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With the new drugs to treat hepatitis C now FDA approved some people are asking if a liver biopsy will be in the mix. Today on the blog we will discuss the newest guidelines presented at the 2011 EASL and the 2009 guidelines from the AASLD in regard to the latest recommendations for undergoing a liver biopsy in the HCV population .
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Alternative noninvasive tests will be covered with links to data that should help aid in a clear understanding of what is available, and how reliable these noninvasive tests are. The patient and their physician will determine if a liver biopsy may be useful, the information provided here today will also give you an update on the noninvasive tests available to monitor disease progression.
Noninvasive measurements (blood tests) of liver fibrosis biomarkers are an alternative to liver biopsy for diagnosing the degree of fibrosis due to HCV infection .The various biomarker tests included in this entry are as follows;
Fibrotest, Fibrometer, Hepascore, AST: platelet ratio index (APRI), Forms, Fib-4, and SHASTA.
Also included is transient elastography (ultrasound-based scan) which is a non-invasive method for evaluating liver fibrosis by measurement of liver stiffness. Better known as FibroScan; the method has been shown to be reliable in the assessment of liver fibrosis in patients with chronic hepatitis C.
According to a paper published in the Jan 2011 issue of Liver International, combined use of transient elastography- TE, example "Fibroscan" and biomarkers (blood test) example "APRI and Fibrotest" could help most patients avoid a liver biopsy who have chronic hepatitis. As noted by the authors;
Numerous biomarkers have been proposed in hepatitis C (18, 19, 20) but the most widely used and validated with transient elastography-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).
In the same paper entitled; How to assess liver fibrosis in chronic hepatitis C: serum markers or transient elastography vs. liver biopsy? the authors concluded that non-invasive tests can be used for the first-line staging of fibrosis in naive patients who will be treating HCV with antiviral therapy, .
Excerpted;
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 transient elastography - TE or several patented biomarkers (FibroTest, Fibrometer and Hepascore) has recently been recommended, based on an independent systematic review by the French Health Authorities . However, this strategy should also take into account HCV genotype, local availability of non-invasive methods and any clinically relevant variable.
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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 "minimal scarring" and F2 "scarring has occurred and is inside the areas of 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 "bridging fibrosis (the fibrosis is spreading and connecting to other areas that contain fibrosis" and F4 "cirrhosis" when cirrhosis is not clinically obvious and to decide when to start screening for hepatocellular carcinoma. However, with the availability of new antiviral treatments, differentiating between F1 and F2 may not be as important for treatment indications.
the liver including blood vessels"
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 . Given the slow rate of the progression of fibrosis in chronic hepatitis C, a non-invasive evaluation can be performed on a yearly basis
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Using Noninvasive Tests To Evaluate Liver Disease Severity Earlier
From Medwire
These noninvasive tests - FibroTest (a liver biomarker test) and liver stiffness (measured by ultrasound scan example;FibroScan) - may help clinicians evaluate liver disease severity earlier in the disease process, and to decide if liver transplant, portosystemic shunts, or surgery will be required by the patient at a later date, say the authors.Reported in the March 2011 issue of journal Gastroenterology an analysis showed that FibroTest and liver stiffness measurements had high predictive accuracies for 5-year chronic hepatitis C survival, with respective area under the receiver operating characteristic curve (AUC) values of 0.80 and 0.82.In contrast, liver biopsy had a lower, albeit clinically acceptable, AUC value of 0.76.The findings arise from a study involving 1457 patients with chronic hepatitis C who were followed-up for 5 years. You can view the abstract here.
Noninvasive Blood Tests (Biomarker Test)
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Fibrotest-FibroTest, known as FibroSure in the US, is a patented biomarker test that uses the results of blood serum tests to generate a score that is correlated with the degree of liver damage in people with a variety of liver diseases. The HCV-FibroSure Test includes the following five markers, as well as age and gender: alpha2-macroglobulin, haptoglobin, gamma-glutamyl transpeptidase (GGT), total bilirubin, apolipoprotein A1, plus alanine aminotransferase (ALT).
Fibrotest-FibroTest, known as FibroSure in the US, is a patented biomarker test that uses the results of blood serum tests to generate a score that is correlated with the degree of liver damage in people with a variety of liver diseases. The HCV-FibroSure Test includes the following five markers, as well as age and gender: alpha2-macroglobulin, haptoglobin, gamma-glutamyl transpeptidase (GGT), total bilirubin, apolipoprotein A1, plus alanine aminotransferase (ALT).
APRI AST: platelet ratio index (APRI),
Abbreviation: (APRI), Definition: AST to platelet ratio index
APRI Score is an easy, low cost and practice alternative method which was described as an alternative for assessing structural changes in chronic hepatitis C .The APRI was designed to be a convenient marker of fibrosis because it incorporates laboratory data that are routinely obtained as the standard of care. Initial studies showed that it performed well in predicting fibrosis and cirrhosis in both a training and validation set of adults with chronic HCV infection. APRI, calculates only the AST to platelet ratio .
Fibrotest and APRI
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Forns: A non-invasive method for monitoring liver disease . The Forns' score combines age, gGT, cholesterol, and platelet count.platelet count.
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Fib-4 A non-invasive method for monitoring liver disease. FIB-4 score, is based on a calculation of a person’s age, alanine transaminase (ALT) levels and the ratio of aspartate transaminase (AST) levels to platelet count.
SHASTA A non-invasive method for monitoring liver disease. The SHASTA index developed consists of serum hyaluronic acid, AST, and albumin
Fibrometer-FibroMeters are non-invasive blood tests for liver fibrosis . The score combines hyaluronate, prothrombin time, platelets, AST, a2 macroglobulin, urea, and age, and the formula is adjusted based on the cause of the liver disease.
EASL 2011- FibroMeter
This study, performed in several populations with C hepatitis, shows that the detailed classification in fibrosis stages of FibroMeter3G (1) is as performant as that of an expert pathologist and significantly superior to that of a first line pathologist or that of other non-invasive tests.
CirrhoMeter is the first validated and marketed test for cirrhosis diagnosis
EASL 2011-CirrhoMeter
This study, performed in 1710 C hepatitis, shows that the CirrhoMeter (5) offers an excellent cirrhosis diagnosis: accuracy superior to that of Fibroscan, on an intention to diagnose basis, with a higher precision
EASL 2011-During the last EASL meeting (Berlin), 5 communications on CirrhoMeter and FibroMeters were presented.
Hepascore- Hepascore is an Australian blood test combining the following clinical and laboratory variables: age, gender, bilirubin, GGT, hyaluronic acid, alpha 2 macroglobin to create a score.
Physical Non-invasive methods for the assessment of liver fibrosis
Hepatic fibrosis can be assessed through serum markers or by the implementation of new non-invasive techniques, such as elastography.
Transient elastography (TE)
Transient elastography that uses ultrasound and low frequency elastic waves to measure liver elasticity67 has improved the ability to define the extent of fibrosis without a liver biopsy, particularly when combined with other noninvasive markers (blood tests) .68 However, it is not yet ready to replace the liver biopsy since it is not FDA approved, the failure rate is higher in obese patients, and there is now evidence that the transient elastography score can be unexpectedly increased in persons with acute hepatitis who have high necroinflammatory activity but no or minimal fibrosis.
Video FibroScan
Excerpted From;
Assessment of liver disease severity
Assessment of the severity of hepatic fibrosis is important in decision making in chronic hepatitis C treatment and prognosis.
Liver biopsy is still regarded as the reference method to assess the grade of inflammation and the stage of fibrosis [22,23]. The shortcomings of biopsy have been highlighted in recent years and alternate non-invasive methods have been developed and extensively evaluated in patients with chronic HCV infection. They include serological markers and transient elastography [24,25]. Their performance,when used alone or together, has been reported to be comparable with liver biopsy [24,25]. Both non-invasive
methods have been shown to accurately identify patients with mild fibrosis or cirrhosis. They are less able to discriminate moderate and severe fibrosis.[22,23].
Assessment of liver disease severity is recommended prior to therapy. Identifying patients with cirrhosis is of particular importance, as their likelihood of responding to therapy and post-treatment prognosis are altered, and surveillance for HCC is required.
Assessment of the stage of fibrosis by biopsy is not required in patients with clinical evidence of cirrhosis. Since significant fibrosis may be present in patients with repeatedly normal ALT, evaluation of disease severity should be performed regardless of ALT patterns. Endoscopy to rule out esophageal varices and portal hypertension should be performed in patients with known cirrhosis.
Liver biopsy remains the reference method. The risk of severe complications is very low (1/4000–10,000), but biopsy remains an invasive procedure. Histological features (necroinflammation = grading; fibrosis = staging) should be reported using a structured, semi-quantitative method. Various scoring systems have been validated for use in chronic hepatitis C. The most widely used in Europe are METAVIR, Scheuer, Ishak, and Knodell’s HAI [63]. Metavir and Scheuer’s scores are more reproducible and less prone to observer variation, but less discriminant both for fibrosis and for necroinflammation than Ishak and Knodell [64].
Based on the abundant literature in chronic hepatitis C, alternative, non-invasive methods can now be used instead of liver biopsy in patients with chronic hepatitis C to assess liver disease severity prior to therapy at a safe level of predictability.
Transient elastography (TE), can be used to assess liver fibrosis in patients with chronic hepatitis C, provided that consideration is given to factors that may adversely affect its performance such as obesity, age, and biochemical necroinflammatory activity. TE results should be evaluated relative to interquartile range and to the success rate of measurements. TE performs better at detecting cirrhosis than lesser degrees of fibrosis [65,66].
The well established panels of biomarkers of fibrosis can be broadly categorized as those that include commonly performed biochemical and hematological tests, such as ALT, AST, prothrombin time, platelets (APRI, AST/ALT ratio, Forns Index); those that include specific indirect markers of liver fibrosis, such as a-2 macroglobulin; those that incorporate only direct markers of liver fibrosis (MP3), or combinations of direct and indirect markers (Hepascore, Fibrometer). Sufficient evidence exists to support the view that algorithms perform well in the detection of significant fibrosis (METAVIR score F2-F4). Thus, their use in patients
with chronic hepatitis C can be recommended for this purpose.
They all perform less well in the detection of lesser degrees of fibrosis [66–69]. The combination of blood tests or the combination of TE and a blood test improve accuracy and reduce the necessity of using liver biopsy to resolve uncertainty. However, they increase the cost [70].[65,66].
Recommendations
(1) Liver disease severity should be assessed prior to therapy
(B1).
(2) Identifying patients with cirrhosis is of particular importance, as their prognosis and likelihood to respond to therapy are altered, and they require surveillance for HCC (A1).
(3) As liver disease can progress in patients with repeatedly normal ALT levels, disease severity evaluation should be performed regardless of ALT levels (B2).
(4) Assessment of the severity of liver fibrosis is important in decision making in patients with chronic hepatitis C (A1).
(5) Liver biopsy is still regarded as the reference method to assess the grade of inflammation and the stage of fibrosis (A2).
(6) Transient elastography (TE) can be used to assess liver fibrosis in patients with chronic hepatitis C (A2).
(7) Non-invasive serum makers can be recommended for the detection of significant fibrosis (METAVIR score F2–F4) (A2).
(8) The combination of blood tests or the combination of transient elastography and a blood test improve accuracy and reduce the necessity of using liver biopsy to resolve uncertainty
Excerpted From; AASLD
Utility of the Liver Biopsy and Noninvasive
Tests of Fibrosis
There are three primary reasons for performing a liver biopsy: it provides helpful information on the current status of the liver injury, it identifies features useful in the decision to embark on therapy, and it may reveal advanced fibrosis or cirrhosis that necessitates surveillance for hepatocellular carcinoma (HCC) and/or screening for varices. The biopsy is assessed for grade and stage of the liver injury, but also provides information on other histological features that might have a bearing on liver disease progression.49 The grade defines the extent of necroinflammatory activity, while the stage establishes the extent of fibrosis or the presence of cirrhosis. Several scoring systems have been conceived, the most common being the French METAVIR, the Batts-Ludwig, the International Association for the Study of the Liver (IASL) and the Ishak Scoring systems.50-54 (Table 7).
The two more common non-HCV conditions that might affect disease progression and possibly impede treatment response are steatosis 49,55,56 and excess hepatocellular iron.57 Identifying either of these two features does not preclude initiating treatment, but their presence provides additional information regarding the likelihood of response to treatment.
The liver biopsy has been widely regarded as the “gold standard” for defining the liver disease status, but it has drawbacks that have prompted questions about its value.
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Table 7 Comparison of Scoring Systems for Histological Stage Stage
HEPATOLOGY, Vol. 49, No. 4, 2009 GHANY ET AL. 1339
The procedure is not without risks (including pain, bleeding and perforation of other organs),63,64 it is
subject to sampling error,65 it requires special expertise for interpreting the histopathology, it adds cost to medical care, and it is anxiety-provoking for the implicated person.
Thus, efforts are underway to seek alternative means of establishing information on the extent of fibrosis by focusing on noninvasive blood marker panels.66 These markers are useful for establishing the two ends of the fibrosis spectrum (minimal fibrosis and cirrhosis) but are less helpful in assessing the mid-ranges of fibrosis or for tracking fibrosis progression.66 The recently developed transient elastography that uses ultrasound and low frequency elastic waves to measure liver elasticity67 has improved the ability to define the extent of fibrosis without a liver biopsy, particularly when combined with other noninvasive markers.68 However, it is not yet ready to replace the liver biopsy since it is not FDA approved, the failure rate is higher in obese patients, and there is now evidence that the transient elastography score can be unexpectedly increased in persons with acute hepatitis who have high necroinflammatory activity but no or minimal fibrosis.69,70
Genotypes
A liver biopsy may be unnecessary in persons with genotypes 2 and 3 HCV infection, since more than 80% of them achieve a sustained virlogical response (SVR) to standard-of-care treatment. There is, however, an ongoing debate about whether a biopsy is warranted for persons infected with HCV, genotype 1, whose response to such treatment approximates 50% among Caucasians and 30% among African Americans.71-73 Even more uncertain is whether there is need for a liver biopsy in persons infected with the other less common genotypes (4 through 6).
A liver biopsy may be unnecessary in persons with genotypes 2 and 3 HCV infection, since more than 80% of them achieve a sustained virlogical response (SVR) to standard-of-care treatment. There is, however, an ongoing debate about whether a biopsy is warranted for persons infected with HCV, genotype 1, whose response to such treatment approximates 50% among Caucasians and 30% among African Americans.71-73 Even more uncertain is whether there is need for a liver biopsy in persons infected with the other less common genotypes (4 through 6).
Thus, although the liver biopsy was previously regarded as routine for defining the fibrosis stage in persons with genotype 1 infection,62 the issue is now in a state of flux and possible transition. Supporters of a biopsy cite the difficult nature and high cost of current antiviral therapy and are therefore willing to withhold or delay treatment if liver histology displays minimal to moderate fibrosis stage 2 (Table 7), especially if the infection is known to have been long-standing. These individuals are regarded as having slowly progressive liver disease that may not be responsible for their ultimate demise74-76
However, treatment is advised for those with more advanced fibrosis stage 3 (Table 7) It must be noted, however,that while information obtained from a biopsy is useful, the procedure is not mandatory for deciding on treatment. If performed and treatment is withheld, a common strategy is to repeat the liver biopsy 4 to 5 years later and to reconsider treatment should there be evidence of disease progression.77
The earlier views that persons with genotype 1 infection and persistently normal aminotransferase values did not require a liver biopsy because they were believed to have minimal liver disease, and that treatment may actually be harmful, are no longer valid.78 It is now apparent that as many as a quarter of such individuals have significant fibrosis,78-81 and that treatment response is similar to that of individuals with abnormal serum aminotransferase levels.82-84
Therefore, the decision to perform a liver biopsy should be based on whether treatment is being considered,taking into account the estimated duration of infection and other indices of advancing liver disease (e.g., the platelet count), the viral genotype, and the patient’s willingness to undergo a liver biopsy and motivation to be treated. If the biopsy is not performed and treatment not undertaken, the patient should continue to be monitored at least annually and a biopsy performed if the aminotransferase values become abnormal and other indicators of progressing liver disease become apparent.
Recommendations
7. A liver biopsy should be considered in patients with chronic hepatitis C infection if the patient and health care provider wish information regarding fibrosis stage for prognostic purposes or to make a decision regarding treatment (Class IIa, Level B)
8. Currently available noninvasive tests may be useful in defining the presence or absence of advanced fibrosis in persons with chronic hepatitis C infection, but should not replace the liver biopsy in routine
clinical practice (Class IIb, Level C).
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Of interest published in the June 2011 issue of the Scandanavian Journal of Gastroenterology;
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Percutaneous liver biopsy is widely approved by patients and is also regarded as a useful procedure, reports June's issue of the Scandanavian Journal of Gastroenterology
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One must know patients' opinion on percutaneous liver biopsy when it comes to comparing it with other procedures.
Dr Luis Fernández-Salazar and colleagues from Spain investigated the point of view of patients undergoing a percutaneous liver biopsy with regard to information provided to them, as well as the procedures and biopsy consequences.
A questionnaire was sent by mail to 178 patients who underwent percutaneous liver biopsy from 2006 to 2010.
Results are expressed in percentages and compared based on gender and age.
The team reported that 90 patients of the group answered, of which 44 were females, with a mean age of 47 years.
The answers revealed that 93% of patients rated the information concerning the reasons for a percutaneous liver biopsy as adequate.
As for the information concerning the objective of the procedure, 88% of patients regarded it as adequate.
As for the information concerning the risks of a biopsy, 78% see it as sufficient.
About 12% of patients did not receive any information on the physician who asked for the percutaneous liver biopsy, or who performed it.
Percutaneous liver biopsy was considered very painful by 14% of patients, painful by 21%, bothersome by 41% and barely bothersome by 23% of patients.
The research team found that 35% of patients required analgesia after the puncture.
The team observed that even though 92% of patients regard percutaneous liver biopsy as a useful procedure, 46% of them have not received any treatment or a different nutritional regime.
The research team found that 80% of patients think that percutaneous liver biopsy has more benefits than drawbacks, although 87% would have opted for a less aggressive technique as long as it would have provided the same information.
However, 21% of patients would have also preferred a less aggressive technique, even though it provided fewer details.
Dr Fernández-Salazar's team concluded, "In general, percutaneous liver biopsy is widely approved by patients and is also regarded as a useful procedure."
"One out of 6 patients would rather choose a less-aggressive technique even if it provided less information."
"Percutaneous liver biopsy does not involve changes in the treatment in around a half of patients."
27 May 2011
Recommended Reading;
COMPARISON OF FIBROSIS DEGREE CLASSIFICATION ACCURACY BY LIVER BIOPSY AND NON-INVASIVE TESTS IN CHRONIC HEPATITIS C-Non-invasive tests have been constructed and evaluated mainly for binary diagnoses such as significant fibrosis. Recently, detailed fibrosis classifications for several non-invasive tests have been developed, but their accuracy has not been evaluated in comparison to liver biopsy, especially in clinical practice.
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