Research Article
Submassive hepatic necrosis distinguishes HBV-associated acute on chronic liver failure from cirrhotic patients with acute decompensation- Hai Li1, 2, 3, , †, ‡, ,
- Qiang Xia4, †,
- Bo Zeng1, 2, 3, †,
- Shu-Ting Li1, 2, 3, †,
- Heng Liu5, 6,
- Qi Li5,
- Jun Li7,
- Shu-Yin Yang1, 2, 3,
- Xiao-Jun Dong1, 2, 3,
- Ting Gao1, 2, 3,
- Stefan Munker5,
- Yan Liu5,
- Roman Liebe5, 8,
- Feng Xue4,
- Qi-Gen Li4,
- Xiao-Song Chen4,
- Qiang Liu9,
- Hui Zeng10,
- Ji-Yao Wang11,
- Qing Xie12,
- Qin-Hua Meng13,
- Jie-Fei Wang14,
- Peter R. Mertens15,
- Frank Lammert8,
- Manfred V. Singer5,
- Steven Dooley5,
- Matthias P.A. Ebert5,
- De-Kai Qiu1, 2, 3,
- Tai-Ling Wang16, , ‡, ,
- Hong-Lei Weng5, , ‡,
- 1 Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- 2 Shanghai Institute of Digestive Disease, Shanghai, China
- 3 Key Laboratory of Gastroenterology & Hepatology, Chinese Ministry of Health (Shanghai Jiao Tong University), Shanghai, China
- 4 Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- 5 Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- 6 Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- 7 Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- 8 Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
- 9 Department of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- 10 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- 11 Department of Gastroenterology, Zhong-shan Hospital, Fu Dan University, Shanghai, China
- 12 Department of Infectious Disease, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- 13 Department of Hepatology, Beijing You’an Hospital, Capital Medical University, Beijing, China
- 14 Severe Hepatitis Department & Intensive Care Unit, Shanghai Public Health Center, Affiliated Fudan University, Shanghai, China
- 15 Department of Nephrology and Hypertension, Otto-von-Guericke-University, Magdeburg, Germany
- 16 Department of Pathology, Beijing China-Japan Friendship Hospital, Beijing, China
Received 8 August 2014, Revised 8 January 2015, Accepted 26 January 2015, Available online 31 January 2015
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doi:10.1016/j.jhep.2015.01.029Get rights and content
Background & AimsDistinguishing between acute on chronic liver failure (ACLF) and decompensated liver cirrhosis is difficult due to a lack of pathological evidence. MethodsA prospective single-center study investigated 174 patients undergoing liver transplantation due to acute decompensation of hepatitis B virus (HBV)-associated liver cirrhosis. Two groups were distinguished by the presence or absence of submassive hepatic necrosis (SMHN, defined as necrosis of 15–90% of the entire liver on explant). Core clinical features of ACLF were compared between these groups. Disease severity scoring systems were applied to describe liver function and organ failure. Serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes were used to study systemic and local inflammatory responses. ResultsSMHN was identified in 69 of 174 patients proven to have cirrhosis by histological means. Characteristic features of SMHN were extensive necrosis along terminal hepatic veins and spanning multiple adjacent cirrhotic nodules accompanied by various degrees of liver progenitor cell-derived regeneration, cholestasis, and ductular bilirubinostasis. Patients with SMHN presented with more severely impaired hepatic function, a higher prevalence of multiple organ failure (as indicated by higher CLIF-SOFA and SOFA scores) and a shorter interval between acute decompensation and liver transplantation than those without SMHN (p <0.01 for all parameters). Further analyzes based on serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes revealed higher levels of anti-inflammatory cytokines in patients with SMHN. ConclusionsSMHN is a critical histological feature of HBV-associated ACLF. Identification of a characteristic pathological feature strongly supports that ACLF is a separate entity in end-stage liver disease.
Graphical abstract
Abbreviations- ACLF, acute on chronic liver failure;
- ALF, acute liver failure;
- AD, acute decompensation;
- MHN, massive hepatic necrosis;
- SMHN, submassive hepatic necrosis;
- HBV, hepatitis B virus;
- LT, liver transplantation;
- SIRS, systemic inflammatory response syndrome;
- TB, total bilirubin;
- CBA, Cytometric Bead Array;
- MELD, model for end-stage liver disease;
- SOFA, sequential organ failure assessment score;
- CLIF-SOFA, chronic liver failure-sequential organ failure assessment score;
- APACHE, acute physiology score, age points, chronic health points;
- H&E, hematoxylin & eosin;
- IHC, immunohistochemistry;
- LPC, liver progenitor cells;
- DR, ductular reaction;
- IH, intermediate hepatocyte;
- SD, standard deviation;
- IQR, interquartile ranges;
- AIH, autoimmune hepatitis;
- ALD, alcoholic liver disease;
- ALT, alanine aminotransferase;
- AUC, area under curve;
- CK7, cytokeratin 7;
- EASL-CLIF, European Association for the Study of the Liver-chronic liver failure;
- INR, international normalized ratio;
- PBC, primary biliary cirrhosis;
- ROC, response operating characteristic;
- TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling
Keywords- Acute-on-chronic liver failure;
- Cirrhosis;
- Submassive hepatic necrosis;
- Liver histology;
- Acute decompensation;
- HBV
Corresponding authors. Addresses: Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Chinese Ministry of Health (Shanghai Jiao Tong University), Shanghai, China. Tel.: +86 21 63200874, +86 21 68382001 (H. Li). Department of Pathology, Beijing China-Japan Friendship Hospital, Beijing, China. Tel.: +86 10 84205476 (T.-L. Wang). Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Tel.: +49 621 383 5603; fax: +49 621 383 1467 (H.-L. Weng).†These authors have contributed equally and share first authorship.
‡These authors have contributed equally and share corresponding authorship.
Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier Ireland Ltd. All rights reserved.
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发表于 2015-6-16 17:32
