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August 23, 2021, 11:06

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TO THE EDITOR Ivan Ranković, Vladimir Milivojević, Mihailo Bezmarević Ivan Ranković, MD, Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Society for Nutrition, Microbiome and Immunometabolism, Belgrade, Serbia Vladimir Milivojević, MD, Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Society for Nutrition, Microbiome and Immunometabolism, Belgrade, Serbia Mihailo Bezmarević, MD, PhD, Department of Hepatobiliary and Pancreatic Surgery, Clinic for General Surgery, Military Medical Academy, Faculty of Medicine, University of Defense, Society for Nutrition, Microbiome and Immunometabolism, Belgrade, Serbia We read with interest the study of Riveiro-Barciela et al [1] which elucidates the possible interplay between hepatitis B virus (HBV) infection and carotid atherosclerosis. It has high yield trial properties due to large sample size and prospective method. Albeit, inclusion and exclusion criteria were precise and broad, as with any other case control study, there remains the possibility of bias as a consequence of inferring causation from statistically significant co-relations which can be complicated by difficulty in determining the chronological order of exposure to HBV i.e. the starting time of infection and latency. The authors have concluded that the presence of subclinical atherosclerosis and carotid plaques were more frequent in patients with HBV infection than controls and that liver damage was an independent factor associated with subclinical atherosclerosis and carotid plaques, regardless of the classical cardiovascular factors. We agree in general with the authors since many of our patients render a similar atherosclerotic disease profile which can’t be attributed solely, sui generis, to the cardiovascular substrate. Therefore, this study has the capacity, not only to raise the index of suspicion of the practicing clinician, but to optimize the established diagnostic framework of HBV patients in order to prevent atherosclerosis occurrence and complications. Furthermore, this study implicates chronic HBV infection i.e. its specific point – naïve HBe antigen negative phase as being an important atherosclerotic contributor. Conversely, prior study of Tong et al [2] has concluded that HBV infection not only negatively correlates with CRP levels but seems not to be associated with coronary atherosclerosis. Additionally, Kiechl et al [3] found no significant association between chronic hepatitis and the development of new carotid atherosclerotic plaques, although they did not specify the type of hepatitis virus. Off course, these conflicting results have to be taken cautiously as they originate from patients in different HBV phases with divergence in research material and methods. With all this said, it may be that the window of opportunity for early atherosclerosis detection and preemptive therapeutic intervention in HBV could be the subpopulation of naïve and HBe antigen negative patients. However, general discrepancies in conclusions of the aforementioned trials made us postulate some intriguing perspective theories. Firstly, it may be that HBV infection harbors specific propensity towards anatomically different vascular structures hence affecting carotid more often that coronary arteries. This is in concordance with the previously published data inferring that viruses have different sites of endothelial predilection [4]. Secondly, we may, perhaps, utilize other, more sophisticated, inflammatory markers, namely high sensitivity CRP with or without homocysteine for optimal HBV patient stratification regarding atherosclerosis risk [5]. Thirdly, potential role of macrophage phenotype variation during HBV infection may be one of the crossroads between the processes of atherosclerosis and HBV infection [6]. Current cardiology investigations revealed significant role of the macrophage encompassing its local, endothelial, as well as, systemic effect via T helper lymphocytes and cytokine release modulation [7]. Having stated that, we postulate that HBV infection may trigger macrophage phenotype alteration rendering it to be the contributive precipitant of atherosclerotic disease as well as the crosslink point between the two diseases. Last but not the least, the study of Riveiro-Barciela et al [1] may open the door for broader statin use therefore addressing concomitantly two end goals: lowering the risk of cirrhosis and hepatocellular carcinoma in viral hepatitis patients [8] and engaging in the prevention and treatment of atherosclerosis and its complications. We believe that prospects in this field should be diversified in the manner that one size does not fit all. Upcoming trials and future viewpoints should render better comprehension of the delicate HBV pathodynamics from which implementation of optimized and specific therapy would be more feasible. Our group envisions many possible pathways between HBV infection and atherosclerosis i.e. cardiovascular diseases which may be potential targets and thus encourages future research work in this field. REFERENCES: 1. Riveiro-Barciela M, Marcos-Fosch C, Martinez-Valle F, Bronte F, Orozco O, Sanz-Pérez I, Torres D, Salcedo MT, Petta S, Esteban R, Craxi A, Buti M. Naïve hepatitis B e antigen-negative chronic hepatitis B patients are at risk of carotid atherosclerosis: A prospective study. World J Gastroenterol 2021; 27(30): 5112-5125 [DOI: 10.3748/wjg.v27.i30.5112] 2. Tong DY, Wang XH, Xu CF, Yang YZ, Xiong SD. Hepatitis B virus infection and coronary atherosclerosis: results from a population with relatively high prevalence of hepatitis B virus. World J Gastroenterol. 2005 Mar 7;11(9):1292-6. doi: 10.3748/wjg.v11.i9.1292. PMID: 15761966; PMCID: PMC4250675. 3. Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W, et al. Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation. 2001;103:1064–1070. 4. Burrell CJ, Howard CR, Murphy FA. Chapter 7 - Pathogenesis of Virus Infections, Editor(s): Christopher J. Burrell, Colin R. Howard, Frederick A. Murphy. Fenner and White's Medical Virology (Fifth Edition), Academic Press, 2017, Pages 77-104, ISBN 9780123751560 5. Ma LN, Liu XY, Luo X, Hu YC, Liu SW, Tang YY, Pan JL, Ding XC. Serum high-sensitivity C-reactive protein are associated with HBV replication, liver damage and fibrosis in patients with chronic hepatitis B. Hepatogastroenterology. 2015 Mar-Apr;62(138):368-72. PMID: 25916065. 6. Li Y, Li S, Duan X, Yang C, Xu M, Chen L. Macrophage Phenotypes and Hepatitis B Virus Infection. J Clin Transl Hepatol. 2020;8(4):424-431. doi:10.14218/JCTH.2020.00046 7. Xu H, Jiang J, Chen W, Li W, Chen Z. Vascular Macrophages in Atherosclerosis. J Immunol Res. 2019 Dec 1;2019:4354786. doi: 10.1155/2019/4354786. PMID: 31886303; PMCID: PMC6914912. 8. Wang Y, Xiong J, Niu M, et al. Statins and the risk of cirrhosis in hepatitis B or C patients: a systematic review and dose-response meta-analysis of observational studies. Oncotarget. 2017;8(35):59666-59676. Published 2017 Jul 27. doi:10.18632/oncotarget.19611

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