Additional Information/Liver Biopsy and Noninvasive Tests For Fibrosis
.
How to assess liver fibrosis in chronic hepatitis C: serum markers or transient elastography vs. liver biopsy?
.
Laurent Castera1,
Pierre Bedossa2
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02380.x
© 2011 John Wiley & Sons A/S
Laurent Castera1,
Pierre Bedossa2
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02380.x
© 2011 John Wiley & Sons A/S
.
Abstract
The assessment of liver fibrosis is a major issue in the management of patients with chronic hepatitis C. Liver biopsy has traditionally been considered the gold standard for the evaluation of tissue damage, including fibrosis. In addition, it detects associated lesions such as steatosis, steatohepatitis or iron overload, which provide useful information for patient management and prognosis. Liver biopsy is, however, an invasive procedure, with a risk of rare but potentially life-threatening complications and it is prone to sampling errors. These limitations have led to the development of non-invasive methods.
Currently available tests rely on two different but complementary approaches: (i) a ‘biological’ approach based on the dosage of serum biomarkers of fibrosis; (ii) a ‘physical’ approach based on the measurement of liver stiffness, using transient elastography. Although significant progress has been made in the non-invasive diagnosis of fibrosis, it is increasingly clear that these methods will not completely replace liver biopsy. Instead, non-invasive methods and liver biopsy should be used in an integrated approach for more efficient and convenient management of patients with chronic hepatitis C.
The aim of this review is to discuss the advantages and limitations of liver biopsy and non-invasive methods and the perspectives for their use in clinical practice.
Liver fibrosis is a result of excessive extracellular matrix deposition in the liver in response to chronic inflammatory injury triggered by persistent hepatitis C virus in the liver. Hepatic fibrosis is determined by the replication balance between fibrogenesis and fibrosis degradation. When this balance favours fibrogenesis, there is a resulting accumulation of collagen and extracellular matrix, leading eventually to cirrhosis. Liver fibrosis and its end-point cirrhosis are the main causes of morbidity and mortality in patients with hepatitis C virus (HCV) infection (1, 2). Besides the development of antiviral drugs, there are intensive efforts to develop drugs to effectively target the mechanism of fibrogenesis or to eliminate fibrous tissue once it has accumulated in the liver (3). Therefore, the assessment of liver fibrosis is a major issue in the management of patients with chronic HCV infection (4, 5).
.
Liver biopsy
For many years, liver biopsy has been considered the gold standard for the evaluation of tissue damage including fibrosis. Histological assessment is based on semiquantitative scoring systems (METAVIR, Ishak score) (4, 5). Fibrosis is scored in stages while necroinflammation is evaluated by grade. Staging fibrosis is an assessment of the combination of the amount of fibrosis and architectural disorganization. These semiquantitative histological scores have been used successfully for years in both clinical trials and for individual evaluation.
However, liver biopsy has certain drawbacks. Because liver biopsy only samples a very small part of the whole organ, there is a risk that this part might be irrelevant in the evaluation of lesions that are heterogeneously distributed throughout the entire liver (5). This may be true for tissue fibrosis. There is extensive literature showing that increasing the length of the liver biopsy decreases the risk of sampling error (6, 7). Except for cirrhosis, for which microfragments may be sufficient (8), a 25 mm long biopsy is considered an optimal specimen for accurate evaluation, while 15 mm is considered sufficient in most studies.
For many years, liver biopsy has been considered the gold standard for the evaluation of tissue damage including fibrosis. Histological assessment is based on semiquantitative scoring systems (METAVIR, Ishak score) (4, 5). Fibrosis is scored in stages while necroinflammation is evaluated by grade. Staging fibrosis is an assessment of the combination of the amount of fibrosis and architectural disorganization. These semiquantitative histological scores have been used successfully for years in both clinical trials and for individual evaluation.
However, liver biopsy has certain drawbacks. Because liver biopsy only samples a very small part of the whole organ, there is a risk that this part might be irrelevant in the evaluation of lesions that are heterogeneously distributed throughout the entire liver (5). This may be true for tissue fibrosis. There is extensive literature showing that increasing the length of the liver biopsy decreases the risk of sampling error (6, 7). Except for cirrhosis, for which microfragments may be sufficient (8), a 25 mm long biopsy is considered an optimal specimen for accurate evaluation, while 15 mm is considered sufficient in most studies.
Observer variation is another potential limitation of biopsy that is related to the difference between pathologist's interpretation of the biopsy (6, 9, 10). The use of histopathological scoring systems for the evaluation of fibrosis has limited this drawback and several studies have shown that agreement between pathologists is satisfactory, especially when the staging of fibrosis is performed by specialized liver pathologists (9, 10). Thus, although liver biopsy has its limitations, appropriate precautions may reduce the flaws inherent in this method.
Because liver biopsy is invasive, the only serious limitations are the potential adverse effects and complications that have been comprehensively reviewed elsewhere (11). Transient and moderate pain along with anxiety and discomfort are common (12, 13). Severe complications such as haemoperitoneum, biliary peritonitis and pneumothorax are rare (0.3–0.5%). Death is exceedingly rare, but has been reported occasionally for biopsies in advanced liver diseases, haemorrhagical tumours and in patients with major comorbidities.
A biopsy via the transjugular route considerably reduces the risk of bleeding in patients with advanced liver disease and coagulation disorders. Biopsy performed by a trained physician, limiting the number of passes and ultrasound guidance can significantly decrease the risk of complications, thus increasing the safety of biopsy. Nevertheless, a liver biopsy should be performed only after carefully balancing the risks of the procedure with the potential benefits in terms of patient management. Despite these limitations, liver biopsy provides invaluable information that none of the non-invasive markers provide. Although the evaluation of fibrosis is a major decision criterion for hepatologists, fibrosis is only one of the many elementary histopathological features present on liver biopsy. In effect, fibrosis is not an autonomous feature, but scar tissue resulting from other pathobiological mechanisms such as inflammatory, degenerative or dystrophical processes.
The simultaneous evaluation of necroinflammation (portal tract inflammation, interface hepatitis, lobular inflammation) shows whether fibrosis is the result of a past event that has stabilized or even regressed or is an ongoing process that may continue to worsen. Associated lesions such as steatosis, steatohepatitis, iron overload, etc., which provide useful information for patient management and prognosis, can also frequently be detected with biopsy (14).
Finally, in difficult diseases such as hepatitis C, liver biopsy may also reveal that abnormal liver function tests are related to unexpected liver diseases other than hepatitis C (15). Clearly, all this information may influence patient management. Therefore, limiting the definition of chronic liver disease to the extent of fibrosis is an oversimplification that may be misleading.
.
Finally, in difficult diseases such as hepatitis C, liver biopsy may also reveal that abnormal liver function tests are related to unexpected liver diseases other than hepatitis C (15). Clearly, all this information may influence patient management. Therefore, limiting the definition of chronic liver disease to the extent of fibrosis is an oversimplification that may be misleading.
.
Non-invasive methods for the assessment of liver fibrosis
There are two distinct approaches among the currently available non-invasive methods: (i) a physical approach based on the measurement of liver stiffness using transient elastography (TE); (ii) a biological approach based on serum biomarkers of fibrosis (16). Although complementary, these two approaches are based on different rationales and conceptions: TE measures liver stiffness in relation to elasticity, corresponding to a genuine and intrinsic physical property of the liver parenchyma, while serum biomarkers are a combination of several, not strictly liver-specific blood parameters optimized to mimic the stages of fibrosis as assessed by liver biopsy (17).
There are two distinct approaches among the currently available non-invasive methods: (i) a physical approach based on the measurement of liver stiffness using transient elastography (TE); (ii) a biological approach based on serum biomarkers of fibrosis (16). Although complementary, these two approaches are based on different rationales and conceptions: TE measures liver stiffness in relation to elasticity, corresponding to a genuine and intrinsic physical property of the liver parenchyma, while serum biomarkers are a combination of several, not strictly liver-specific blood parameters optimized to mimic the stages of fibrosis as assessed by liver biopsy (17).
Numerous biomarkers have been proposed in hepatitis C (18, 19, 20) but the most widely used and validated with TE are the aspartate-to-platelet ratio index (APRI) (a free non-patented index) and the FibroTest (21, 22, 23).
The results of TE and serum biomarkers for the diagnosis of significant fibrosis have been shown to be equivalent in patients with chronic hepatitis C infection (24, 25). Indeed, in the largest study to date (n=1307) (25), comparing TE with several patented and non-patented biomarkers (FibroTest, Fibrometre, Hepascore and APRI) and using liver biopsy as a reference, the AUROCs of TE (0.76) did not differ from those of serum biomarkers (0.72–0.78).
In order to increase the diagnostic accuracy of these tests, the sequential combination of biomarkers (26, 27) or the concomitant combination of TE and biomarkers (24, 28, 29) has been proposed. The latter strategy may be more effective for diagnosing significant fibrosis, leading to a reduction in the use of liver biopsy in more than 70% of cases compared with 50% when using biomarkers (APRI and FibroTest) sequentially (30). Another advantage of combining two unrelated methods such as TE and biomarkers rather than two biomarkers is that TE provides a more direct measurement of liver structure than biomarkers and there is no relationship between the applicability of TE and biomarkers such as the FibroTest (28).
For the diagnosis of cirrhosis, the situation is different because TE appears to be the most accurate method compared with currently available biomarkers and routine blood tests, preventing the need for a liver biopsy in around 90% of cases (25, 31). As a result, a combination of both methods does not seem to increase the diagnostic accuracy (30).
,
Serum markers
Although the applicability and interlaboratory reproducibility of different tests have been shown to be satisfactory for use in clinical practice (32, 33), interpretation of each test requires critical analysis to avoid false-positive or false-negative results (34).
Although the applicability and interlaboratory reproducibility of different tests have been shown to be satisfactory for use in clinical practice (32, 33), interpretation of each test requires critical analysis to avoid false-positive or false-negative results (34).
.
Transient elastography
Although the reproducibility of TE has been shown to be excellent for inter- and intra-observer agreement (35, 36), its applicability may not be as good as that of biomarkers. Indeed, in our experience of more than 13 000 exams over a 5-year period, liver stiffness measurements (LSM) could not be interpreted in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results that did not meet the manufacturer's recommendations in 17%) (37). The principal reasons were obesity, particularly increased waist circumference, and limited operator experience.
Although the reproducibility of TE has been shown to be excellent for inter- and intra-observer agreement (35, 36), its applicability may not be as good as that of biomarkers. Indeed, in our experience of more than 13 000 exams over a 5-year period, liver stiffness measurements (LSM) could not be interpreted in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results that did not meet the manufacturer's recommendations in 17%) (37). The principal reasons were obesity, particularly increased waist circumference, and limited operator experience.
Finally, because the liver is an organ wrapped in an expandable but non-elastic envelope (Glisson's capsula), additional space-occupying tissue abnormalities independent of fibrosis, such as oedema and inflammation, cholestasis and congestion, may interfere with LSM. The risk of overestimating liver stiffness values has been reported in the case of alanine aminotransferase flares in patients with acute viral hepatitis or chronic hepatitis B (38, 39, 40) as well as in cases of extrahepatic cholestasis (41) or congestive heart failure (42).
How to use liver biopsy and non-invasive methods in clinical practice?
A liver biopsy should be performed in the case of comorbidities such as alcoholism or metabolic syndrome when non-invasive methods cannot be used or in any unclear situation such as discordant results of non-invasive tests. Conversely, liver biopsy should not be performed when the clinical diagnosis is obvious (cirrhosis) or when no benefit can be expected from the biopsy for patient management. Although there is no optimal threshold, the longer the specimen, the more accurate the staging will be (43). A 20–25 mm long biopsy is considered optimal although a robust evaluation is often possible on a 15 mm long biopsy. Ideally, the biopsy should be read by an experienced liver pathologist because it decreases the source of variability in the histological interpretation (44).
In naïve patients without comorbidities who are candidates for antiviral treatment, non-invasive tests can be used for the first-line staging of fibrosis. The use of either TE or several patented biomarkers (FibroTest, Fibrometer and Hepascore) has recently been recommended, based on an independent systematic review by the French Health Authorities (45). However, this strategy should also take into account HCV genotype, local availability of non-invasive methods and any clinically relevant variable.
.
For instance, when there is a strong clinical suspicion of cirrhosis, in most cases the use of TE is enough to confirm the diagnosis without a liver biopsy. Conversely, a liver biopsy may be necessary to differentiate between F1 and F2 in genotype 1-infected patients before making a decision on antiviral treatment. In the same way, a liver biopsy may be useful to differentiate between F3 and F4 when cirrhosis is not clinically obvious and to decide when to start screening for hepatocellular carcinoma. However, with the availability of new antiviral treatments (46, 47), differentiating between F1 and F2 may not be as important for treatment indications.
When deciding on retreatment, a liver biopsy may be indicated to investigate the presence of factors of impaired response such as non-alcoholic steatohepatitis or to obtain a prognosis especially if a liver biopsy has not been performed previously.
When deciding on retreatment, a liver biopsy may be indicated to investigate the presence of factors of impaired response such as non-alcoholic steatohepatitis or to obtain a prognosis especially if a liver biopsy has not been performed previously.
Finally, non-invasive methods can be of interest in the follow-up of untreated patients (48). Given the slow rate of the progression of fibrosis in chronic hepatitis C, a non-invasive evaluation can be performed on a yearly basis.
There is an urgent need to pursue the development of non-invasive tests in addition to a liver biopsy for the staging of fibrosis. Because of the conditional relationship with biopsy, the development of serum markers will always have obvious limitations. Promising preliminary results suggest that novel alternative imaging techniques such as magnetic resonance elastography, acoustic radiation force impulse imaging or perfusion computed tomography will eventually be refined to reach an acceptable level of accuracy, especially for the evaluation of early and intermediate stages of fibrosis (49–51). These might become less pertinent as antiviral treatments become more efficient, with fewer side effects.
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Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology 2002; 36 (Suppl. 1): S47–56.
Direct Link:
Abstract
PDF(1161K)
References
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Talwalkar JA. Antifibrotic therapies – emerging biomarkers as treatment end points. Nat Rev Gastroenterol Hepatol 2010; 7: 59–61.
CrossRef,
ChemPort,
Web of Science® Times Cited: 1
4
Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR cooperative study group. Hepatology 1996; 24: 289–93.
Direct Link:
Abstract
PDF(977K)
References
5
Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696–9.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 1661
6
Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002; 97: 2614–8.
Direct Link:
7
Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003; 38: 1449–57.
PubMed,
Web of Science® Times Cited: 539
8
Colloredo G, Guido M, Sonzogni A, et al. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol 2003; 39: 239–44.
PubMed,
Web of Science® Times Cited: 236
9
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.
PubMed
10
Goldin RD, Goldin JG, Burt AD, et al. Intra-observer and inter-observer variation in the histopathological assessment of chronic viral hepatitis. J Hepatol 1996; 25: 649–54.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 73
11
Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology 2000; 32: 477–81.
PubMed,
ChemPort,
Web of Science® Times Cited: 295
12
Castera L, Negre I, Samii K, et al. Pain experienced during percutaneous liver biopsy. Hepatology 1999; 30: 1529–30.
Direct Link:
Abstract
PDF(52K)
References
13
Castera L, Negre I, Samii K, et al. Patient-administered nitrous oxide/oxygen inhalation provides safe and effective analgesia for percutaneous liver biopsy: a randomized placebo-controlled trial. Am J Gastroenterol 2001; 96: 1553–7.
ChemPort
14
Bedossa P, Moucari R, Chelbi E, et al. Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study. Hepatology 2007; 46: 380–7.
PubMed,
ChemPort,
Web of Science® Times Cited: 28
15
Saadeh S, Cammell G, Carey WD, et al. The role of liver biopsy in chronic hepatitis C. Hepatology 2001; 33: 196–200.
Direct Link:
Abstract
PDF(126K)
References
16
Castera L, Pinzani M. Non-invasive assessment of liver fibrosis: are we ready? Lancet 2010; 375: 1419–20.
17
Bedossa P, Carrat F. Liver biopsy: the best, not the gold standard. J Hepatol 2009; 50: 1–3.
PubMed
18
Pinzani M, Vizzutti F, Arena U, et al. Technology Insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol Hepatol 2008; 5: 95–106.
PubMed,
ChemPort,
Web of Science® Times Cited: 48
19
Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008; 134: 1670–81.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 49
20
Castera L, Pinzani M. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango? Gut 2010; 59: 861–6.
21
Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134: 960–74.
PubMed,
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