Factors Associated With Unreliable Liver Stiffness Measurement Of Hepatitis C Virus Patients
Hepatitis C Virus (HCV) is a tiny enveloped RNA virus, whose genomic RNA is single-stranded with positive polarity including a 5’un-translated regions (UTR), an open reading frame (ORF) and 3’UTR. The most conserved region is the 5’UTR usually being selected as the target of choice for HCV genome detection, while envelope glycoproteins in ORF have the most variable region, especially envelope proteins (E2) contains hypervariable regions causing up to 80% differences between HCV isolates. HCV infection regulates signaling and pathways of metabolic and leads host antiviral immune response resulting in chronic inflammation, which contributes to liver fibrogenesis.
HCV takes up over 15% cases of acute hepatitis. 50% to 80% of HCV patients will contract chronic infection after acute infection. About 170 million people suffer from HCV worldwide and each year more than 350 thousand individuals are dead due to the diseases related to HCV. Liver fibrosis is regarded as a response of chronic liver injury because of redundant accumulation of extracellular matrix (ECM) proteins.
The hepatic stellate cell (HSC) is the crucial fibrogenetic factor to response liver injury and experience transformation to proliferative and contractile myofibroblasts once activated by the stimuli of inflammation. The balance between deposition and dissolution of ECM proteins would be destroyed by activated HSCs that are the constituent of ECM production, bringing about the process from fibrotic scarring to liver cirrhosis. The pathology development of chronic hepatitis C (CHC) can be accountable for the cumulation of liver fibrosis. The accumulation of liver fibrosis can cause cirrhosis and end-stage liver complications. Patients are diagnosed with absent or mild fibrosis having a risk about 25% of developing cirrhosis over next 20 years. It is initial to identify the stage the liver stage of patients for clinical management. In order to diagnose the HCV infection for infected persons, Fibroscan is employed for staging liver fibrosis and monitoring both the disease progression and treatment efficacy at the same time.
The principle of Vibration Controlled Transient Elastography (VCTE) which Fibroscan followed is that a vibrator is used at the skin surface to transmit a vibration of mild amplitude and low frequency (50 Hz) through the intercostal space. An elastic shear wave propagating through the hepatic tissue is induced by the vibration. The velocity of the shear wave tightly connected to tissue stiffness is identified as a result of the use of pulse echo ultra-sound acquisition. The degree of hardness of tissue is positively correlated to the speed of shear wave propagation. In other words, the harder the tissue, the faster the shear wave. The liver stiffness is expressed in kilopascal (kPa), which is computed from velocity. S2 probes were developed for children and lean patients. M probes were suitable for most population. XL probes were designed for obese patients.
Liver biopsy which used to be considered as a gold standard assessment for evaluating the stage of fibrosis classification is invasive and related to complications (pain and bleeding), sample error, observer variability, required hospitalization and high cost. The procedure of a liver biopsy is accomplished by inserting a thin needle into the liver for collecting a small piece of tissue. The sample tissue would be fixed, paraffin-embedded and stained for staging. Compared to Liver biopsy, Fibroscan is novel non-invasive and inexpensive. But Myers’s research showed that one in seven cases was discordant between transient elastography and liver biopsy. TE error was responsible for 40% of discordances and biopsy error was responsible for 23% of discordances.
A technical review from Singh et al. (2017) believed that VCTE had good sensitivity and specificity, as well as low false positive and false negative rate for adults with chronic HCV. Nezam et al. (2015) confirmed excellent performance of VCTE for detecting fibrosis F2 (area under the receiver operating characteristic curve, AUROC of 0. 89), advanced fibrosis F3 (AUROC, 0. 92) and cirrhosis F4. TE had superior ability for staging cirrhosis in HIV-HCV co-infection patients with 94% accuracy. However, based on the meta-analysis from Tsochatzis et al (2010), Fibroscan did not always provide the excellent sensitivity and specificity in different stages of liver stiffness. Liver stiffness measurement (LSM) failure is defined as no valid shots and unreliable examinations mean fewer than 10 valid shots, ratio interquartile range /median value of liver stiffness measurement (IQR/LSM)>0. 3 or a success rate <0. 6.
High body mass index (≥30kg/m^2) was the most common cause of unsuccessful elastography measurements in Tsochatzis’s research. Besides, a 5-year prospective study designed to analyze the factors accounting for LSM failure and unreliable results from Caste ́ra et al (2009) presented that obesity, especially increased waist circumference, and limited operator experience should account for nearly one in five cases of invalid measurements. Armstrong et al. (2013) affirmed that minimal operator training (≥10 observed on patients) was essential to require a valid liver stiffness evaluation. Lucidarme et al. (2008) held opposite views that success rate did not affect the accuracy of the diagnosis of the hepatic.
