Transient elastography is a widely used non-invasive method for assessment of hepatic fibrosis (scarring of the liver tissue), leading to stiffening of the liver. Transient elastography investigation for liver fibrosis by measuring the liver stiffness has already been validated in many people with chronic liver diseases (Sandrin 2003; Nahon 2008). An important aspect of liver stiffness measurements are cut-off values that characterise different stages of fibrosis. However, the cut-off levels for the stages of fibrosis are different in the different chronic liver diseases, but what is more, the cut-off levels for people with alcoholic liver disease are not established yet (Rockey 2008). The presence and progression of hepatic fibrosis into cirrhosis is a main prognostic variable having impact on survival in people with alcoholic liver disease. Transient elastography may indicate the amount of hepatic fibrosis in people with alcoholic liver disease (de Lédinghen 2010). A number of clinical studies have compared liver stiffness measured by transient elastography with presence of hepatic fibrosis detected on liver biopsy, reaching a conclusion that transient elastography is a reliable method for assessment of hepatic fibrosis (Foucher 2006; Gómez-Domínguez 2006; Ivashkin 2011a; Tsochatzis 2011). In addition, studies have found a correlation between the level of liver stiffness and the degree of hepatic fibrosis in people with alcoholic liver disease (Nguyen-Khac 2008; Nahon 2009; Mueller 2010). The prevalence of hepatic fibrosis in heavy drinkers is not well known. In a series of 1407 people with alcoholic liver disease diagnosed on liver biopsy, 809 (57.5%) people had developed liver fibrosis (Naveau 1997). This is why the correct staging of liver stiffness is of paramount importance for the treatment strategy of people with liver injuries (O'Shea 2010).
Target condition being diagnosed
Hepatic fibrosis in people with alcoholic liver disease
All people with alcoholic liver disease are at risk of developing liver fibrosis. This risk is especially higher in people who are binge drinkers, people with increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, or in people with severe steatohepatitis on liver biopsy (Bouchier 1992).
Hepatic fibrosis may develop due to weekly alcohol consumption of seven to 13 beverages for women (one beverage = 12 g alcohol) and 14 to 27 beverages for men in the course of five or more years (Savolainen 1993; Becker 1996). The risk ratio of progression of fibrosis to cirrhosis increases significantly with a daily consumption of 20 to 40 g ethanol in women and more than 80 g ethanol in men (Sherlock 1997; O'Shea 2010). Fatty liver, the most common lesion that develops due to excessive ethanol intake, is potentially reversible through abstinence, but the amount of fat in the liver is an important predictor of the risk of subsequent cirrhosis in those who continue to drink (Sørensen 1984).
The liver is the main site of alcohol metabolism acting through two hepatic enzymes, alcohol dehydrogenase and cytochrome P-450 (CYP) 2E1. Increased alcohol intake disrupts the metabolic liver function, and, as a result, alcoholic liver disease develops (Stewart 2001). Histologically, alcoholic liver disease occurs in three forms: fatty liver or steatosis, alcoholic hepatitis, and chronic hepatitis with hepatic fibrosis and cirrhosis (O'Shea 2010). Morphological features that predict progression to hepatic fibrosis and cirrhosis include severe steatosis, giant mitochondria, and the presence of mixed macrovesicular-microvesicular steatosis (Teli 1995).
Timely staging of hepatic fibrosis in people with alcoholic liver diseases could motivate patients and physicians in finding an optimal strategy for treatment of the disease. A single staging system for evaluating hepatic fibrosis in alcoholic liver disease does not exist. 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 - portal fibrous expansion, F2 - thin fibrous septa emanating from portal triads, F3 - 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 greater than F2, using METAVIR score (Franciscus 2007). In Table 1 we have also included other widely used systems for classification of fibrosis in people with alcoholic liver disease (Knodell 1981; Desmet 1994; Ishak 1995; Brunt 1999; Kleiner 2005).
Transient elastography is designed to measure liver stiffness, using FibroScan® equipment (Echosens, Paris, France; Echosens 2009). A probe, consisting of an ultrasound transducer located at the end of a vibrating piston, is put on the skin surface overlying the liver (the person is in supine position). 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 velocities 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, corresponding to increasing severity of fibrosis.
Liver stiffness is expressed as a median value of 10 measurements in kiloPascals (kPa). The findings of 'normal' liver stiffness values for apparently healthy women and men differ in different studies, lying between 3.3 kPa and 7.0 kPa, using the 5th and 95th percentiles (Roulot 2008; Kim 2012). While age is not found to affect liver stiffness, men compared to women have slightly higher liver stiffness values (Roulot 2008). A predefined cut-off of 8.00 kPa is predictive of severe hepatic fibrosis in alcoholic liver disease, equal or greater than F3 by the METAVIR scoring system (Mueller 2010). The transient elastography method is non-invasive, simple, highly reproducible, and allows examination of at least 100 times larger volume of liver tissue compared to a liver sample obtained through liver biopsy (de Lédinghen 2008). This is why the sampling error of transient elastography investigation is less than with liver biopsy (Ingiliz 2009). Other advantages of transient elastography are that it has a higher performance in detecting cirrhosis and has likely higher prognostic value in cirrhosis. Transient elastography increases its diagnostic accuracy when applied in combination with serum markers (Castera 2010). The diagnostic accuracy of transient elastography was compared with alternative tests such as acoustic radiation forced impulse (ARFI) imaging and a serum marker, enhanced liver fibrosis (ELF), concluding that transient elastography can be used for diagnosis of liver fibrosis alone or in combination with any of them (Crespo 2012). Janssens et al have shown that transient elastography is more accurate than other currently available serum markers for people with chronic hepatitis C (Janssens 2010). However, the diagnostic accuracy of transient elastography in people with alcoholic liver disease is not established yet.
Different methods to perform elasticity measurements have been developed since 1990. They are aimed at quantifying the elasticity or viscoelasticity of the liver tissue. There are two common elements in every elasticity imaging method: a force or stress is applied on the liver tissue and the obtained mechanical response is measured.
Siemens Ltd. (i.e. ACUSON S2000) is a medical technology that can detect hepatic fibrosis, and hence, it enables the quantification of the hepatic fibrosis in its different stages. The technology is also called liver elastography, performed using ARFI imaging (Iyo 2009). ARFI imaging is faster than conventional methods as ARFI uses higher frequencies that are comparable to those used in colour Doppler imaging. The images have greater contrast and the boundary of the focal lesions are better defined compared with the conventional ultrasonography imagining techniques (Iyo 2009).
Ultrasonography measures the progression, stagnation, or regression of hepatic fibrosis in alcoholic liver disease (Caballeria 1998). It allows investigation of the hepatic tissue through generation of ultrasonic waves. Different ultrasonography impedance indices based on Echo-colour Doppler variables of the liver blood flow have been proposed for indirect estimation of the stage of hepatic fibrosis (Ersoz 1999; Hizli 2010; Ivashkin 2011a). We are undertaking a systematic review to assess the diagnostic accuracy of ultrasonography for diagnosis of hepatic fibrosis and cirrhosis in people with alcoholic liver disease (Pavlov 2013a).
Supersonic shear imaging (SSI) is a technique that investigates tissue elasticity to detect hepatic fibrosis and steatosis. It is based on velocity estimation of a shear wave, generated by a radiation force (Bercoff 2004).
Magnetic resonance elastography (MRE) combines magnetic resonance imaging (MRI) with sound waves to create a visual map (elastogram), showing the stiffness of the liver tissue. It is used primarily to detect hardening of the liver caused by different types of liver diseases, including those of alcoholic aetiology (Jin 2007).
Other alternative non-invasive tests (apart from venepuncture) to transient elastography are laboratory tests such as ALT and AST ratio, prothrombin index, hyaluronic acid, ELF, etc. (Crespo 2012; Liu 2012). All of these tests are used as surrogate markers for estimation of hepatic fibrosis. In addition, different combinations of biochemical tests such as FibroTest® and Fibrometre® are used for diagnosis of hepatic fibrosis in people with alcoholic liver disease (Morra 2007; Poynard 2007; Poynard 2008; Angulo 2009). We are also undertaking a systematic review to determine the diagnostic accuracy of transient elastography plus FibroTest® versus FibroTest® alone for diagnosis of hepatic fibrosis in adults with chronic hepatitis C (Pavlov 2013b).
The clinical pathway in diagnosis of alcoholic liver disease is presented in Figure 1.
Liver biopsy has so far been considered the standard method for detection of hepatic fibrosis and its staging, using different semi-quantitative morphological scores on liver tissue samples with a size of no more than 1 to 2 cm3 (Table 1). One advantage of liver biopsy is that it may give diagnostic information for concurrent liver diseases (Poulsen 1979; Ismail 2011). However, there are a number of disadvantages with liver biopsy; it is invasive, and it may hide potential risks to the person such as punctures of abdominal organs and haemorrhage. Liver biopsy can be painful, time-consuming, and stressful for the person and depends on the physician's experience and skills (Grant 1999; O'Shea 2010; Ivashkin 2011b). The risk of haemorrhage and death after liver biopsy is especially higher in people with a platelet count of 60,000 per mm3 or less, and also in those with an international normalisation ratio greater than 1.3 (Seeff 2010). The small size of the tissue samples may also lead to sampling errors.
Consensus on using transient elastography as a non-invasive method for diagnosis of hepatic fibrosis has not been established (Rockey 2008). It is still under debate if confounding factors such as inflammation, cholestasis, and increased hepatic vein congestion, such as in chronic heart failure, influence the precision of transient elastography in people with alcoholic liver disease (Rockey 2008). Increased body mass index, sex, and age are not considered confounding factors, but they may affect the number of reliable results (i.e. success rate).
Published meta-analyses demonstrated that cause is the most important factor leading to heterogeneity, thus indicating that the different chronic liver diseases should be analysed separately (Friedrich-Rust 2008; Poynard 2008; Stebbing 2010; Tsochatzis 2011). However, in these meta-analyses, results are obtained for all causes of liver disease together, which may become a limitation for determining the diagnostic accuracy of the method of transient elastography when used to diagnose hepatic fibrosis in people with alcoholic liver disease. Furthermore, these meta-analyses do not examine in detail the possible confounding influences of factors such as the degree of hepatic steatosis or the level of liver inflammation activity in people with alcoholic liver disease (Sackett 2002). This review aims to complete present research and to study further the diagnostic accuracy of transient elastography in detecting the presence or absence of hepatic fibrosis in people with alcoholic liver disease, following the Cochrane methodology (SRDTA Handbook). In addition, this review will help researchers working on designing interventions for people with alcoholic liver disease by knowing the grade and progression of fibrosis and cirrhosis.