Hepatic fibrosis is the main consequence of necroinflammation in liver tissue, most often caused by chronic viral hepatitis B or C. When fibrosis advances, it causes bridging between the portal areas or between the portal area and the central vein, and causes the formation of pseudo-lobule (i.e., cirrhosis develops). Hepatitis C virus infection is a major cause of severe illness and death. The economic burden of the disease is high. Worldwide, 130 million to 150 million people are infected with hepatitis C virus (WHO 2014). Every year, another three to four million people acquire the infection, and 350,000 to 500,000 people die from hepatitis C-related liver diseases in a year (WHO 2014). About 15% to 45% of infected people may eliminate the virus without any treatment, but 55% to 85% of chronically infected people will develop a chronic liver disease. About 30% to 50% of people infected with hepatitis C virus will develop hepatic fibrosis without clinical or laboratory symptoms of significant liver disease (Ascione 2007). However, the progress of hepatic fibrosis to cirrhosis in people with chronic hepatitis C is slow (Kenny-Walsh 1999; Wiese 2005). About 15% to 30% of infected people will develop liver cirrhosis within 20 years, and 1% to 5% of those will die from liver cirrhosis decompensation or liver cancer (WHO 2014).
Severe fibrosis and cirrhosis should be regarded with highest priority in terms of treatment in an attempt to prevent the development of further complications from the end stage of chronic hepatitis C virus infection such as oesophageal bleeding, hepatocellular carcinoma, hepatic insufficiency, etc. So far, four classes of direct-acting antiviral agents have become available, claiming their ability to eradicate the hepatitis C virus, irrespective of the stage of fibrosis (Pockros 2015). The direct-acting antiviral agents have also led to new interpretations of the hepatitis C virus ribonucleic acid (RNA) concentration results. The longer the delay in diagnosing and staging correctly the hepatitis C virus, the higher the risk of developing advanced fibrosis and the poorer the survival prognosis (AASLD/IDSA/IAS-USA 2015; EASL 2015; EASL-ALEH 2015).
The natural course of chronic hepatitis C virus infection depends on age at time of infection; sex; degree of inflammation presented; co-infection with human immunodeficiency virus (HIV) or hepatitis B virus infection; and co-morbid conditions such as immunosuppression, insulin resistance, non-alcoholic steatohepatitis, haemochromatosis, and schistosomiasis (Chen 2006; Ascione 2007). Approximately 80% of people with hepatitis C infection do not exhibit symptoms, and the stage of liver disease remains unknown (Marcellin 1999; WHO 2014).
Liver biopsy is considered reference standard for diagnosing severe and advanced hepatic fibrosis in people with chronic hepatitis C, who are expected to have higher benefit from treatment (Castera 2011).
Liver biopsy provides information on the degree of inflammation and the amount of established fibrosis. Liver biopsy is obtained in three ways: percutaneous, transjugular or transfemoral, and laparoscopic (Kuntz 2008). Specimens are obtained either with a core aspiration needle (Menghini, Jamshidi, Klatskin style) or sheathed cutting needle (Tru-Cut style) that is at least 16-gauge in calibre. Specimens of liver tissue with a mean length of at least 15 mm and at least seven portal tracts are among the factors that can provide reliable morphological staging of hepatic fibrosis and grading of inflammation (Rockey 2009). As liver biopsy is painful, and in some cases it may lead to severe complications, people are not willing to undergo it (Castéra 2005). The accuracy of liver biopsy may also be affected by sampling errors and intra- and interobserver variability (Bedossa 2003). Various non-invasive methods have been suggested and used to detect or confirm the diagnosis of chronic hepatitis C infection (WHO 2014; EASL-ALEH 2015).
Non-invasive methods use two different approaches for diagnosing stages of liver fibrosis in chronic liver disease: one based on the quantification of biomarkers in serum blood samples (e.g., FibroTest®, Forns® Index, APRI (aspartate aminotransferase (AST) to platelet ratio index), etc.) and the other based on the measurement of liver stiffness (e.g., transient elastography, ARFI (acoustic radiation force impulse), magnetic resonance elastography (MRE), etc.) (EASL-ALEH 2015). Guidelines suggest that blood tests in combination with liver stiffness measurements may improve the diagnostic accuracy when stage of hepatic fibrosis is assessed, resulting in a significant reduction in the number of liver biopsies and in a better selection of patients to be investigated with the biopsy procedure (Castera 2011; EASL 2011).
Target condition being diagnosed
Severe hepatic fibrosis and cirrhosis in adults with chronic hepatitis C. The diagnosis of chronic hepatitis C includes detection of both hepatitis C virus antibodies and hepatitis C virus RNA (lower limit of detection less than 15 IU/mL) in the presence of biological or histological signs of chronic hepatitis (either by elevated aminotransferases or by histological changes of chronic hepatitis C) (WHO 2014; EASL 2015). We chose to study a homogeneous group of people as pathogenesis of liver injury may be influenced by different aetiological factors, co-infected patients may require different treatments, and the time for progression of fibrosis into cirrhosis.
There are a number of staging systems for evaluating hepatic fibrosis in people with chronic hepatitis C. METAVIR is the most widely used scoring system for interpretation of liver biopsy results based on the stage of fibrosis where F0 indicates no fibrosis, F1 indicates portal fibrous expansion, F2 indicates thin fibrous septa emanating from portal triads, F3 indicates fibrous septa bridging portal triads and central veins, and F4 indicates cirrhosis (Table 1). Hepatic fibrosis could be considered clinically significant if defined as F2 or worse, using METAVIR score (Franciscus 2007). Hepatic fibrosis could be considered clinically severe if defined as F3 or worse, using METAVIR score (F3 and F4), which is the subject of our review. In Table 1, we have also included other widely used systems for classification of hepatic fibrosis in people with chronic hepatitis C (Knodell 1981; Desmet 1994; Ishak 1995; Brunt 1999; Kleiner 2005), as liver pathologists have reached no universal consensus on the standardisation of scoring systems.
FibroTest (i.e., BioPredictive®, Paris, France and registered as FibroSureTM in the USA), is a test for determining the stage of hepatic fibrosis in people with chronic hepatitis C. The test uses six serum markers for identification of the existence of fibrosis in the liver tissue; alpha-2-macroglobulin, haptoglobin, gamma-glutamyl transpeptidase (GGT), total bilirubin, apolipoprotein A1, and alanine aminotransferase (ALT). In addition, it takes into account the age and sex of the people when defining the stage of hepatic fibrosis (Shaheen 2007; Gressner 2009). It can be performed in ambulatory conditions. However, there are also disadvantages. It is non-liver specific, is unable to discriminate between intermediate stages of fibrosis, has limited availability due to proprietary rights, and can be influenced by haemolysis, Gilbert's syndrome, or systematic inflammation (EASL-ALEH 2015). During its evaluation, the FibroTest was assessed on control liver biopsies using the METAVIR scoring system for substantial fibrosis of F2 or worse and activity score of the biopsy specimens (Imbert-Bismut 2001).
Transient elastography (i.e., FibroScan® equipment, Echosens, Paris, France) is a mechanical test designed to measure liver stiffness in people with chronic hepatitis C virus. A probe is put on the skin surface overlying the liver. After pressing the button on the probe, a pulse wave is transmitted across the liver parenchyma. After a short interval, a second ultrasound wave is transmitted. The difference between the velocity of the two waves in the liver parenchyma is calculated using the Doppler technique (Sandrin 2003; Nahon 2008). As it is known from physical principles, the velocity of the pulse wave increases with the stiffness of the liver parenchyma.
Liver stiffness is expressed as a median value in kiloPascals (kPa). A pre-defined cut-off of 8.00 kPa is predictive of severe hepatic fibrosis in chronic hepatitis C that is F3 or worse by the METAVIR scoring system (Mueller 2010). The transient elastography method is simple, highly reproducible, and allows examination of at least 100 times larger volume of liver tissue than a biopsy sample (de Lédinghen 2008). Extrahepatic cholestasis, food intake, and excessive alcohol use are among the factors influencing transient elastography measurements (EASL-ALEH 2015).
The first-line diagnostic test for hepatitis C virus infection is measurement of hepatitis C viral antibodies. People with detectable hepatitis C viral antibodies, before undergoing anti-viral therapy, should have hepatitis C virus RNA levels (expressed in IU/mL) detected and quantified by molecular tests with a lower limit of detection of 15 IU/mL or less based on real-time reverse transcription polymerase chain reaction methods (EASL 2015). The hepatitis C virus genotype, levels of transaminases, and liver synthetic function should be assessed before start of treatment in order to determine the appropriate treatment regimens and duration. The severity of fibrosis should be assessed along with the presence of any co-morbid conditions possibly influencing the progression of the liver disease. Following EASL 2015, the stage of fibrosis using non-invasive methods should be assessed after the diagnosis of chronic hepatitis C and before start of its treatment. However, the stage of fibrosis using liver biopsy should be reserved for people with advanced stage fibrosis and with suspected additional aetiologies of liver injury or in case of discordance in the results obtained through any of the non-invasive methods (EASL 2015). Monitoring of hepatitis C virus viral load is performed to guide treatment duration, that is, to continue on therapy, or to determine whether to stop therapy.
Transient elastography, FibroTest, or their combination are recommended as non-invasive tests for diagnosis of severe fibrosis or cirrhosis in people with chronic hepatitis C (EASL-ALEH 2015).
Hepatitis C virus antibody, hepatitis C virus RNA test, liver function tests (ALT, AST), FibroTest alone, transient elastography method alone, and combined FibroTest and transient elastography method could potentially be some of the first tests that people undergo after being diagnosed with chronic hepatitis C.
Role of index test(s)
FibroTest, transient elastography method, and combined FibroTest and transient elastography method are non-invasive methods for the assessment of severe hepatic fibrosis and cirrhosis that could be used as triage or replacement tests of liver biopsy. We have not taken the cost-effectiveness into account when defining the role of the listed index tests, as this is not possible in this review.
There are different alternative non-invasive methods for measuring hepatic fibrosis. Based on their principle of defining fibrosis in people with hepatitis C virus, tests are grouped as follows:
Based on biochemical variables: ALT and AST ratio, prothrombin time, hyaluronic acid, platelets (aspartate aminotransferase/platelet ratio index (APRI), Forn's index - combines age, GGT, cholesterol, and platelet count). The tests are based on recordings of liver biochemical variables. All the tests are used as surrogate markers for fibrosis, are inexpensive laboratory tests, performed routinely in people with chronic liver disease (Wai 2003; Degos 2010; EASL 2011).
Magnetic resonance is another imaging method which includes unenhanced magnetic resonance imaging (MRI), MRE, MRI with diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy.
A few of the mentioned alternative tests are currently being studied in Cochrane diagnostic test accuracy reviews (Kalafateli 2015; Kalafateli 2016). However, their role and place in the clinical pathway in terms of diagnosing people with chronic hepatitis C still needs to be established.
Identifying people with cirrhosis or people with advanced fibrosis is of particular importance as their prognosis and their response to treatment differ (EASL 2011; EASL 2015). Liver biopsy is still regarded as the reference standard for assessing fibrosis in people with chronic hepatitis C. The advantage of liver biopsy for staging fibrosis in chronic hepatitis C is that this test not only fulfils its purpose, but it may also give diagnostic information for concurrent liver diseases such as alcoholic or non-alcoholic steatohepatitis, autoimmune liver disease, etc. (Poulsen 1979; Ismail 2011). Using liver biopsy for diagnosis of chronic hepatitis C is limited by sampling error, different levels of experience of the morphologists, invasiveness of procedure, and risk of both serious and non-serious complications (Seeff 2010; Castera 2011).
2015 clinical recommendations refer to the use of non-invasive serum markers (FibroTest, APRI, FIB4, etc.) and transient elastography for detection of hepatic fibrosis (EASL-ALEH 2015). It is suggested that the combined use of different non-invasive methods would possibly reduce the necessity of liver biopsy (EASL 2011). Non-invasive methods could also be used in the follow-up of people infected with chronic hepatitis C (Castera 2011). However, the optimal algorithm for use of non-invasive methods still needs to be established (Castera 2011).
We found no diagnostic test accuracy review prepared with Cochrane methodology to determine the diagnostic test accuracy of FibroTest, transient elastography method, combined FibroTest and transient elastography method, no matter the sequence, using liver biopsy as reference standard, for assessment of severe hepatic fibrosis and cirrhosis in adults with chronic hepatitis C.