[转帖]Liver Biopsy Sampling in Chronic Viral Hepatitis

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                      Liver Biopsy Sampling in Chronic Viral Hepatitis

From Seminars in Liver Disease
Liver Biopsy Sampling in Chronic Viral Hepatitis
Posted 05/04/2004
Maria Guido, M.D.; Massimo Rugge, M.D.
Abstract and Introduction
Abstract
In chronic viral hepatitis, liver biopsy is performed to grade and stage
liver damage. Liver biopsy samples are usually taken with a needle using a
percutaneous procedure. This method produces a core of tissue representing
approximately 1/50,000th of the liver mass, which raises concern about how
representative a needle biopsy can be. A critical review of the literature
reveals methodological limits unacceptable in this era of evidence-based
medicine. Integrating earlier experience with more recently produced data
indicates that a biopsy sample 2 cm or more in length containing at least 11
complete portal tracts should be reliable for grading and staging chronic
viral hepatitis.
Introduction
In the past 20 years, pathologists have radically changed the way they
generate their reports. In the fields of neoplastic and inflammatory
diseases, increasingly sophisticated information, such as the results of
molecular studies, is needed for diagnosis and treatment. The introduction
of new methods for analyzing tissues has prompted an ever-closer interaction
between clinician and pathologist to ensure the most appropriate sampling in
a given clinical context. This is also true of liver diseases, particularly
in chronic viral hepatitis, which means taking a new look at the old liver
biopsy procedure.
Liver biopsy was introduced by Paul Ehrlich[1] more than 100 years ago and
has since been widely used, enabling substantial progress in our
understanding of liver histology, pathophysiology, and pathology. The
diffusion of the use of liver biopsy was mainly because of the Menghini
"one-second liver biopsy" technique,[2] which provided samples suitable for
various morphological studies, including the histochemical,
immunohistochemical, ultrastructural and, more recently, molecular biology
studies. Low mortality and relatively low morbidity rates have facilitated
the widespread use of liver biopsy procedures.[3]
Because of advances in imaging techniques and the development of reliable
serological and virological tests, the indications for liver biopsy have
changed dramatically, and the technical biopsy procedures have also been
refined.[4] Different methods for obtaining liver biopsy samples are
available,[5] and the choice of technique is dictated by the clinical
setting (e.g., associated coagulation disorders, presence or absence of
ascites, results of prior ultrasound examination), the operator';s preference
and experience, and the nature of the disease prompting the histological
investigation.
The purpose of this article is not to review the topic of "liver biopsy,"
which includes many relevant (and still debated) issues, such as clinical
indications and contraindications, complications, costs, and benefits. Our
aim is to focus on the problem of "sampling errors" and when a sample can be
considered to be "adequate" if a liver biopsy is needed to evaluate the
severity of chronic hepatitis, especially in cases due to the most frequent
hepatotropic viruses, in other words, hepatitis B virus (HBV) and hepatitis
C virus (HCV).
As we have learned from epidemiological studies, sampling errors occur when
the samples considered fail to represent the target population (e.g., tissue
in our setting) from which it is derived. Considering that a biopsy sample
taken from an adult corresponds to a fraction of just 1/50,000th to
1/100,000th of the whole liver, a biopsy specimen would seem to be
inadequate in the case of nonfocal diseases, such as a chronic viral
hepatitis, in which the liver changes may be unevenly distributed.
There are several facets to the problem, but, from a practical point of
view, it can be brought down to two partially overlapping questions: (1)
could a random sample reflect damage to the organ as a whole and (2) would
the sample size affect the histological assessment of chronic hepatitis in
terms of grade and stage?

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Morphological Approach to Chronic Viral Hepatitis
Because of the identification of HCV and the effectiveness of antiviral
treatments, the diagnostic approach to chronic hepatitis has undergone a
"Copernican revolution" in the last two decades.[6-10] The unfavorable
prognostic value of the "time-honored concept of chronic active hepatitis"
(CAH)[10] based on the presence of interface hepatitis (formerly piecemeal
necrosis), as opposed to the favorable diagnosis of "chronic persistent
hepatitis" (without interface hepatitis by definition), is no longer
accepted. The new reporting system integrates etiology with morphological
findings to define prognosis and treatment indications.[11] The grading and
staging system, borrowed from oncological practice,[11,12] takes into
account (along with interface hepatitis) the whole spectrum of morphological
lesions affecting progression to cirrhosis. Grading reflects
necroinflammatory severity of the different elementary histological lesions
(e.g., portal inflammation, interface hepatitis, focal and confluent lobular
necrosis). Staging quantifies the extent of fibrosis and defines disease
progression toward its potential cirrhotic end point.
While an etiologic diagnosis of chronic hepatitis is easily obtained in most
cases using serological and virological tests, biopsy is currently indicated
for the grading and staging of liver damage.[13-17] In practice,
pathologists establish the grade and stage of disease by scoring each
elementary lesion according to semiquantitative numerical
systems.[6,11,18-21] Several studies have evaluated intraobserver and
interobserver consistency using such scoring systems[22-24] and have shown
an acceptable consistency for necroinflammatory lesions and an almost
perfect agreement for fibrosis, whatever the scoring system used. In
clinical practice, numerical scores may be translated into descriptive
severity categories (mild, moderate, and severe) and have been shown to have
prognostic and therapeutic implications.[25,26] Scoring has been routinely
applied in clinical trials on the treatment of chronic hepatitis B and
C[27-30] to evaluate treatment eligibility and effects. Although much effort
has been made (and must still be made) to identify alternative, noninvasive
methods,[31-34] liver biopsy remains the gold standard for grading and
staging chronic viral hepatitis.[35-37] Unfortunately, none of the different
scoring systems went so far as to evaluate the minimum sample size needed
for the scores to be reliable.
Types of Biopsy Sample
Two different types of liver tissue sample can be obtained: wedge and needle
biopsy specimens.[38] A wedge biopsy can be taken during laparoscopic or
open surgery. All pathologists would agree, however, that a wedge biopsy
(which is a subcapsular sample) should not be taken to evaluate diffuse
disease and chronic hepatitis in particular. In fact, fibrous septa
spreading from Glisson';s capsule to the adjacent parenchyma may mimic
cirrhosis, which means that the stage of disease is overestimated. In
addition, because of the surgical procedure, the subcapsular region is often
affected by nonspecific necroinflammatory lesions, which can result in an
overestimation of the grade of the disease';sinflammatory component. So, even
when laparoscopy or laparotomy is performed for clinical reasons, unless a
focal lesion is to be tested, a needle biopsy (sampling the parenchyma in
depth) should be preferred. Wedge biopsies are more suitable for biochemical
studies, given the larger amount of tissue obtained. The risks and
complications of wedge biopsies relate to the laparoscopy or laparotomy
procedure.
Needle biopsy samples can be taken (1) during laparoscopic or open surgery;
(2) percutaneously, either "blindly" or under radiological or ultrasound
(US) guidance; and (3) by transjugular catheter.[3] This last procedure is
reserved for subjects with severe coagulation disorders and is performed
under cardiac monitoring, due to the risk of arrhythmia. Even in the most
expert hands, it often produces only fragmented specimens.
Laparoscopic (or laparotomic) needle biopsy has declined considerably and is
now used mainly when focal lesions are accidentally found during routine
surgery. It can also be used in patients with focal lesions and coagulopathy
instead of the transvenous procedure.
In current practice, percutaneous needle biopsy is the quickest, safest, and
most-used technique for assessing diffuse diseases and for grading and
staging chronic viral hepatitis.[13] Many centers use US or computed
tomography (CT) guidance because of the lower rate of complications reported
in some studies.[39,40] Whether, when, and how radiological or US guidance
is indicated in liver biopsy is a matter that is still under debate.[39-43]
Two main types of needle are currently used: the Tru-Cut, which is a cutting
needle, and the Menghini needle, which uses a suction technique.[40] The
cutting needle usually produces a larger sample but has been associated with
a higher risk of complications,[44] probably because the needle remains in
the liver longer. A suction needle tends to produce more fragmented samples.
As emphasized in the original article,[2] the advantage of the Menghini
technique is that the needle remains in the parenchyma just "one second,"
which minimizes the risk of rupturing the capsule. The size of the specimen
varies, depending on the type of needle: a biopsy obtained with 14-gauge (G)
to 21G needle is usually defined as "large," whereas needles less than 21G
result in "thin" or "fine" biopsy samples with a core less than 1 mm in
diameter. The thin biopsy is universally recommended for the diagnosis of
focal lesions; its use for grading and staging is under debate.[45]
Complications after percutaneous liver sampling are related to the patient';s
clinical conditions, the operator';s expertise, the type of needle, and the
number of passes.[46] Elderly patients with malignant hepatic tumors or
severe liver failure, or both, are at the greatest risk for developing
complications.[4,47-49] A detailed discussion of liver biopsy
contraindications and complications is beyond the purpose of this article,
and readers are referred to specific references.[4,46-50] Guidelines have
also been published on the practice of liver biopsy.
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Could a Random Sample Reflect Damage to the Organ as a Whole?
Answering this question is complicated by difficulties in designing
satisfactory study models. Establishing a gold standard would involve
testing the entire liver to compare different types of needle biopsy.
Various approaches have been used to overcome this drawback in clinical
studies.
The Historical Perspective
Earlier studies focused mainly on diagnosing cirrhosis, which is still a
relevant clinical issue. The diagnosis of cirrhosis has important prognostic
implications in terms of quality of life or life expectancy, or both.
Cirrhosis has a significantly lower response to interferon treatment.
Moreover, a diagnosis of cirrhosis prompts a follow-up program with a view
to the early diagnosis of hepatocellular carcinoma.[54]
A first group of studies compared the morphological findings of multiple
needle biopsy samples obtained from different portions of the liver.[55-58]
On the whole, these studies varied considerably in terms of the number of
patients involved, the study design (including biopsy and autopsy series),
the type of needle (the diameter of which is often not mentioned), and the
morphological criteria adopted. Diseases of different etiologies were
included in the groups studied, which made it difficult to transfer the
conclusions to the context of chronic viral hepatitis. In addition, these
studies did not evaluate the extent of noncirrhotic fibrosis, so no
information can be gleaned on sampling errors in precirrhotic stages, which
is currently important in the management of chronic viral hepatitis.
Finally, most of these studies did not include any evaluation of
intraobserver and interobserver agreement, which is crucial in dealing with
morphology implicating subjective interpretations. Overall, these studies
reported a sampling error ranging from 10 to 70%.[55-59]
Among the "historical" studies, the one by Soloway et al[56] is one of the
most quoted to support the inadequacy of percutaneous biopsy. In this study,
based on the assumption that cirrhosis is irreversible, three to five needle
biopsies were taken in 19 patients at 6- or 12-month intervals after the
detection of cirrhosis. Multiple simultaneous biopsies from adjacent areas
were also taken in 13 subjects. The authors concluded that "...evaluation of
multiple simultaneous biopsies showed that the presence and grade of
hepatitis in a single biopsy accurately reflected hepatitis in adjacent
areas," yet "there were many discrepancies in the presence and grade of
cirrhosis."[56] For several reasons, the results of this study can no longer
be considered reliable: (1) the number of cases was limited; (2) the series
included patients with not otherwise specified "chronic active liver
diseases"; (3) there is no indication of the gold standard used to measure
how representative the liver samples were; (4) there is no mention of the
sample size, and particularly whether paired, multiple, or consecutive
biopsies were of equivalent length and width (which is also a critical point
in this type of study); (5) cirrhosis was "graded" on three levels, grade 1
indicating early cirrhosis or doubtful cases and grades 2 and 3 indicating
definite cirrhosis (unfortunately the differences between grades 2 and 3
were not explained).
Three biopsy samples were obtained prior to autopsy using a modified
Menghini method in the study by Abdi et al.[57] An 80% accuracy for the
diagnosis of cirrhosis was demonstrated on the strength of one sample, and
this rose to 100% when all three samples were evaluated jointly. Specimens
were considered adequate if they were no less than 25 mm long, but no
information was given on the diameter of the biopsy cores.
In the study by Baunsgaard et al,[58] two specimens were simultaneously
taken from the right lobe, 4 to 6 cm apart, in 70 patients using a Menghini
needle. The indications for liver biopsy were not reported. To be considered
in the study, biopsy samples had to be no shorter than "1 cm for specimens
composed of 1 to 3 fragments and 1.5 cm for specimens comprising 4 or more
fragments." Diagnostic consistency was evaluated for cirrhosis and different
types and grades of lesions, including steatosis, Mallory bodies,
acidophilic bodies, portal and septal fibrosis, portal inflammation, focal
intralobular necrosis, bile duct proliferation, alcoholic hepatitis, and
cholestasis. The highest diagnostic consistency between paired samples was
demonstrated for steatosis (t = 0.82), cholestasis (t = 0.91), and cirrhosis
(t = 0.83). Diagnostic inconsistency, however, is not necessarily due to
sampling error: intraobserver variation was not evaluated, and it is not
clear whether the minimum size referred to the sum of the various fragments
or to the length of the longest one. The study did not mention the diameter
of the sample and did not explain whether paired samples from the same
subjects were of equivalent size.
The superiority of multiple samples over a single biopsy was also reported
by Maharaj et al,[59] but the study did not give any information on the
sample size or on the etiology of the cirrhosis. Although multiple samples
were obtained from the same patient, no complications were observed in any
of the 75 subjects enrolled.
The conclusion that can be drawn from the previous studies is that the more
tissue there is available, the greater is the accuracy of the diagnosis.
A different approach to the issue of sampling errors has been to compare the
diagnostic accuracy of laparoscopy (with or without associated laparoscopic
biopsy) versus blind needle biopsy. Generally speaking, most such studies
suggest that laparoscopy (alone or associated with biopsy) is more accurate
than blind percutaneous biopsy is, which produces false-negative diagnoses
of cirrhosis in 9 to 32% of cases.
Pagliaro et al[60] designed a prospective and randomized study to compare
the diagnostic accuracy of blind percutaneous biopsy versus laparoscopic
biopsy, which showed that liver cirrhosis was missed by percutaneous biopsy
in 20% of cases. For various methodological reasons, this result is no
longer convincing: (1) the gold standard for testing the strength of the two
methods in diagnosing cirrhosis is not clear because the study enrolled
patients with "clinical evidence of chronic diffuse well-compensated liver
diseases," which did not necessarily mean cirrhosis; (2) blind percutaneous
biopsies and laparoscopic biopsies were performed in different subjects; (3)
specimens were considered adequate if they were at least 1 cm long, but the
mean length ± standard deviation of the specimens from the whole group was
not reported; and (4) both the laparoscopy and the histological evaluation
were performed by two different operators, but interobserver reproducibility
was only reported for the laparoscopic diagnosis. A lesson applicable to
clinical practice can still be found in the Pagliaro et al study: a final
diagnosis can be reached by accurately integrating all the clinical and
morphological findings. In the proper clinical context, even "minor"
histological lesions can acquire "major" diagnostic significance.
In a more recent study by Poniachik et al,[61] a 32% histological sampling
error was reported in patients with a laparoscopic diagnosis of cirrhosis.
The study included primary biliary cirrhosis and primary sclerosing
cholangitis, diseases known to feature different stages at the same
time.[62]
More encouraging results were reported in a well-designed study comparing a
blind needle biopsy with two additional biopsy samples obtained at
laparoscopy from the right and left lobe of the same patient.[63] This study
involved 60 patients, and various findings (other than cirrhosis) were
assessed, including normal liver, minimal changes, chronic persistent
hepatitis, and CAH. The diagnosis was based on a single percutaneous biopsy
and coincided in all cases with the final diagnosis emerging from a joint
evaluation of the laparoscopic biopsy findings. It is worth noting that all
the biopsy specimens considered in this study were >/=2 cm long.
More recently, abdominal US has been deemed more accurate than percutaneous
biopsy is in the diagnosis of cirrhosis in a study of 212 subjects.[64]
Histology, however, revealed cirrhosis in 10 cases found negative after US,
whereas US suggested cirrhosis in 32 histologically negative cases. The two
procedures were not tested against any external gold standard, so it is not
clear whether histology underestimated or US overestimated the presence of
cirrhosis.[64]
The Present Perspective
Few published studies have addressed sampling error in the context of a
modern morphological approach, which involves evaluating the grade and stage
of hepatitis (Table 1).
Fanning et al[65] performed a study based on double biopsies taken from
subjects with chronic hepatitis C, their main goal being to evaluate viral
load variability. Although viral load proved consistent between samples, 33%
(4 of 12) and 25% (3 of 12) of the paired biopsies showed a discrepancy of
>/=2 grades of inflammation and fibrosis, as evaluated using Ishak';s score.
The study included only 16 cases; however, it did not mention the size of
the samples or the mean number of portal tracts observed in the series as a
whole (a minimum of five portal tracts was among the inclusion criteria),
and it provided no information on observer variations.
In the study by Regev et al,[66] 124 patients with chronic HCV hepatitis
underwent liver needle biopsy from the right and left lobes during
laparoscopy. A sample was considered adequate if it was "at least 1.5 cm
long and with 5 or more portal zones." Grading and staging were done
according to a modified Scheuer score system. The comparison between right
and left lobes showed a 2-point difference in grade in 1 case (1.6%), and 30
patients (24.2%) had a difference of 1 point. As for the stage, differences
in fibrosis score were observed in 33% of cases (with a 1-point difference
in 30.6%). The authors emphasized that the difference in stage amounted to
9.7% when stages 3 and 4 were considered as one stage (because they have
similar clinical implications). Interobserver agreement proved to be high.
It would have been interesting, however, to know the specimens'; length and
also the number of portal tracts in the pairs of biopsies yielding different
scores.
Different conclusions were reached by Persico et al,[67] who evaluated 52
consecutive chronic hepatitis C patients by means of a double, right, and
left lobe percutaneous liver biopsy obtained with a modified Menghini 18-G
needle. Two independent pathologists whose general interobserver agreement
was 90% performed grading and staging based on Ishak';s scoring system. No
difference was observed between the two lobes in either grade or stage. The
mean length of specimens was 2.8 + 1.1 cm in the right lobe and 2.5 + 0.9 cm
in the left.
In 2003, Siddique et al[68] reported a surprisingly high variability in the
samples: 69 and 62% for activity and fibrosis, respectively. This study
analyzed 29 paired biopsies using the Knodell histological activity index:
20 of 29 paired biopsies showed a difference in necroinflammatory lesions
>/=2, and 10 revealed a difference >/=4; the difference in fibrosis score
was >/=1 in 11 cases and >/=2 in 6. All samples contained four to five
portal tracts. The differences in the histological scores may stem from the
discontinuous numerical scale of the Knodell scoring system, which tends to
highlight any scoring inconsistencies.

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Would the Sample Size Affect the Histological Assessment of Chronic
Hepatitis in Terms of Grade and Stage?
Before evidence-based medicine and before grading and staging, Sherlock
postulated that "a satisfactory biopsy is 1-4 cm long and weighs 10-50
mg."[3] This was a general principle applicable to all kinds of liver
disease, but Sherlock noted that "in macronodular cirrhosis it is possible
to aspirate a large nodule and find normal architecture" and that "there is
sampling variability in the diagnosis of cirrhosis and chronic active
hepatitis."[3] Authoritative literature[13] suggests that a biopsy 1.5 cm
long suffices for the histological assessment of chronic hepatitis and that
pathologists are "satisfied" with samples containing four to six portal
tracts (we might add that it is a matter of satisfying not the pathologists';
needs but the patients'; needs), and these standards have been extensively
adopted in clinical studies.
The Historical Perspective
Two studies performed by the same group investigated the relationship
between sample variability and sample size.
The first evaluated 100 liver needle biopsies from patients with a
clinically established diagnosis of acute or chronic hepatitis and cirrhosis
of various etiology.[69] Biopsies longer than 2.5 cm were selected, but no
attention was paid to their diameter. All samples were reviewed blindly at
five different sessions, changing the length of the sample with the aid of
opaque paper tape. The study demonstrated that, although acute viral
hepatitis was reliably diagnosed, even in samples 5 mm long, only 30 and 40%
of cases of CAH and cirrhosis, respectively, were diagnosed in 5-mm samples.
Predictive positive and negative values increased significantly with
increasing sample lengths. The study concluded that "a considerable number
of biopsies less than 25 mm long are not diagnostic" for cirrhosis.
The second study[70] mainly addressed the accuracy of a diagnosis of CAH
using the same method as before, except for the needle, which was a 16-G
Menghini needle in all cases. The gold standard was, here again, the
original liver sample, which had to be no less than 25 mm long. The study
showed that the specificity of the diagnosis of CAH with or without
cirrhosis rose significantly when the length of the biopsied tissue changed
from 5 to 15 mm. Moreover, 65% of all diagnostic errors were made on
biopsies up to 10 mm long, and the error was always on the side of less
severe conditions. The study concluded that a specimen at least 15 mm long
is needed for an acceptable accuracy in the diagnosis of CAH, but larger
needle biopsy samples are warranted when cirrhosis is suspected.
Expanding on earlier data,[71] a study by Colombo et al[72] demonstrated the
superiority of the Tru-Cut (89.5% accuracy) over the Menghini needle (65.5%
accuracy) in diagnosing cirrhosis. Differences were attributed to the
greater fragmentation of liver samples obtained with the Menghini needle.
Although this was not specifically highlighted in the study, it emerged that
diagnostic accuracy depended on the number of complete portal tracts within
the biopsy samples and that 34.8% of the portal tracts in the Menghini
biopsy specimens were incomplete, compared with 19.6% in the Tru-Cut biopsy
specimens.
A weakness of the previous studies lay in the lack of intraobserver and
interobserver agreement tests, which was partially overcome by the
experience of the pathologists who performed the histological examination.
In fact, diagnostic consistency improves when the assessment is performed by
experienced pathologists specializing in liver diseases.
The Present Perspective
A more recent approach to the problem of specimen size has been to compare
"large" versus "thin" liver biopsies in the diagnosis of diffuse diseases.
The rationale behind these studies is that taking biopsies with larger
needles can cause more complications. Fine-needle biopsies are easier to
perform in outpatients under local anesthesia, and patients are more
compliant. Using a finer needle is also an advantage in clinical conditions
in which large-needle biopsy is contraindicated.
Rocken et al[73] compared thin and large biopsy samples and concluded that
the amount of tissue available correlated strongly with the type of needle,
although thin biopsies (20G) yield sufficient material to make a diagnosis
of diffuse liver disease of various etiologies. The study, however, did not
address the grading and staging of chronic hepatitis.
This was the aim of a more recently published study by the same group,[74]
in which large (17G Menghini needle) and thin (20G modified cutting Menghini
needle) biopsies from 88 patients with chronic type B or C hepatitis were
retrospectively re-evaluated for grading and staging purposes. The study
concluded that a thin biopsy is as good as a large one for the grading and
staging of chronic viral hepatitis. It is important to note, however, that
(1) the thin and large samples came from different patients; (2) there was
no clearly defined gold standard for assessing diagnostic accuracy; and (3)
because the study was retrospective, patients were not randomized to undergo
large or thin biopsy, and patients with thin biopsies were more often found
to have low platelet counts and high alanine aminotransferase levels, which
introduce a selection bias. It is also worth noting that, in the small
subgroup of patients whose clinical diagnosis of cirrhosis was taken as the
gold standard, cirrhosis was histologically diagnosed by thin samples in 44%
of cases and by large biopsies in 60%, which means that biopsy size becomes
relevant when a gold standard is established.
More recently, a study was designed to evaluate the effect of core length
and diameter on the grading and staging of chronic types B and C
hepatitis.[75] The method was similar to the one used in previous
studies[69,70] and consisted of progressively reducing the length and width
of the original samples, which were all at least 30 mm long and 1.4 mm wide.
The same pathologist reviewed all the slides throughout the various sessions
and intraobserver agreement proved to be high. This study provided evidence
that both the length and the diameter of the biopsy core affect grading and
staging and (as in the previous studies[69,70]) that examining shorter and
thinner samples leads to an underestimation of the severity of disease.
Disease activity and fibrosis were underestimated in thin biopsies (i.e., 1
mm wide) regardless of the length of the biopsy, suggesting that the main
problem lies in the lower number of complete portal tracts in the smaller
samples. Portal areas are the elective sites of damage in chronic hepatitis,
and they must be intact for disease grading and staging. The study
demonstrated that 11 to 15 complete portal tracts was the critical number
below which disease grade and stage were significantly underestimated and
that a liver biopsy 2 cm long and 1.4 mm wide guaranteed this number of
portal tracts in 94% of cases. The study also suggested that the number of
complete portal tracts should be mentioned in the histological report to
focus the clinicians'; attention on the adequacy of their samples and on the
limits of histological interpretation.
Conclusions
Clinicians having to decide whether to perform a liver biopsy will gain
little from reading this article, which is concerned exclusively with what
happens after such a decision has been made.
For this article, we tried to answer two questions: (1) Can a random sample
reflect damage to the organ as a whole? Sherlock had the answer[3]: "It is
surprising that such a small biopsy should so often be representative of
changes in the whole liver." Available data confirm that, in diffuse
processes such as acute and chronic hepatitis, a needle biopsy is
representative of the liver disease, ensuring an accurate diagnostic
classification.[56,69,70] In practice, needle liver biopsy is still
indicated to diagnose chronic viral hepatitis when clinical or serological
data, or both, produce inconsistent results or when confirmation is required
for clinical purposes (e.g., in the liver transplantation setting) or
research.
(2) Can the sample size affect the histological assessment of chronic
hepatitis in terms of grade and stage? Our earlier analyses showed that most
of the available data predated the recent grading and staging system of
chronic viral hepatitis. Almost all studies agreed that the more tissue
there is, the greater is the diagnostic accuracy—a fact that has to be
balanced against the patient';s safety (primum non nocere). The traditional
assumption that a sample 1.5 mm long or containing four to six portal
tracts, or both, is adequate is no longer true for the grading and staging
of chronic hepatitis. In fact, none of the studies using this standard
length produced consistent results[57,58,64,66-69,75] and when
different-sized samples were compared, the smaller specimens resulted in a
diagnosis of less severe[69,70,75] Samples at least 2 cm long can ensure
greater diagnostic accuracy.[63,67,69,70] Below this length, grade and stage
are significantly underestimated.[75] As for the portal tracts, their number
clearly correlates with sample size,[73-75] and there is evidence that four
to five portal tracts are not enough, not for grading and staging at least;
with fewer than 11 to 15 portal tracts, grade and stage are significantly
underestimated.[75] The study by Colloredo et al[75] introduced the concept
of a "minimum number of complete portal tracts." The lower number of
complete portal tracts may explain the lower diagnostic accuracy obtained
with smaller samples.[68,71,73]
Although technological advances are making medical practice progressively
less bloody and painful (e.g., with the wider diffusion of mini-invasive
surgery and refinement of endoscopic techniques), many medical procedures in
daily practice nevertheless remain invasive. Invasiveness is a feature of
both therapeutic and diagnostic procedures, including morphological
analyses, and liver biopsies are no exception. Their potential harmfulness
is often stressed in the current lively debate on whether it is appropriate
to take liver biopsies in chronic viral hepatitis. "First, do no harm."[76]
No one would disagree with this ethic, but this is not necessarily the same
as saying "Do no biopsy." Harm can also be done by failing to perform a
biopsy[77] or by basing action on the strength of an inadequate sample.
In the current scenario of chronic viral hepatitis, the main goal of liver
biopsy is to grade and stage the liver damage for prognosis and treatment.
An adequate (although probably still imperfect) sample, pending the
availability of reliable noninvasive methods, needs to be at least 2 cm long
and to contain no fewer than 11 complete portal tracts.
Procedures for obtaining such an "adequate" biopsy sample are currently
available and in routine use at most liver units.
While this article was in press, two additional articles have been published
dealing with the same topic. In the first one, Bedossa et al, (Hepatology
2003; 38:1446-57) addressed the problem of sampling variability by using a
virtual, computer assisted, analysis. In the second, Brunetti et al (J
Hepatol 2004; 40:501-6) evaluated the diagnostic yield of a series of
paired, fine and coarse liver blopsies obtained in 149 consecutive patients
with chronic hepatitis C. Both these studies further support our conclusions
on the characteristics of liver sample to be considered adequate for
assessing grading and staging in chronic hepatitis.
CME Information
The print version of this article was originally certified for CME credit.
For accreditation details, contact the publisher. Seminars in Liver Disease,
Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001.
Reprint Address
Maria Guido, M.D., Istituto di Anatomia Patologica, Via Gabelli, 61, 35100
Padova, Italy. E-mail: mguido@unipd.it.
Abbreviation Notes
CAH, chronic active hepatitis; CT, computed tomography; HBV, hepatitis B
virus; HCV, hepatitis C virus; US, ultrasound
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