The Diagnostic value of FibroScan for the degree of liver fibrosis in patients with ALT<2×ULN chronic hepatitis B

Liver fi brosis is a pathological process in the development of chronic hepatitis B to cirrhosis, accurate evaluation of the degree of liver fi brosis is helpful to guide clinical diagnosis and treatment. At present, the gold standard for liver fi brosis evaluating is liver pathological examination of liver biopsy, however, due to invasiveness, sampling error, observer error and inability to observe dynamically, it is diffi cult to conduct as a general survey or routine examination, and also limits the application in clinic. FibroScan (FS) is a non-invasive ultrasound technique for survey the liver stiff ness rapidly, it refl ect liver fi brosis by measuring Liver Stiff ness Measurement (LSM), because of its non-invasive, simple, rapid, easy to operate, Abstract

Citation: Shi  reproducible, safe and well tolerated characteristics, it has been recommended as an important means of clinical evaluation for hepatitis B and C virus-related liver fi ber by AASLD, EASL and China Guidelines for the prevention and treatment of CHB [1][2][3]. In addition, China guidelines for the prevention and treatment of CHB (2015 update) indicated that: people who in ALT <2×ULN and with normal bilirubin level and never received antiviral therapy, when LSM was greater than or equal to 10.6 kPa can be diagnosed as cirrhosis; LSM≥9.4 kPa can be diagnosed as signifi cant liver fi brosis; and LSM<7.4 kPa can be excluded progressive liver fi brosis; people with LSM between 7.4-9.4 kPa, if it is diffi cult to make a correct clinical decision, liver biopsy can be considered [4]. In this study, FS and liver biopsy were performed on 100 CHB patients with normal bilirubin levels and ALT<2×ULN to observe the diagnostic value of LSM to liver stiff ness.

Subjects
A total of 100 patients with CHB who are in the Second People's Hospital of Lanzhou, Gansu province, P. R. China from January 2017 to May 2019 were invited in this study as below inclusion criteria: the diagnostic criteria were based on the guidelines for the prevention and treatment of CHB formulated by the Chinese Medical Association in 2015 [2], and excluded from clear interference factors, at the same time conform to the following conditions: patients with the ALT normal or increased twice as much as normal, total bilirubin was normal and HBV-DNA positive, body mass index <28kg / m 2 , has not received antiviral and anti-enzyme drugs, and exclude alcoholic liver disease, drug-induced hepatitis, non-alcoholic fatty liver, overlap with other hepadnavirus infections, no autoimmune liver disease and congenital genetic diseases. All patients underwent blood cell analysis, and biochemistry, coagulation, HBV-M, HBV-DNA, liver biopsy examination.

Laboratory test
Blood cell analysis, biochemistry and HBV-M, HBV-DNA detection were tested in all patients with blood cell analyzer (BC-3000, Shenzhen Maiduan Company), Beckman biochemical analyzer (AU680, American Beckman Olympus Company), Abbott automatic chemiluminescence analyzer(American), Step one plus PCR fl uorescence analyzer (American) respectively, and relevant test results were collected.

Liver biopsy and pathological diagnosis
The liver tissue was located and obtained by ultrasoundguided puncture. Observed under light microscope after fi xation, embedding, sectioning, HE staining and modifi ed Goniri reticular fi ber staining. The staging (S) criteria of liver fi brosis was in accordance with the "Hepatic Fibrosis Diagnosis and Effi cacy Assessment Consensus" developed by the Liver Fiber Chemistry Group of the Chinese Liver Disease Society in 2002.

Fibroscan
The FS (purchased from Echosens, France, probe M) was used to measure the patient's LSM within one week before liver biopsy, refer to the FS user manual for specifi c methods.

Statistical methods
All statistical analyses were carried out by the SPSS 19.0 and MedCalc 9.3 statistical software, the measurement data conforming to the normal distribution was represented by ( s x  ), we used t-test of two independent samples for comparison between groups; the data of non-normal distribution was indicated by M (P25, P75), and adopted Wilcoxon W test; the count data is analyzed by chi-square test.
Taking liver histopathological changes as the gold standard, using the receiver operating characteristic curve (ROC), calculating the area under the curve (AUC), calculating the Youden's index, then get the optimal cut-off s and its sensitivity and specifi city were calculated to evaluate the diagnostic value of FS, the diff erence was statistically signifi cant at P<0.05. In this study, patients with the ALT standard, or increased but less two times higher than the standard value total bilirubin normal, HBV-DNA positive, body mass index <28kg / m 2 , has not received antiviral and anti-enzyme drugs, and exclude alcoholic liver disease, drug-induced hepatitis, non-alcoholic fatty liver, overlap with other hepadnavirus infections, no autoimmune liver disease and congenital genetic diseases were be choosen as the research object, exclude the impact of the above factors on FS measurements, the results showed that there were diff erences between LSM, hepatic infl ammatory activity and the degree of fi brosis in 91 patients with CHB, here, we found when the LSM optimal cut-off value of patients with signifi cant fi brosis in liver biopsy was 5.35, the sensitivity was 0.824 and the specifi city was 0.736, therefore, for patients with CHB and HBV-DNA positive, if the transaminase is normal or slightly elevated, and the liver hardness value reaches 5.35, the liver tissue may be fi brotic, in addition, it is diff erent from the previous study that LSM less than 7.4KPa can rule out progressive liver fi brosis, the intensive research is needed by further expand the number of cases.

Compliance with ethical standards
Ethical approval This present study was approved by the Ethics Committee of Lanzhou Second People's Hospital.
Informed consent Informed consent was obtained from each participant before enrolling in this study.

Discussion
The liver is a silent organ, most chronic hepatitis and even early cirrhosis without specifi c symptoms, signs and biochemical indicators, however, once patients have been found some obvious symptoms and signs, most of them have cirrhosis and even liver failure [7][8][9]. In consequence, the diagnosis of liver fi brosis is of great value in the prognosis evaluation and treatment decision of chronic liver disease, it is a key step in the management of chronic liver disease to timely evaluate and fi nd advance liver fi brosis and early diagnosis of liver cirrhosis. As a relatively mature non-invasive inspection, TE has the advantages of simple operation, good reproducibility, and accurate identifi cation of mild liver fi brosis and progressive liver fi brosis or early cirrhosis [2,10]. After a decade of development, it has been verifi ed that FS can be used to assess the degree of liver fi brosis in diff erent liver diseases, but its clinical diagnostic threshold still lacks a large number of liver biopsy to be clear [10,11]. Yuan lichao et al. performed liver biopsy and pathological staging on 45 patients with CHB, and diagnosed of liver fi brosis with FS, then the analysis of the receiver operati ng characteristic curve found that the degree of liver fi brosis ≥Sl, ≥S2, ≥ S3 and ≥S4, the area under the receiver operating characteristic curve were 0.889, 0.941, 0.908 and 0.911, respectively, it indicates that FS is eff ectly in staging diagnosis of liver fi brosis. A metaanalysis of a total of 2772 patients with CHB , included 18 studies showed that when the liver fi brosis stage≥S2, S3-S4, S4 ,and thresholds were 7.9 kPa, 8.8 kPa, 11.7 kPa, respectively, and LSM values of 11.7 kPa as diagnose cirrhosis, the critical value has a sensitivity of 84.6% and a specifi city of 81.5% [12]. The FS principle uses liver stiff ness to refl ect the degree of liver fi brosis, but the measured value does not depend entirely on the degree of liver fi brosis. Some experts argued that FS measurements have many infl uencing factors, such as body weight, gender, diabetes, ALT and liver steatosis, jaundice, infl ammation, diet, etc [13][14][15][16].