the development of serum (or blood) markers, which may be divided into direct or indirect tests, either singly, or combined as serum panel markers, and the application of imaging-based technologies, such as ultrasound and magnetic resonance techniques.
SERUM MARKERS Serum may be obtained at routine venepuncture, making it quick and acceptable to most patients. Sampling variability is negated, although site- specificity to hepatic processes may be questioned. Serum markers may broadly be divided into indirect and direct markers of hepatic fibrosis. Indirect markers are those where the indices measured correlate with fibrosis stage, but are not integral to the pathogenesis of disease. Such markers include so-called liver function tests, such as aspartate and alanine aminotransferases (AST and ALT), and composite or panel markers, such as the AST-to-platelet ratio index (APRI) and the Fibrotest/Actitest markers. On the other hand, direct markers are those measuring intermediates or metabolites of fibrogenesis, such as hyaluronic acid and panel markers such as the Enhanced Liver Fibrosis (ELF) test, consisting of metalloproteinase-1 (TIMP-1), procollagenase 3 and hyaluronic acid. The performance of a number of these tests for the detection of cirrhosis is displayed in Table 1.
dpe rm Lm e l 05 atd fo i t a. 20.
Figure 1: Transient elastography. A specialist nurse places the probe perpendicular to the surface of the liver. A low frequency shear wave is generated along the same axis as the ultrasound transducer. The velocity of the shear wave through the liver is measured by a high frequency ultrasound signal and the output displayed as stiffness, in kPa, alongside a two- dimensional “elastogram”. The output is the median of 10 measurements, with a success rate of >66% and an interquartile range of measurements <1/3 of the median considered satisfactory.
IMAGING-BASED MARKERS Investigations based on imaging modalities, including ultrasound and magnetic resonance (MR), are liver-specific and often provide hepatic structural information. Although a number of structural changes are associated with cirrhosis and portal hypertension, these signs alone are neither sensitive nor specific enough to stage chronic liver disease. A number of specialized applications have, however, shown promise and imaging
Figure 2: Hepatic vascular transit times (HVTT). Time intensity curves from the hepatic vein are plotted in a normal patient and a patient with cirrhosis, showing earlier arrival of contrast in the cirrhotic liver. A 0.5
0.4 0.3 0.2 0.2 -20 0 0.5 0.4 0.3 0.2 0.2 -20 0 -10 0 58
www.lifesciencesmagazines.com 10 20 30 Time (s) 40 50 60 70 80
Cirrhosis (early HVTT) injection
-10 0 10 20 30 Time (s) 40 50 60 70 80
Normal (late HVTT) injection
techniques have the added benefit of providing real-time information to the operator and patient.
TRANSIENT ELASTOGRAPHY Transient elastography is an ultrasound elastography technique that measures the propagation of a low-frequency shear wave through the liver (see figure 1). Its velocity is dependent on the ‘stiffness’ of the liver and this reflects the degree of fibrosis. The technique currently requires use of dedicated equipment marketed as FibroScan®
and its performance has been
scrutinised in a large number of studies over the last five years. However, while transient elastography performs well for the assessment of cirrhosis, with sensitivity and specificity quoted between 77% and 100%, there has been less clear separation of stages of precirrhotic disease. Cut-off values between histological stages vary substantially between studies, patient groups and aetiology of disease. More recently, liver stiffness has been shown to increase in flares of viral hepatitis and in acute hepatitis, to levels seen in cirrhosis, but in the absence of significant fibrosis. Further studies have demonstrated compelling correlation between liver stiffness and portal pressure, while cardiac failure, infiltrative conditions and even hepatic steatosis may affect stiffness values.
Amplitude
Amplitude
Image © Prof. Simon Taylor Robinson
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