Feng'e Liu

The First Hospital of Changsha

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Jixiong Hu

Central South University

Zhongzhou Si

Yangtze University

Zhihong Zhang

Anhui Provincial Hospital

Ning Zhou

Shanghai Jiao Tong University

Le Rao

Chinese PLA General Hospital

Shuyu Kuang-Zeng

Zhuzhou Central Hospital

Biyuan Luo

Central South University

Yongfang Jiang

Second Xiangya Hospital of Central South University

Zhihong Li

China Agricultural University

Chunying Liu

Affiliated Hospital of Shaanxi University of Chinese Medicine

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Central South University

Second Xiangya Hospital of Central South University

The First Hospital of Changsha

Xiangya Hospital Central South University

Soochow University

Southern Medical University

Burning Rock Biotech (China)

Zhejiang University

Nanjing Medical University

Dalian University of Technology

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Cell-free DNA methylation markers for differential diagnosis of hepatocellular carcinoma

BMC Medicine (2022)

Biyuan Luo Fang Ma Hao Liu Jixiong Hu Le Rao

Abstract Background Aberrant DNA methylation may offer opportunities in revolutionizing cancer screening and diagnosis. We sought to identify a non-invasive DNA methylation-based screening approach using cell-free DNA (cfDNA) for early detection of hepatocellular carcinoma (HCC). Methods Differentially, DNA methylation blocks were determined by comparing methylation profiles of biopsy-proven HCC, liver cirrhosis, and normal tissue samples with high throughput DNA bisulfite sequencing. A multi-layer HCC screening model was subsequently constructed based on tissue-derived differentially methylated blocks (DMBs). This model was tested in a cohort consisting of 120 HCC, 92 liver cirrhotic, and 290 healthy plasma samples including 65 hepatitis B surface antigen-seropositive (HBsAg+) samples, independently validated in a cohort consisting of 67 HCC, 111 liver cirrhotic, and 242 healthy plasma samples including 56 HBsAg+ samples. Results Based on methylation profiling of tissue samples, 2321 DMBs were identified, which were subsequently used to construct a cfDNA-based HCC screening model, achieved a sensitivity of 86% and specificity of 98% in the training cohort and a sensitivity of 84% and specificity of 96% in the independent validation cohort. This model obtained a sensitivity of 76% in 37 early-stage HCC (Barcelona clinical liver cancer [BCLC] stage 0-A) patients. The screening model can effectively discriminate HCC patients from non-HCC controls, including liver cirrhotic patients, asymptomatic HBsAg+ and healthy individuals, achieving an AUC of 0.957(95% CI 0.939–0.975), whereas serum α-fetoprotein (AFP) only achieved an AUC of 0.803 (95% CI 0.758–0.847). Besides detecting patients with early-stage HCC from non-HCC controls, this model showed high capacity for distinguishing early-stage HCC from a high risk population (AUC=0.934; 95% CI 0.905–0.963), also significantly outperforming AFP. Furthermore, our model also showed superior performance in distinguishing HCC with normal AFP (< 20ng ml −1 ) from high risk population (AUC=0.93; 95% CI 0.892–0.969). Conclusions We have developed a sensitive blood-based non-invasive HCC screening model which can effectively distinguish early-stage HCC patients from high risk population and demonstrated its performance through an independent validation cohort. Trial registration The study was approved by the ethic committee of The Second Xiangya Hospital of Central South University (KYLL2018072) and Chongqing University Cancer Hospital (2019167). The study is registered at ClinicalTrials.gov(# NCT04383353 ).

Cell-free fetal DNA

10.1186/s12916-021-02201-3

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Value of liver/spleen stiffness combined with serum adenosine deaminase in predicting severe esophageal varices in patients with hepatitis B cirrhosis

临床肝胆病杂志 (2021)

Qing Xie Li Zeng Zhen Tang Jinqiang Li Feng'e Liu

Objective To investigate the value of liver stiffness measurement (LSM) and spleen stiffness measurement (SSM) based on FibroTouch (FT) transient elastography combined with serum adenosine deaminase (ADA) in predicting severe esophageal varices (EV) in patients with hepatitis B cirrhosis. Methods Related clinical data were collected from 120 patients with hepatitis B cirrhosis who attended Department of Infectious Diseases, Changsha First Hospital, from December 2017 to June 2020. FT was used to measure LSM and SSM, and related examinations were performed, including electronic gastroscopy and serum levels of ADA, hemoglobin, albumin, alanine aminotransferase, and aspartate aminotransferase and platelet count. The serum liver fibrosis markers aspartate aminotransferase-to-platelet ratio index (APRI), aspartate aminotransferase/alanine aminotransferase ratio (AAR), and fibrosis-4 (FIB-4) were calculated. According to the severity of EV under gastroscopy, the subjects were divided into severe EV group with 58 patients and non-severe EV (without EV or with mild-to-moderate EV) group with 62 patients. The t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. The Spearman rank correlation test was used to investigate the correlation of LSM, SSM, and ADA with severe EV. The receiver operating characteristic (ROC) curve was used to analyze the efficacy of LSM, SSM, and ADA in the diagnosis of severe EV, and sensitivity and specificity were calculated. A multivariate binary logistic regression analysis was performed to calculate the area under the ROC curve (AUC) of the combined indicators, and the Z test was used for comparison of AUC. Results There were significant differences in LSM, SSM, and ADA between the two groups (all P Conclusion Liver/spleen stiffness combined with serum ADA has a good value in predicting severe EV, which can provide a preliminary diagnostic basis for severe EV in patients who refuse to undergo gastroscopy.

Rank correlation

10.3969/j.issn.1001-5256.2021.06.020

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Circulating Tumor DNA Methylation Markers for Differential Diagnosis of Hepatocellular Carcinoma

SSRN Electronic Journal (2021)

Biyuan Luo Fang Ma Hao Liu Jixiong Hu Le Rao

Background: An effective blood-based method for hepatocellular carcinoma (HCC) early detection has not yet been developed. Aberrant DNA methylation may offer opportunities in revolutionizing cancer screening and diagnosis. We sought to identified a non-invasive DNA methylation-based diagnostic approach using cell-free DNA for HCC early detection in high risk population.Methods: Differentially methylated DNA methylation blocks were determined by comparing methylation profiles of biopsy-proven HCC, cirrhotic and healthy liver tissues using targeted bisulfite sequencing. A multi-layer HCC screening model was subsequently constructed based on tissue-derived differentially methylated makers using plasma samples from 120 HCC patients, 92 cirrhotic patients and 290 healthy individuals. This model was independently validated in a cohort consisting of 67 HCC patients, 115 cirrhotic patients and 242 healthy individuals. The clinical parameters of misclassified samples were also investigated. Findings: Based on methylation profiling of tissue samples, a total of 2,321 DNA methylation markers were derived, which were subsequently used to construct a cfDNA-based HCC screening model, achieving a sensitivity of 86% and specificity of 97% in the training cohort and a sensitivity of 82% and specificity of 96% in the independent validation cohort. The HCC screening model can effectively discriminate HCC patients from non-HCC patients, including patients with cirrhosis, HBV infection and healthy individuals, achieving an AUC of 0.956; whereas serum alpha-fetoprotein (AFP) achieved an AUC of 0.803.Interpretation: We have developed and validated an HCC screening model which can effectivelydistinguish early stage HCC patients from cirrhotic patients and symptomatic HBsAg-seropositiveindividuals.Funding: Key Research and Development Program of Hunan Province, Natural ScienceFoundation of Hunan Province, China.Declaration of Interest: None to declare. Ethical Approval: The study was approved by the ethic committee of The Second Xiangya Hospital of Central South University (KYLL2018072) and Chongqing University Cancer Hospital (2019167). All collection and usage of human sample and clinical data were in accordance with the principles of the Declaration of Helsinki. Written informed content was obtained from every participant for the use of their tissue or plasma samples.

10.2139/ssrn.3854620

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[Report of a rare case of hereditary hemochromatosis and Gilbert syndrome].

PubMed (2014)

Xangjun Li Jin Lu Feng'e Liu Liping Li Changming Liu

1.患者资料:患者女性,40岁,因反复乏力、皮肤巩膜黄染30余年,发现肝硬化6年于2013年8月1日入院.入院时查体:慢性肝病面容,全身皮肤、巩膜中度黄染,肝掌可疑,无蜘蛛痣,无出血点及皮疹.颈软,心肺无异常发现.腹平软,无压痛、反跳痛,肝右肋下约2.0cm,剑突下4.0cm,质中,无触痛,脾左肋下约6.0cm,质中,无触痛,肝区轻叩痛,移动性浊音阴性,肠鸣音正常.双下肢无水肿,左侧胫前皮肤可见约12cm×5cm色素沉着,其间可见丘疹样改变及抓痕.既往史:6岁左右因“皮肤巩膜黄染”多次在外院检查,诊断“体质性黄疸”. 关键词：血色素沉着症;Gilbert综合征;肝硬化;黄疸

Hereditary hemochromatosis

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