How intrahepatic cholestasis affects liver stiffness in patients with chronic hepatitis B: a study of 1197 patients with liver biopsy

  • Huanyi Guo
  • Mei Liao
  • Jieyang Jin
  • Jie Zeng
  • Shuoyang Li
  • Darrell R. Schroeder
  • Jian Zheng
  • Rongqin ZhengEmail author
  • Shigao Chen



To evaluate the impact of intrahepatic cholestasis on liver fibrosis staging using liver stiffness measurements (LSM).


Between July 2011 and September 2016, a total of 1197 patients with chronic hepatitis B (CHB) infection were enrolled to collect clinical, biological, 2D shear wave elastography (SWE), and histological (METAVIR scoring system) data. LSM was compared in patients with normal total bilirubin (TB) versus abnormal TB for each group of fibrosis stage, alanine aminotransferase (ALT) levels, and inflammation grade. Logistic regression and ROC analyses were performed to assess the benefit of adding TB and to LSM for fibrosis staging.


Nine hundred and seventy-three patients were analyzed. Within the same fibrosis stage, LSMs showed significantly higher value in patients with abnormal TB than those with normal TB. Increased LSM for abnormal TB was generally found within different sub-groups of patients (≤ F2 or ≥ F3; ALT < 2 × upper limit of normal (ULN) or ALT ≥ 2 × ULN; METAVIR activity grade ≤ 1 or ≥ 2). Patients with abnormal TB level showed higher optimal cutoff values: 10.46 kPa for ≥ F2, 10.94 kPa for ≥ F3, and 15.88 kPa for F4, than those with normal TB (7.62 kPa, 8.26 kPa, and 11.01 kPa, respectively). LSM assessed fibrosis stage (≥ F2, ≥ F3, F4) showed higher false positive rate in patients with abnormal TB level (44.6%, 45.1%, 39.6%) than those with normal TB (20.7%, 17.1%, 14.4%). However, the area under the ROC curve did not change appreciably when adding TB to LSM for fibrosis stage.


Intrahepatic cholestasis showed slight effect on LSM in patients with CHB, also leading to overestimation of liver fibrosis stages. But adding TB level to LSM did not improve the overall diagnostic performance of liver fibrosis stage.

Key Points

• Intrahepatic cholestasis showed slight effect on liver stiffness measurements (LSMs) in chronic HBV patients.

• Patients with abnormal total bilirubin (TB) level showed higher optimal cutoff values and false positive rate.

• When taking into account intrahepatic cholestasis, the diagnostic performance of LSM for liver fibrosis staging in patients with chronic HBV infection will not improve.


Sonoelastography Diagnostic ultrasound Liver fibrosis Bilirubin Hepatitis B virus infection 



2D shear wave elastography


Serum alkaline phosphatase


Alanine aminotransferase


Aspartate aminotransferase


Body mass index


chronic hepatitis B


Gamma-glutamyl transpeptidase


Hepatitis B virus


Hepatocellular carcinoma




Liver stiffness measurements


Platelet count


Prothrombin activity


Receiver operating characteristic


Total bilirubin


Upper limit of normal



The authors thank Caixia Zhang (School of Public Health, Sun Yat-sen University) who helped with the statistics.

Funding information

This study received financial support from the National Natural Science Foundation of China (No. 81601503) and the National Key Research and Development Program of China (No. 2017YFC0112000).

Compliance with ethical standards


The scientific guarantor of this publication is Rong-Qin Zheng.

Conflict of interest

All authors disclosed no relevant relationships of conflict of interest.

Statistics and biometry

Darrell R. Schroeder (Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester MN) and Caixia Zhang (School of Public Health, Sun Yat-sen University) kindly provided statistical advice for this manuscript.

Informed consent

Written informed consent was obtained from all subjects in this study.

Ethical approval

Institutional Review Board approval was obtained.

Study subjects or cohorts overlap

Some study subjects have been previously reported in two articles entitled “Diagnostic accuracy of two-dimensional shear wave elastography for the non-invasive staging of hepatic fibrosis in chronic hepatitis B: a cohort study with internal validation” and “Shear wave elastography for liver fibrosis in chronic hepatitis B: Adapting the cut-offs to alanine aminotransferase levels improves accuracy.”


• Prospective

• Diagnostic or prognostic study

• Performed at one institution

Supplementary material

330_2019_6451_MOESM1_ESM.docx (450 kb)
ESM 1 (DOCX 449 kb)


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Copyright information

© European Society of Radiology 2019

Authors and Affiliations

  1. 1.Department of Medical Ultrasonics and Guangdong Key Laboratory of Liver Disease ResearchThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
  2. 2.Faculty of Engineering & Information SciencesUniversity of WollongongWollongongAustralia
  3. 3.Division of Biomedical Statistics and InformaticsMayo ClinicRochesterUSA
  4. 4.Department of UltrasoundThird People’s Hospital of Longgang District of ShenzhenShenzhenChina
  5. 5.Department of RadiologyMayo ClinicRochesterUSA

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