Posttreatment Nonalcoholic Fatty Liver Disease Fibrosis Scores for Predicting Liver-related Complications in Patients With Chronic Hepatitis C Receiving Direct-acting Antiviral Agents

Wei-Fan Hsu; Hsueh-Chou Lai; Po-Heng Chuang; Wen-Pang Su; Sheng-Hung Chen; Hung-Yao Chen; Hung-Wei Wang; Guan-Tarn Huang; Cheng-Yuan Peng


J Viral Hepat. 2022;29(9):785-79. 

In This Article

Materials and Methods


Between September 2012 and December 2020, 1625 consecutive patients with CHC were enrolled on this retrospective study at China Medical University Hospital. The inclusion criteria were as follows: age ≥18 years; a diagnosis of CHC, defined as the presence of serum anti-HCV antibodies for >6 months and detectable HCV RNA (COBAS Ampliprep and COBAS TaqMan HCV test); and completion of DAA therapy. The exclusion criteria were as follows: the presence of hepatitis B virus infection, defined as positive serum hepatitis B surface antigens (HBsAg; n = 129), and human immunodeficiency virus (HIV) infection (n = 70); non-SVR (n = 58); HCC at baseline (n = 138); decompensated liver disease (DLD) at baseline (n = 93); end-stage renal disease (n = 68); and unknown status of metabolic syndrome (MS, n = 300). Some patients had more than one exclusion criterion. Of the 906 patients who were eligible for investigation, 590 patients with both NFS at baseline and 3 or 6 months after DAA therapy (PW12) were enrolled in the analysis (Figure S1). The selection of NFS for further comparison will be discussed in the following section.

Body mass index (BMI) and comorbidities were recorded at baseline, and hematologic and biochemical values and virological data were collected at baseline, end of therapy (EOT) and PW12.

This study was conducted in accordance with the 1975 Declaration of Helsinki and was approved by the Research Ethics Committee of China Medical University Hospital, Taichung, Taiwan (CMUH107-REC1-057). Each patient's identification number was encrypted for privacy protection, and the need for informed consent was waived.

Laboratory Tests

Hemogram analyses (Sysmex HST series) and biochemistry tests (Beckman Coulter) were performed in the central laboratory of the hospital. HCV genotyping was performed using the Abbott RealTime HCV Genotype II assay (Abbott Molecular). The ultrasonographic diagnosis of fatty liver was performed based on the guidelines of the Asian Pacific Association for the Study of the Liver; fatty liver was diagnosed if two or more of the following criteria were present: (1) increased echogenicity of the liver compared with the kidney or spleen; (2) blurred vascularity; and (3) signal attenuation in deeper parts of the liver.[15] Liver cirrhosis (LC) was defined based on the results of unequivocal clinical, ultrasonographic or histological analyses.

Definition of MS

Based on the third report of the National Cholesterol Education Program[16] and Asia World Health Organization criteria,[17] MS was defined as the presence of at least three of the following five components: (1) central obesity (waist circumference ≥90 cm in men and ≥80 cm in women); (2) systemic blood pressure (BP) ≥130 mmHg or diastolic BP ≥85 mmHg or treatment for previously diagnosed hypertension; (3) high fasting plasma glucose ≥100 mg/dl or previously diagnosed type 2 DM; (4) high triglyceride ≥150 mg/dl; and (5) low high-density lipoprotein (HDL, <40 mg/dl in men or <50 mg/dl in women) or specific treatment for dyslipidaemia.

Noninvasive Indices for Liver Fibrosis

We computed APRI,[18] FIB-4,[19] and NFS values[13] using the following formulas:

where ULN is the upper limit of normal and ULN = 34 U/L for AST.

The formula for HFS is complex, and the coefficients are different for each variable in the different ranges. Briefly, the formula includes variables of age, sex, DM, AST, albumin, platelet count and the homeostatic model assessment of insulin resistance.[14]

Definition of LRCs

In this study, LRCs included DLD and HCC. DLDs included ascites, high-risk oesophageal (F2, F3 or with red colour signs) or bleeding gastric varices, hepatic encephalopathy and hepatorenal syndrome.[20,21] HCC was diagnosed on the basis of histology or typical radiological presentations in at least two imaging modalities, including abdominal ultrasonography, contrast-enhanced dynamic computed tomography, magnetic resonance imaging and hepatic arterial angiography.[22,23] Follow-up duration was calculated from the date of the EOT. Data collection for a patient was stopped when any of the following occurred: death, loss to follow-up or the end of follow-up (until 31 December 2020).

Selection of Noninvasive Assessments

This study investigated the application of NAFLD-related noninvasive fibrosis assessments for predicting LRCs and HCC occurrence in patients with CHC. In a subgroup of patients with available APRI, FIB-4, NFS and HFS (n = 613) values, the predictive performance of the four noninvasive assessments for LRCs was examined by performing an area under the receiver operating characteristic curve (AUROC) analysis using the DeLong test. NFS at baseline and PW12 AUROCs had the highest values (Figure S2A,B). Therefore, we selected NFS for comparison with the widely used FIB-4.[10,11,19]

Statistical Analyses

Categorical variables are presented as frequency (percentage), and continuous variables are presented as the median (1st quartile–3rd quartile). Between-group comparisons of variables were performed using the Mann–Whitney U test. Variables with p < .20 in the univariate analysis were included in a multivariate Cox regression analysis to determine their associations with LRCs or HCC. Collinearity to perform statistical analysis on the same variables at different time points was identified, and variables were analysed separately at different time points. The predictive performance of NFS for LRCs at baseline and PW12 was examined by performing a time-dependent AUROC analysis using the DeLong test. A Kaplan–Meier analysis with a log-rank test was used to compare the LRCs among patient subgroups. All statistical analyses were performed using SPSS (version 25.0, IBM). A two-sided p value of <.05 was considered statistically significant.