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Keywords:

  • Fibrosis;
  • liver biopsy;
  • noninvasive markers

Abstract

  1. Top of page
  2. Abstract
  3. Liver biopsy: strengths and weaknesses
  4. Non-invasive markers: strengths and weaknesses
  5. Non-invasive fibrosis markers and/or liver biopsy in chronic viral hepatitis?
  6. Conflicts of interest
  7. References

Chronic viral hepatitis is a prolonged inflammatory disease of the liver that may lead to the development of fibrosis, necro-inflammation and other associated pathological features. Because fibrosis and its end-point cirrhosis are the main causes of morbidity and mortality, fibrosis assessment is considered as the most relevant information for the evaluation of the severity of the disease and as a useful indicator for prognosis and treatment decision. Because fibrosis implies morphological damage, liver biopsy has come to be the natural gold standard for staging the disease. However, the high prevalence of chronic hepatitis C in addition to the cost and constraints generated by this procedure have triggered an intensive search for alternative methods for fibrosis evaluation. In this article, the strengths and weaknesses of liver biopsy and of non-invasive markers will be reviewed and their respective roles in management of patients with chronic hepatitis C will be discussed.


Liver biopsy: strengths and weaknesses

  1. Top of page
  2. Abstract
  3. Liver biopsy: strengths and weaknesses
  4. Non-invasive markers: strengths and weaknesses
  5. Non-invasive fibrosis markers and/or liver biopsy in chronic viral hepatitis?
  6. Conflicts of interest
  7. References

Liver biopsy is a time-honoured procedure that has given rise to landmarks in hepatology. In clinical practice, it has been widely used for the diagnosis and management of patients with liver disease. In the field of research, liver biopsy has provided an insight into the physiopathology, contributing to a better understanding of liver disease mechanisms. For therapeutic purposes, biopsy has been used for treatment decision as it can accurately assess treatment efficacy and adverse effects. However, the better evaluation of risks and limitations involved in this procedure has fuelled discussion on the right place of liver biopsy.

Because liver biopsy is an invasive method, there are potential adverse effects and complications that have been comprehensively reviewed in retrospective and prospective studies (1–8). Transient and moderate pain, along with anxiety and discomfort, are common (5–20%), while vaso-vagal episodes are infrequent. Severe complications such as a haemoperitoneum, biliary peritonitis and pneumothorax are rare (0.3–0.5%). Death is exceedingly rare, but has occasionally been reported for biopsies in advanced liver diseases and haemorrhagical tumours and in patients with major comorbidities. Because of these adverse events, patients may be reluctant to undergo a biopsy, but the acceptability by the patients remains highly dependent on the physician's convictions and belief in biopsy.

Certain precautions and means minimize the risks of adverse events. A biopsy via the transjugular route greatly reduces the risk of bleeding in patients with advanced liver disease and coagulation disorders. Biopsy conducted by a trained physician, use of only a limited number of passes and ultrasound guidance can significantly decrease the risk of complications, thereby enhancing the safety of biopsy. However, even if these recommendations are closely followed, a liver biopsy will never be completely safe. Therefore, a liver biopsy should be performed only after carefully balancing the risks of the procedure with potential benefits in terms of patient management.

The main drawbacks of liver biopsy as a diagnostic procedure lie in sampling and observation errors (9). Because a liver biopsy involves only a very small part of the whole organ, there is a risk that this part might be irrelevant for evaluation of any lesion in the whole liver because of heterogeneity in its distribution. This risk is partly theoretical, because liver fibrosis and inflammation occur during the course of chronic disease that affects the whole organ. Extensive literature has shown that increasing the length of a liver biopsy decreases the risk of sampling error (10–12). Length and width thresholds have been discussed by several authors. Except for cirrhosis, for which microfragments may be sufficient, a 25-mm-long biopsy is considered an optimal specimen for accurate evaluation, although 15 mm is considered sufficient in most studies. In addition to the length, the width of the core is of importance, and it has been clearly shown that samples obtained with a fine needle biopsy (20–22 G needle) are inappropriate for accurate staging and grading in chronic liver diseases, whereas a biopsy obtained with a 16–18 G needle is much more relevant for this purpose (13).

Observer variation is another potential limitation of biopsy that is related to the discordance between pathologists in biopsy interpretation. The use of histopathological scoring systems for evaluation of fibrosis and necro-inflammation has limited this drawback. Several studies have shown that observer variation is higher for grading than staging, and in terms of fibrosis scores, concordance between pathologists is considered satisfactory (14, 15). Training and specialization of pathologists is of major importance for reducing observer variation, and problems related to interobserver variation would be alleviated if pathologists have a subspecialty in liver pathology for several years and practice within an academic department (16). Thus, although a liver biopsy has its limitations, appropriate precautions may reduce the flaws inherent in this method.

Besides these limitations, a liver biopsy provides invaluable information that none of the non-invasive markers provide. Owing to their accuracy, standardized scoring systems for evaluation of fibrosis (staging) have proven to be relevant for describing the natural history of chronic liver diseases through assessment of the rate of progression of the disease. It is noteworthy that staging of fibrosis combines evaluation of several histological features including assessment of the extent of extracellular matrix deposition, the localization of the deposition within the liver lobule and changes in lobular architecture. These features are then integrated into a semiquantitative scoring system (17, 18). This level of accuracy is particularly important in the context of viral hepatitis, where a distinction between F1 and F2 Metavir stage is often used to make the decision to treat a patient with antiviral therapy, and distinguishing F3 from F4 is important for screening and preventing complications such as portal hypertension and hepatocellular carcinoma.

Although strong input has been placed in evaluation of fibrosis as a major decision criterion for hepatologists, fibrosis is only one among the many elementary histopathological features present at the same time in a liver biopsy. In effect, fibrosis is not an autonomous feature, but rather scar tissue resulting from other pathobiological mechanisms such as inflammatory, degenerative or dystrophic processes. In order to provide relevant information, fibrosis should be viewed in light of its histopathological context. Simultaneous evaluation of necro-inflammation (portal tract inflammation, interface hepatitis and lobular inflammation) enables assessment of 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. Frequently, biopsy also detects associated lesions such as steatosis, steatohepatitis, iron overload, etc., which provide useful information for patient management and prognosis (19).

Finally, it is noteworthy that, in diseases with a high burden like hepatitis C, a liver biopsy may also reveal that abnormal liver function tests are related to an unexpected liver disease other than hepatitis C. Clearly, all this information may influence patient management. Therefore, equating chronic liver disease with only the extent of fibrosis is an oversimplification that may be misleading.

Non-invasive markers: strengths and weaknesses

  1. Top of page
  2. Abstract
  3. Liver biopsy: strengths and weaknesses
  4. Non-invasive markers: strengths and weaknesses
  5. Non-invasive fibrosis markers and/or liver biopsy in chronic viral hepatitis?
  6. Conflicts of interest
  7. References

The main alternatives to liver biopsy that have been developed in the past 10 years are based on two very different concepts: serum markers and liver stiffness (20). They differ substantially both in their rationale and in their concepts but they both have an obvious advantage: they are non-invasive procedures. Although they both generate a significant cost and are not available everywhere, they are easy to handle, and with some adequate precautions, can both considered as highly reproducible procedures.

Stiffness, as assessed by ultrasound (Fibroscan, Echosens, France) and more recently by magnetic resonance scanning, evaluates the velocity of propagation of a shock wave within the liver tissue. This method examines a physical parameter of liver tissue that is related to its elasticity. The rationale behind it is that normal liver is viscous and not favourable to wave propagation, whereas fibrosis increases the hardness of the tissue and favours more rapid propagation. The main drawback of this approach is that additional space-occupying lesions often encountered in hepatitis C such as steatosis, oedema and inflammation develop within an organ wrapped in a distensible but non-elastic envelope (Glisson's capsula), and contribute to modifying liver texture acting as a confounding factor when stiffness is concerned. Nevertheless, there exist strong arguments supporting the hypothesis that elasticity parallels the stage of fibrosis at precirrhotic or cirrhotic stages. A recent meta-analysis showed that the area under the receiver operating curve (AUROC) value of Fibroscan reaches a very high value for the diagnosis of cirrhosis (21). However, it is noteworthy that changing the definition of ‘diseased’ liver from F4 to F3F4 or F2F3F4 is associated with a progressive decrease in the AUROC value, suggesting that this approach is valid for the diagnosis of cirrhosis but less adequate when assessing the transition from one stage to a higher one. Finally, an additional advantage of Fibroscan is that this approach provides a wide range of stiffness values within the group of cirrhotic livers that would overcome one major limitation of the biopsy (i.e. one histological stage for all types of cirrhosis), and could thus provide an additional prognostic value within this group.

Serum markers are combinations of several blood parameters that are optimized to mirror the stage of liver fibrosis. Several markers are already available, with some being free of access, while others are commercially available [for a review, see (20)]. Despite the wide number of proposed combinations, they are all designed in the same way: they are meant to optimize the choice of blood parameters and to maximize the algorithm to match histological stages as assessed using a liver biopsy. This is a fundamental difference compared with Fibroscan. While Fibroscan assesses one genuine characteristic of liver tissue, the serum marker algorithm is constructed to mimic a biopsy irrespective of the biopsy accuracy. Therefore, any limitation of the biopsy procedure will also negatively impact the performances of serum markers. Nevertheless, the most widely tested serum markers have demonstrated acceptable accuracy for the diagnosis of significant vs non-significant fibrosis (22, 23).

One major limitation of any of these surrogates lies in their concept and/or their validation using a dichotomized approach (significant vs non-significant fibrosis). In addition to the question of what should be considered to be ‘significant’ fibrosis, a definition that is variable according to the study and aims pursued, staging fibrosis cannot be summed up by such a binary approach. The dichotomized approach used for surrogates is imposed by the use of AUROC that tests a binary hypothesis. Using this approach, there is a significant loss of information and a dependence on the proportion of each stage of fibrosis in the study sample. In most works, these limitations have been artificially bypassed by considering the different histological stages as linear variables and extrapolating intermediate values for each of the stages. However, this is an erroneous supposition as scores are categories, not continuous variables. When considering the extent of fibrosis, one component of fibrosis stage that can be easily quantified by image analysis, studies have shown the absence of linearity between the extent of fibrosis and histological stage (24, 25). Such an approximation explains why, when considering only adjacent stages (F1 vs F2 or F2 vs F3 …), AUROC values are unacceptably low, leading to considering these surrogates as inadequate tools for individual follow-up (22).

Finally equating chronic liver disease with the fibrosis alone is an oversimplification that could be useful for physicians but could also be misleading. Other surrogates that have been developed for the non-invasive approach of other associated features have not been extensively validated and suffer from the same drawbacks.

Non-invasive fibrosis markers and/or liver biopsy in chronic viral hepatitis?

  1. Top of page
  2. Abstract
  3. Liver biopsy: strengths and weaknesses
  4. Non-invasive markers: strengths and weaknesses
  5. Non-invasive fibrosis markers and/or liver biopsy in chronic viral hepatitis?
  6. Conflicts of interest
  7. References

The French Health Authority wisely stated that surrogate markers are valid approaches to assess significant fibrosis or cirrhosis but are not valid for individual follow-up or in case of associated comorbidities (which are often discovered on the biopsy alone).

This statement suggests that surrogate markers should be used alone when there is no discussion in indications for treatment such as patients with hepatitis C, genotype 2 or 3, who will always be treated or patients in whom treatment is mandatory for other reasons such as severe extrahepatic manifestations. Patients with contraindications to antiviral drugs should also not be biopsied on first evaluation. In these contexts, a rough evaluation of significant vs non-significant fibrosis with a non-invasive marker seems adequate, but the biopsy should be performed if any abnormal symptom or atypical evolution occurs. Similarly, a biopsy is not mandatory in patients with obvious cirrhosis taking into consideration the excellent performance of non-invasive markers for confirming such a diagnosis.

When a discussion to treat or not treat a patient is raised, then biopsy comes first. This encompasses all patients with hepatitis B and hepatitis C with genotype 1. Because antiviral drugs are far from being completely efficacious and might have significant adverse effects, an accurate evaluation of liver lesions with a biopsy is needed. This will rely on a biopsy because non-invasive markers would confidently diagnose only cirrhosis, a stage where antiviral treatments are less effective and the chances of a cure are lower.

Finally, and as stated recently by the American Gastroenterological Association, ‘Neither clinical nor laboratory markers, individually or in combination, predict accurately the degree of necroinflammatory activity or the level of fibrosis in the liver. Therefore, despite sampling error, liver biopsy remains the gold standard for determining histologic grade and stage. Patients in whom antiviral therapy is being considered are candidates for liver biopsy to assess the current status of the liver and to provide prognostic information for future disease progression’ (26). The major question that remains concerns the time point at which such an accurate evaluation is needed.

References

  1. Top of page
  2. Abstract
  3. Liver biopsy: strengths and weaknesses
  4. Non-invasive markers: strengths and weaknesses
  5. Non-invasive fibrosis markers and/or liver biopsy in chronic viral hepatitis?
  6. Conflicts of interest
  7. References