develop non-invasive methods.
Japanese
researchers conducted a study of 402 chronic hepatitis C patients who
underwent liver biopsy between April 1994 and March 2004; those with
pre-existing cirrhosis were excluded. Blood samples were collected
within 3 days of the biopsies, and the investigators identified
routinely measured markers associated with fibrosis progression. The
resulting index was then test in a group of 30 patients who underwent a
second biopsy more than 1 year after treatment with interferon-based
therapy.
Results
•
Based on the original 402 subjects, the researchers identified 3
markers as independent predictors of fibrosis, collectively dubbed "FibroIndex":
- platelet count;
-
aspartate aminotransferase (AST);
- gamma-globulin (a type of antibody).
•
The areas under the receiver operating characteristic curves (AUROCs)
of FibroIndex for predicting significant fibrosis were 0.83 and
0.82.
•
FibroIndex was more accurate in predicting significant or severe
fibrosis than the Forns index or the AST-to-platelet ratio index (APRI).
•
Using the best cutoff values to identify the absence or presence of
significant fibrosis, 101 patients (35%) could have avoided liver
biopsy.
•
For the 30 treated patients, changes in FibroIndex directly
correlated with changes in fibrosis as determined by biopsy, while
the Forns and APRI indices did not show this association.
•
FibroIndex scores decreased significantly in 14 patients whose
fibrosis stage improved, but increased significantly in 5 patients
whose fibrosis stage deteriorated.
•
FibroIndex was also accurate in a subset of patients with normal
levels of alanine aminotransferase (ALT), a third of whom had
significant fibrosis.
Conclusion
The researchers
concluded that, "The FibroIndex is a simple and reliable index for
predicting significant fibrosis in [patients with] chronic hepatitis C
and could also be used as a surrogate marker during anti-fibrotic
treatment for chronic hepatitis C."
The authors noted
that platelet count, AST, and gamma globulin are easily determined using
routine blood tests available in most hospitals and laboratories, making
it a widely accessible tool for determining fibrosis.
"The utilization
of FibroIndex should decrease the number of liver biopsies necessary
during follow-up of patients with hepatitis C and could safely provide
longitudinal data on the progression of liver fibrosis," they added.
Accurate
non-invasive fibrosis tests could be especially important for HIV
positive individuals coinfected with HCV, who tend to experience more
rapid liver disease progression.
02/06/07
References
M Koda, Y Matunaga, M Kawakami, and others. FibroIndex, a
Practical Index for Predicting Significant Fibrosis in Patients with
Chronic Hepatitis C. Hepatology 45(2): 297-306. February 2007.
|
What is
the best non invasive method for early prediction of cirrhosis
in chronic hepatitis C? Prospective comparison between Fibroscan
and serum markers (Lok index, APRI, AST/ALT ratio, platelet
count and Fibrotest)
|
| |
Reported by Jules Levin
AASLD, Nov 2-6, 2007, Boston, MA
L. Castera1, 2; P. Bernard2; B. Le Bail3; J. Foucher1, 2; W.
Merrouche1; P. Couzigou1; V. de Ledinghen1
1. Hepatology, Hopital Haut Leveque, CHU Bordeaux, Pessac,
France.
2. Hepatology, Hopital St Andre, CHU Bordeaux, Bordeaux, France.
3. Pathology, Hopital Pellegrin, CHU Bordeaux, Bordeaux, France.
Background: Several non invasive methods have been proposed for
the diagnosis of cirrhosis in patient with hepatitis C. They
include routinely available markers (platelet count, AST/ALT
ratio (AAR), AST to Platelet ratio (APRI), scores (Fibrotest
(FT), Lok index (platelet count, AST/ALT ratio, and INR), and
lately transient elastography (Fibroscan (FS).
Aim: to prospectively compare the performance of these different
methods for the early prediction of cirrhosis in the same
population of patients with chronic hepatitis C.
Methods: 305 consecutive HCV patients (males 57%, mean age:
52±12) who undergone a liver biopsy (>10 mm) were studied. All
patients had FS, FT, APRI, Lok index, AAR and platelet count in
the same lab the day of liver biopsy, taken as reference.
Cut-offs used for each test were those defined in the original
studies. Performances were compared in intention to treat
analysis (FS failure was considered as need for liver biopsy).
Results: Significant fibrosis (Metavir F2-F3-F4) was present in
228 (75%) and cirrhosis (F4) in 77 (25%) (Child-Pugh A 90%; B
10%, oesophageal varices 39%). The mean liver biopsy length was:
19±8 mm. FS failure was observed in 10 patients (3%).
Performances of the different methods are shown in the table.
32 out of 77 (42%) cirrhotic patients had no clinical or
biochemical or US signs suggestive of cirrhosis. Among these 32
patients, cirrhosis could have been detected in 5 (16%) using
the Lok index, in 5 (16%) using the AAR, in 8 (25%) using the
APRI, in 14 (44%) using FT, and in 22 (70%) using FS,
respectively. In addition, at a cut-off of 21 kPa, the
performance of FS for detecting oesophageal varices was: Se 79%;
Sp 72%, PPV 65%, and NPV 84%.
Conclusions: Fibroscan is the best non invasive method for
prediction of cirrhosis in chronic hepatitis C, as compared with
other available methods, saving the need for liver biopsy in 90%
of cases. In patients without any signs of cirrhosis, early
diagnosis can be made in 70% of cases.
 |
| |
Battle of the New, Non-invasive Measures of
Fibrosis: FibroScan versus FibroTest
FIBROSpect™
What?
FIBROSpect™ is a proprietary set of blood tests used together to
differentiate no/mild liver fibrosis from severe fibrosis.
Why Test?
Liver biopsy remains the most certain method of determining the
presence and degree of liver fibrosis. However, some people are
hesitant to have a liver biopsy because it is an invasive test and
has an associated risk of rare but serious complications. While
FIBROSpect™ is not a substitute for liver
biopsy, it can possibly provide some useful information
for people who cannot or do not wish to have a liver biopsy.
Fibrosure™
Other Names
FibroTest-ActiTest, HCV Fibrosure
What?
Fibrosure™ is a proprietary set of blood tests used together to
differentiate no/mild liver fibrosis from severe fibrosis.
Why Test?
Liver biopsy remains the most certain method of determining the
presence and degree of liver fibrosis. However, some people are
hesitant to have a liver biopsy because it is an invasive test and
has an associated risk of rare but serious complications. While
Fibrosure™ is not a substitute for liver
biopsy, it can possibly provide some useful information
for people who cannot or do not wish to have a liver biopsy.
Battle of the New, Non-invasive Measures of
Fibrosis: FibroScan versus FibroTest
By Ronald Baker, PhD
Liver fibrosis
is the principal feature of the injury caused by chronic liver disease
and determines the major clinical events that lead to
liver-related deaths. For this reason alone, an accurate
assessment of fibrosis is vital to the management of patients with liver
disease.
Measuring the extent of liver disease is
also a significant factor when considering whether to use
treatment, to assess the response to therapy and to make
other important decisions related to progression of fibrosis, such as
screening for
hepatocellular carcinoma and
varices.
For 60 years,
liver biopsy has been regarded as the
gold standard diagnostic
for assessing the
progression of fibrosis in chronic hepatitis C patients.
However, despite its longstanding utility, liver biopsy has some
significantly negative features. First, patients often resist undergoing
liver biopsy due to the discomfort resulting from its invasiveness.
There is also some risk to the patient of experiencing an adverse event
from liver biopsy. In addition to these negative features, there is a
sampling error of at least 24% due to inadequate liver specimen length
or fragmentation. Finally, there are inconsistencies in the
interpretation of liver biopsy results because of errors on the part of
one or more observers of the specimens.
As a result of these drawbacks to liver
biopsy, interest continues to grow in new, non-invasive methods of
assessing fibrosis, including biochemical markers, biomarkers, and new
imaging techniques.
FibroScan and FibroTest
One such advance in the field is
FibroScan, a type of ultrasound machine that uses
transient elastography to measure liver stiffness. The device reports a
value that is measured in kilopascals (kPa). This value can be
extrapolated to a fibrosis score.
FibroTest (aka
FibroTest-ActiTest)
is another non-invasive diagnostic for
assessing fibrosis. Available through BioPredictive (www.biopredictive.com),
FibroTest uses an algorithm to combine the results of serum tests of
beta 2-macroglobulin, haptoglobulin, apolipoprotien A1, total bilirubin,
gamma glutamyltranspeptidase (GGT), and
alanine aminotransferase (ALT) to assess the level of
fibrosis and necroinflammatory activity.
Comparison of FibroScan and FibroTest to
Detect Fibrosis Progression among HCV Carriers with
Normal
Aminotransferases
An article published in the October 2005
issue of Hepatology by Colletta et al compared the value of
FibroScan and FibroTest in HCV carriers with normal ALT levels [1].
The study evaluated 40 untreated HCV RNA positive subjects who had two
liver biopsies, with a median interval of 78.5 months, during which ALT
levels never exceeded 1.2 times the upper normal limit.
The study authors
concluded that FibroScan yielded results that showed perfect
agreement between FibroScan and liver biopsy [emphasis
added—Ed]. In addition, the study concludes that the diagnostic
accuracy of FibroScan was 100%. Further, the authors write, “FibroScan
is superior to the FibroTest in the noninvasive identification of
fibrosis, for which excess
alcohol consumption in the past and high viral load
represent risk factors” [2].
The glowing review by Colletta et al of
the diagnostic superiority of FibroScan compared to FibroTest has now
been strongly challenged by other experts in the field, specifically L
Castera et al and T Poynard et al. Their contrasting opinions appear in
the “Correspondence” section of the February 2006 issue of Hepatology
[3,4]. A reply by Colletta et al to Castera et al and to Poynard
et al also appears in the February 2006 issue of Hepatology. The
major arguments of each of the three teams of experts concerning the
original study by Colletta et al are summarized here.
FibroScan and
FibroTest to Assess Liver Fibrosis in HCV with
Normal
Aminotransferases (L Castera and others)
Although Castera et al agree with the
opinion of Colletta et al that these non invasive diagnostics could
“someday become an alternative” to liver biopsy in patients with
persistently normal ALT levels (PNAL), the authors state
they feel compelled to voice several methodological concerns about the
study by Colletta et al.
Castera et al raise three major issues about the study:
1. The stated capability of FibroScan to identify the entire spectrum of
fibrosis stage in individuals with PNAL contracts sharply with the
results noted in all other published studies. Due in part to the small
number of patients in their study, Colletta et al need to interpret
their data more cautiously concerning the “perfect agreement” between
FibroScan and liver biopsy, write Castera et al.
The performance of FibroScan in this study shows a surprising diagnostic
accuracy of 100%. A critical issue in assessing accuracy is the cutoff
value for identifying patients with significant fibrosis. Colletta et al
give no justification for the choice of their cutoff point of O.31.
Using the cutoff proposed by Castera et al, the results by Colletta et
al most likely would be quite different than what they report, with
lower diagnostic accuracy: sensitivity 100%, specificity 46%, diagnostic
accuracy 46%, positive predictive value 50%, negative predictive value
100%).
2. Second,
Colletta et al offer no information on the proportion of patients in
whom liver elasticity measurements could not be obtained.
3.
Third, Colletta et al should be
cautious in asserting that FibroScan has much better correlation with
liver biopsy than FibroTest. In their study, FibroTest yields a
surprisingly high false positive rate, which contrasts with the results
of prior published studies that show high specificity for FibroTest.
Castera et al propose avoiding the
limitations of both FibroScan and FibroTest by employing an algorithm
that combines both tests. When doing so, the authors found that in 97 of
100 consecutive HCV patients with normal ALT levels, concordance between
FibroScan and FibroTest for significant fibrosis was 67%.
In conclusion, Castera et al write, “We
believe combining FibroScan and FibroTest as a first-line noninvasive
assessment of liver fibrosis might prove particularly useful in the
setting of HCV carriers with normal ALT levels and should be further
evaluated.”
Service
d'Hépato-Gastroenterologie, Hôpital Haut Léveque, C.H.U.Bordeaux,
Pessac, France
Diagnostic Value of
FibroTest with
Normal Serum Aminotransferases (T Poynard et
al)
Colletta et al have
concluded that FibroScan is superior to
FibroTest. Their study yielded “perfect” diagnostic measurements for
FibroScan, but for FibroTest (at the 0.31 cutoff) only 64% sensitivity
and 31% specificity for the diagnosis of advanced fibrosis.
In the observations of Poynard et al, such
“poor” results have not been found for FibroTest, nor are they reflected
in the results of other published studies using the services of
BioPredictive, “the sole company allowed to market FibroTest.”
In a FibroTest analysis of 537 patients
with chronic hepatitis C (129 with normal ALT and 408 with elevated
ALT), there were no differences in area under the ROC curves between
patients with normal or elevated ALT. Furthermore, the AUROC was 0.76,
higher than the 43% accuracy observed by Colletta et al.
The Poynard group also analyzed
prospectively the specificity of FibroTest in 954 blood donors without
liver biopsy, 917 with normal ALT. Excluding the 25 patients with high
risk of false positive/negative, 877 of the remaining 892 patients
(98.2%) have normal FibroTest and 15 (1.8%) had FibroTest between 0.31
and 0.48 and none above. “These figures are very different than the 69%
false positive of Colletta et al,” according to Poynard at al.
Poynard et al propose four possible
explanations for these discrepancies:
1. The small number of patients in the
study by Colletta et al.
2.An error in the calculation of FibroTest
if the professional website (www.BioPredictive.com)
was not used.
3.
The non exclusion of patients with high risk profile of false
positive/negative. (These patients would have been identified by the
security algorithms on the BioPredictive website).
4.
Use of the FibroTest threshold at 0.31 for F2F3F4 detection
instead of 0.48 which is the recommended threshold.
Finally, in evaluating the concordance
between the two tests in 70 consecutive subjects with baseline normal
ALT: 60 patients (44 HCV, 5 hepatitis B, 11 others), and 10 apparently
healthy volunteers, FibroScan was not applicable in 3 subjects
(abdominal fat) and FibroTest in 5 (high risk profile). In the remaining
62 subjects the concordance was fair with 78% (48/62) of concordance for
stage F2F3F4 when using the 0.31 threshold, and even better (82% (51/62)
at the recommended threshold (0.48). These concordance rates were
similar to the 77% observed by Castera et al.
In conclusion, Poynard et al write, “We
think the comparisons between noninvasive markers should be performed
according to professional recommendations, respecting applicability
reports to exclude high risk of false negative or false positive results
and in populations with sufficient sample size.”
Service d
Hepato-Gastroenterologie,
GH Pitie-Salpetriere, Pans, France; BioPredictive, Paris, France
Colletta et al Reply to Poynard et al and
Castera at al
Colletta et al dismiss two of the
explanations for the discrepancies between their study and the study by
Poynard et al by stating that all FibroTest values were calculated using
the BioPredictive website. Further, the five serum markers used in this
fibrosis index were measured following the strict requirements specified
by BioPredictive, say Colletta et al.
Concerning the use of the 0.31 cutoff,
Colletta et al maintain that this is the most sensitive cutoff to
exclude significant fibrosis. Further, if the data are re-analyzed using
the 0.48 cutoff, the diagnostic value of FibroTest in the studied
patients would be: sensitivity, 21%, specificity, 81%, positive
predictive value, 38%, negative predictive value, 66%.
While acknowledging that future, larger
studies might reach different conclusions than theirs, Colletta et al
emphasize that the selection of patients for these future studies will
require the use of very strict criteria, such as those used by them (no
value >1.2 times the upper normal limit in a minimum of 17
determinations, along more than 5 years), and which Poynard et al did
not follow. This included the using patients with PNAL who have ALT
within the normal limits on the day a liver biopsy was performed.
Regarding the objections of Castera et al
related to the cutoff chosen for liver elasticity (8.7%kPa), using a
cutoff that reduces the overall value of a test is not justifiable, say
Colletta et al.
With regard to the second issue raised by
Castera et al., the proportion of patients in whom liver elasticity
measurements could not be obtained, Colletta et al reply,
“Unfortunately, Castera et al neither specify why their patients could
not have liver elasticity measured, nor define the HCV carriers with
normal ALT they studied in terms of length of follow-up and number of
ALT determinations.”
Finally, the authors question the
appropriateness of Castera et al to equate the specificity of FibroTest
in blood donors without hepatitis C (and no liver biopsy) to that in HCV
carriers with normal ALT, “since these two populations should not be
considered equivalent.”
It would appear that FibroScan has certain
advantages over other diagnostic indices or predictive models based on
laboratory tests in that it is completely noninvasive, provides a more
direct measure of fibrosis, should not be affected by other disease
states, and should theoretically be applicable to all chronic liver
diseases, explain Ghany and Doo in an editorial that accompanies the
study by Colletta et al [7].
Conclusion
What will be the future of the liver
biopsy and the newer, non-invasive diagnostics such as FibroScan and
FibroTest?
If as expected, new antivirals become
available for the treatment of chronic hepatitis C, there will be an
increasing need to assess fibrosis as a method of monitoring the effect
of these treatments. Liver biopsy no doubt will continue to be employed
in the diagnosis, grading and assessment of chronic liver disease. Yet
despite a continuing role for liver biopsy, non invasive methods likely
will soon become the diagnostic of choice for assessing liver fibrosis.
02/07/06
Sources
C Colletta C and others. Value of two
noninvasive methods to detect progression of fibrosis among HCV carriers
with normal aminotransferases. Hepatology 42(4): 838-845. October
2005.
L Castera, J
Foucher, J Bertet, P Couzigou, and V de Ledinghen.
FibroScan and
FibroTest to assess liver fibrosis in HCV with normal aminotransferases.
Hepatology 43(2): 373-374. February 2006.
T Poynard, M Munteanu, Y Ngo, M Torres, Y Benhamou, D Thabut, and V
Ratziu.
Diagnostic value of FibroTest with normal serum aminotransferases.
Hepatology 43(2): 374-375. February 2006.
References
1.
C Colletta
and
others. Value of two noninvasive methods to detect
progression of fibrosis among HCV carriers with normal
aminotransferases. Hepatology 42(4): 838-845. October 2005.
2.
Ibid.
3.
L Castera, J Foucher, J Bertet, P Couzigou, and V de Ledinghen.
FibroScan and FibroTest to assess liver fibrosis in HCV with normal
aminotransferases. Hepatology 43(2): 373-374. February 2006.
4.T Poynard, M Munteanu, Y Ngo, M Torres,
Y Benhamou, D Thabut, and V Ratziu. Diagnostic value of FibroTest with
normal serum aminotransferases. Hepatology 43(2): 374-375.
February 2006.
5.C Colletta and
others. Reply to L Castera et al and T Poynard et al. Hepatology
43(2): 375-376. February 2006.
6.M G Ghany and
E Doo. Assessment of liver fibrosis: Palpate, poke or pulse?
(editorial). Hepatology 42(4): 759-761. February 2006.
CT Scans for
Monitoring Liver Fibrosis
In an effort to reduce the need for repeated biopsies, researchers have
explored alternative ways to diagnose and monitor liver fibrosis,
including various blood markers and non-invasive imaging methods. As
reported in the December 20, 2007, advance online edition of
Hepatology. M. Romero-Gomez and colleagues evaluated conventional
digitized helical computed tomography (CT) scans as a method for
assessing liver fibrosis in 141 chronic hepatitis C patients. On a scale
of F0 to F4, fibrosis scores according to CT imaging correlated with
histology scores as determined from liver biopsies by two blinded
pathologists. Receiver operating characteristics curve values (a measure
of accuracy) were 0.83 for diagnosing significant fibrosis (stage F2 or
higher) and 0.86 for diagnosing advanced fibrosis (stage F3 or higher).
The correlation between CT and biopsy findings was higher for patients
with homogeneous fibrosis distribution throughout their livers than for
those with inconsistent distribution. The investigators concluded that,
“Fibro-CT is a simple to use, readily available, and useful method for
the diagnosis of fibrosis in patients with chronic hepatitis C.”
http://www.hcvadvocate.org/news/newsRev/2008/HJR-5.2.html#4
Liver
biopsy is the undisputed best way to assess liver
fibrosis or cirrhosis; however, it is an invasive
procedure that can cause rare, but potentially
life-threatening complications. Researchers have been
seeking less invasive ways to diagnose liver disease,
developing and testing clinical tools, like the Original
European Liver Fibrosis Panel and transient elastography.
