Hematologic system damage is common and related to severity in patients with acute hepatitis E

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This article is to report hematologic systemdamage caused by hepatitis E. Methods : A retrospective study enrolled 170 patients with acute hepatitis E. The study analyzed the proportion of patients with decreased white blood cell, hemoglobin, and platelet levels in their blood routine, along with their potential clinical significance. 49 patients with HA were also included as controls to compare and analyze the differences in biochemical indicators and hematologic damage. Results: Among the 170 patients with hepatitis E, 47 cases (27.64%) presented with leukopenia, 94 cases (55.29%) exhibited anemia, and 33 cases (19.41%) experienced thrombocytopenia. The findings indicated that hemoglobin and platelets are lower in patients with hepatitis E than in patients with hepatitis A, and anemia is more common in patients with hepatitis E. The anemia group had significantly lower levels of albumin, alanine aminotransferase, and cholinesterase compared to the normal group (p<0.001, p=0.005, p<0.001). Additionally, total bilirubin and alkaline phosphatase were significantly higher in the anemia group than in the normal group (p=0.031, p=0.003). Moreover, the anemia group showed a higher likelihood of experiencing spontaneous bacterial peritonitis (p=0.025). In comparison to the normal platelet group, the thrombocytopenia group exhibited significantly lower levels of albumin, cholinesterase, and prothrombin activity (p=0.036, p=0.015, p<0.001). Patients with decreased platelet have the higher incidence of death, spontaneous bacterial peritonitis, upper gastrointestinal bleeding and hepatorenal syndrome (p<0.001, p<0.001, p=0.027, p=0.014). Conclusion: Hepatitis E patients with hematologic system damage are common. Patients with hepatitis Ehave lower levels of hemoglobin and platelets compared to patients with hepatitis A. The presence of anemia and low platelets in patients with hepatitis Eindicates a more severe condition. hepatitis E hepatitis A white blood cells anemia platelet Figures Figure 1 Figure 2 1. Introduction Hepatitis E (HE) is an acute infectious disease caused by infection with the HE virus, which is mainly transmitted through the digestive tract. Most people with hepatitis E virus (HEV) infection are asymptomatic or self-limited. HEV, belonging to the family flavivirus, is a new pathogen discovered by investigators in an outbreak of unexplained hepatitis in 1983 that can circulate between multiple species and cause zoonotic diseases( 1 ). It contains 4 open reading frames, ORF1 encodes non-structural polyproteins for viral replication and transcription, ORF2 encodes capsid proteins that elicit neutralizing antibodies, ORF3 fractions overlap ORF2, and encodes multifunctional proteins involved in virion morphogenesis and pathogenesis( 2 ). At present, 8 genotypes have been identified, genotypes 1 and 2 only infect humans, transmitted by water, mainly causing pandemics or outbreaks in developing countries with poor sanitation( 3 ),genotypes 3 and 4 are zoonotic pathogens, generally infected by eating undercooked contaminated meat, often causing sporadic cases in developed countries( 4 ),genotypes 5 and 6 have been found in wild animals in Japan, Genotypes 7 and 8 were detected in camels. Previous studies have found that HE is an intrahepatic inflammatory disease caused by HEV infection, and recent studies have found that HE can lead to a variety of extrahepatic manifestations, mainly acute pancreatitis ( 5 ), nervous system diseases ( 6 ), kidney damage ( 7 ), blood system diseases ( 8 ) etc. Therefore, HEV infection should be considered a systemic disease, not just an inflammatory disease within the liver. Previous studies have reported that hematologic damage caused by HEV infection is mainly manifested by thrombocytopenia and anemia, Kemming et al ( 9 ) showed that chronic HEV infection is associated with specific CD8 + T cell depletion, especially in immunosuppressed populations. While another study showed that increased reactive CD4 + T cells and CD8 + T cells could be detected in acute hepatitis E(AHE) infection ( 10 ). However, few studies have shown that AHE leads to a decrease in leukocytes. At present, thrombocytopenia caused by HE infection has been reported in France, Japan, India and other countries, mainly including genotypes 1 and 3, and these patients will have purpura, bleeding and other manifestations in addition to jaundice, poor feeding, elevated transaminases and other manifestations( 11 ). Similarly, Mu et al( 12 ) found HEV infection leads to a decrease in platelets and can serve as a short-term prognostic marker for patients with acute HE liver failure. HE infection in patients with G-6-PD deficiency can lead to the development of hemolytic anemia( 13 ). However, most of the previous studies on the extrahepatic manifestations of HE infection were limited to case report, and there was a lack of research on the clinical features and related complications of a large number of HE patients. Therefore, we retrospectively investigated 170 patients diagnosed with acute HE and 49 patients with acute hepatitis A(AHA) to further elucidate the incidence and clinical significance of hematologic system damage in patients with acute HE. 2. Information and methodology 2.1 Definition of patients with acute HE and hematologic system damage A total of 170 patients diagnosed with sporadic AHE and 49 patients with AHA in the First Affiliated Hospital of Chongqing Medical University from January 2013 to March 2023 were included in the analysis. Patients who were discharged from hospital were followed up to six months, taking death as a clinical outcome. Acute HE infection is defined as a marked elevation of aminotransferases (ALT ≧ 2.5 × upper limit of normal (ULN)) and positive anti-HEV IgM or HEV RNA( 14 ). Definition of anemia According to the World Health Organization's diagnostic criteria for anemia, hemoglobin (Hb) < 120 g/L in premenopausal women and < 130 g/L in postmenopausal women and men of all ages are called anemia. Thrombocytopenia Platelet (PLT) < 100×10 9 /L were defined as thrombocytopenia( 15 ). Leukopenia The normal reference range for total white blood cell (WBC) number is 4–10×10 12 /L. And if the WBC < 4×10 12 /L, it was defined as leukopenia ( 16 ) . The definition of suspicious drug Including proton pump inhibitors, antibiotics, antiviral drugs and so on. 2.2 Detection of anti-HEV IgM and IgG Serum anti-HEV-IgM and anti-HEV-IgG antibodies were detected by enzyme-linked immunosorbent kit (Beijing Hyundai Gundam 2012–2019, Beijing Wantai Company 2019–2022). The S/CO value ≥ 1 was positive. 2.3 Statistics Quantitative data are expressed as mean ± standard deviation, and qualitative data are expressed as absolute values and absolute percentages. The quantitative data were tested by T-test, and the qualitative data were tested by chi-square test or Fisher’s precision probability test. All tests are double-tailed tests. p < 0.05 is considered statistically significant. 3. Outcomes 3.1 Comparison of demographic characteristics between HE and HA Comparative analysis of the demographic information of the two groups of hepatitis A(HA) and HE, as shown in Table 1 . HE patients did not differ from HA patients in terms of gender, but were older than HA patients, and there was no significant difference between HA and HE in terms of the use of suspected drugs. Patients with HE show no difference from those with HA in terms of decreased WBC and PLT counts, but HE patients are more commonly associated with anemia. In addition, patients with HE may experience more clinical complications and are more prone to death. Although there's no apparent statistical difference, it might also be due to a small sample size. Table 1 Demographic characteristics of patients with HE and HA Parameters HAV(n = 49) HEV(n = 170) P value Gender Male (%) 29 (59.20%) 121 (71.20%) 0.111 Female (%) 20 (40.80%) 49 (28.80%) Age (years) 44.43 ± 15.46 54.26 ± 15.20 < 0.001 Suspicious drugs 34(69.40%) 113(66.50%) 0.702 Leucopenia 10(20.40%) 47(27.60%) 0.309 Neutropenia 8(16.30%) 22(12.90%) 0.544 Lymphopenia 15(30.60%) 59(34.70%) 0.594 Monocytopenia 0(0.00%) 3(1.80%) 0.349 Anemia 16(32.70%) 94(55.30%) 0.005 Thrombocytopenia 6(12.20%) 33(19.40%) 0.248 Liver failure 6(12.20%) 24 (14.11%) 0.737 Spontaneous bacterial peritonitis 1 (2.00%) 8 (4.70%) 0.675 Upper gastrointestinal hemorrhage 0 (0.00%) 4 (2.40%) 0.575 Hepatic encephalopathy 0 (0.00%) 4 (2.40%) 0.575 Hepatorenal syndrome 0 (0.00%) 6 (3.50%) 0.342 Death 0 (0.00%) 6 (3.50%) 0.342 3.2 HE patients have lower hemoglobin and platelet levels To understand the differences in laboratory indicators between HE and HA patients, a comparison was made between 170 cases of HE patients and 49 cases of HA patients. The results are shown in Table 2 . HE patients experience more severe liver function damage compared to HA patients. However, unlike previous reports( 17 ), our study suggests that HE patients have lower levels of hemoglobin and platelets. It's noteworthy that among WBC classifications, HE patients have lower levels of lymphocytes compared to HA patients. Table 2 Comparison of laboratory indicators of HA and HE Parameters HAV(n = 49) HEV(n = 170) P value ALB(g/L) 37.83 ± 6.60 33.60 ± 5.24 < 0.001 TB (umol/L) 100.08 ± 101.34 154.74 ± 133.67 0.003 ALT(U/L) 928.46 ± 1227.43 1313.49 ± 1365.90 0.077 AST(U/L) 560.59 ± 814.69 1004.88 ± 1226.45 0.004 ALP(U/L) 165.20 ± 74.80 210.41 ± 146.29 0.004 GGT(U/L) 247.87 ± 187.96 257.19 ± 236.39 0.800 LDH(U/L) 975.94 ± 1620.05 661.59 ± 653.59 0.190 CHE(U/L) 6133.09 ± 2427.30 4804.58 ± 2013.19 0.001 PTA(%) 87.28 ± 30.63 38.93 ± 8.47 0.070 INR 1.23 ± 0.49 1.23 ± 0.43 0.965 APTT 40.23 ± 7.95 38.93 ± 8.47 0.338 WBC (×10 12 /L) 5.45 ± 2.02 5.29 ± 2.20 0.654 Neutrophil 3.13 ± 1.80 3.28 ± 1.85 0.621 Lymphocyte 1.67 ± 0.77 1.34 ± 0.56 0.008 Monocyte 0.53 ± 0.26 0.49 ± 0.25 0.276 Eosinophil 0.09 ± 0.07 0.13 ± 0.13 0.012 Basophil 0.03 ± 0.04 0.02 ± 0.02 0.161 HB (g/L) 130.80 ± 15.89 118.91 ± 21.97 < 0.001 PLT (×10 9 /L) 198.78 ± 89.24 166.75 ± 79.10 0.016 ALB: Albumin; TB: Total bilirubin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltranspeptidase; LDH: Lactate dehydrogenase; CHE: Cholinesterase; PTA: Prothrombin activity; INR: International normalized ratio; APTT: Activated partial thromboplastin time; WBC: White blood cells; HB: Hemoglobin; PLT: Platelet; 3.3 Anemic patients exhibit more severe liver dysfunction and higher incidence of spontaneous bacterial peritonitis A total of 94 patients were diagnosed with anemia, resulting in an incidence rate of 55.29%. To explore the additional clinical significance of anemia in patients, we conducted a comparative analysis between the anemic group and the non-anemic group, as presented in [Additional file 1]. The results showed that patients in the anemic group were older and had longer hospital stay. Interestingly, patients in the anemic group exhibited decreased indicators of liver synthetic function, such as albumin (ALB) and cholinesterase (CHE). The anemic group experienced more severe liver dysfunction, with higher levels of total bilirubin (TB) and alkaline phosphatase (ALP), and lower levels of alanine aminotransferase (ALT), indicating cholestatic enzyme dissociation. Regarding complications, patients in the anemic group had a higher rate of spontaneous bacterial peritonitis. 3.4 Thrombocytopenia indicates a more severe condition A total of 33 patients with HE exhibited thrombocytopenia, resulting in an incidence of 19.41%. The patients in the thrombocytopenia group were older. In laboratory tests, the levels of ALB and CHE, which reflect the synthetic function of the liver, were found to be decreased compared to the normal group. Patients with decreased PLT count have lower prothrombin activity (PTA) and higher international normalized ratio (INR), indicating impaired coagulation function. Regarding complications, [Additional file 1] demonstrates that the group with low PLT group exhibited a higher rate of experiencing mortality, spontaneous bacterial peritonitis, upper gastrointestinal bleeding, and hepatorenal syndrome. 3.5. Several representatives of patients with hepatitis E The causes of changes affecting blood counts are more common, and hematologic disorders, drug effects, and hypersplenism cannot be excluded. Patients affected by hypersplenism have been excluded from this data, and there was no difference between the HA and HE groups in terms of the effect of medication. All patients are hospitalized and treated in the same way. Significantly, these patients with hematologic damage gradually normalized their baseline values as they recovered, as shown in Fig. 1 and Fig. 2 . 4. Discussion HE is a group of diseases characterized by hepatocellular damage resulting from infection with the HE virus, which triggers inflammation. However, the HE virus can also disseminate to other tissues and cells, indicating that a more comprehensive understanding of HE should consider it as a multi-system damage disease. Several studies have reported that HE can cause damage to the hematologic system, but the frequency of these features has not been clearly indicated. This study conducted a retrospective analysis of 170 patients with acute HE to ascertain the incidence of hematologic damage and explore its additional clinical significance. The surprising finding is that hematologic system damage is very common. In this study, among the 170 patients with HE, 47 cases (27.64%) were found to have leukopenia. This marks the first time that leukopenia has been reported as a consequence of AHE infection. The study by Mu( 12 ) et al suggested that leukocyte levels were higher in patients with hepatitis E acute liver failure (HE-ALF) compared to healthy controls, but our results found lower leukocytes in HE patients. However, their leukocyte levels may be associated with PCT and inflammatory factors. Studies have shown that HAV( 18 ), HBV( 19 )and HCV( 20 ) can lead to leukopenia. However, it should be noted that there are few previous studies reporting that HE infection causes leukopenia. These patients had no history of splenomegaly, autoimmune diseases, malignancies, or pregnancy. During hospitalization, the blood routine of HE patients showed a trough, with most of the parameters returning to normal either at admission or before discharge. The reason behind why HE infection causes leukopenia remains unclear. Previous studies have shown that the leukopenia caused by hepatitis C is related to antibodies( 21 ). Another study suggests that chronic HE infection may be associated with decreased lymphocytes( 9 ). These studies suggest that hepatitis E-induced leukopenia may be related to immune factors. Anemia occurs in both HA and HE. In patients with HA, aplastic anemia is the most common form of anemia, whereas in patients with HE, hemolytic anemia due to G-6-PD deficiency is the most common form of anemia. We found that hemoglobin levels were lower in HE patients. This could be due to the older age of patients with HE, leading to a decline in bodily functions. Significantly, patients in the anemia group exhibited more severe liver injury and a higher rate of spontaneous peritonitis. These results suggest that low Hb levels may indicate a more severe condition. Studies have shown that hypoxia plays a role in intestinal barrier function( 22 )and may lead to the occurrence of microecological disorder. This may result in a higher incidence of spontaneous bacterial peritonitis. The specific reason for this is not yet clear. Future large-sample studies may provide insights to help us address this question. 33 (19.41%) patients with HE had thrombocytopenia, with the lowest recorded PLT count being 47×10 9 /L. Severe thrombocytopenia may be associated with genotypes 3( 23 ). In this study, the majority of patients with thrombocytopenia had PLT values greater than 50×10 9 /L, One possible reason for this observation could be that China is currently predominantly affected by genotype 4 of the virus. Different genotypes can have varying degrees of virulence, and over time, the infectivity and pathogenicity of the virus may decrease.( 24 ). The findings of this study revealed that patients in the low PLT group exhibited impaired liver synthetic function and were at a higher rate of mortality, spontaneous bacterial peritonitis, upper gastrointestinal bleeding, and hepatorenal syndrome. The study by Mu et al( 12 )showed that low PLT levels can be as effective as the model for end-stage Liver Disease (MELD) score in predicting mortality in patients with acute liver failure caused by HE, and may even outperform the king's college criteria (KCC) score. Therefore, the detection of PLT in patients with HE should be strengthened clinically. HE patients had lower mean PLT values than HA patients, but there was no difference in the proportion of patients with thrombocytopenia. Future studies with larger sample sizes are needed to confirm. In conclusion, our study highlights that HE can lead to damage in the hematologic system. Furthermore, the study by Sayed et al( 25 )suggests that the replication of HEV within human monocytes, macrophages, and bone marrow-derived macrophages has been implicated as a potential factor contributing to certain hematologic system diseases. Antibodies( 23 ) or immune factors( 26 ) may also mediate the mechanism of extrahepatic manifestations of HE. However, the specific mechanism still requires further investigation. It is worth noting that the decrease in WBC observed in patients with HE opens up new clinical avenues for research and exploration. Additionally, the decrease in Hb and PLT levels indicates a more severe condition, and clinicians should actively monitor changes in these indicators and intervene early. However, this study was a small sample retrospective study, so the results may be biased. And future multicenter, large-sample prospective studies are needed to elucidate the mechanism of extrahepatic manifestations of HE hematologic damage and its clinical significance. Abbreviations HE: Hepatitis E; HEV: Hepatitis E virus; AHE: Acute hepatitis E; HA: Hepatitis A; AHA: Acute hepatitis A; ALB: Albumin; TB: Total bilirubin; DB: Direct bilirubin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltranspeptidase; LDH: Lactate dehydrogenase; CHE: Cholinesterase; PTA: Prothrombin activity; INR: International normalized ratio; WBC: White blood cells; HB: Hemoglobin; PLT: Platelet; Declarations Acknowledgements Not applicable. Author s ' contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by XMC, JC, YLY and YSL. The first draft of the manuscript was written by XMC. SJZ contributed to writing—review & editing. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding This work was supported by Joint Project of Chongqing Health Commission and Science and Technology Bureau (Nos. 2019MSXM076 and 2020FYYX007) and Senior Medical Talents Program of Chongqing for Young and Middle-aged (2019-181). Medical Writing, Editorial, and Other Assistance Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study was conducted in accordance with the protocol and the principles of the Declaration of Helsinki. The protocol was approved by the Ethical Committee of the First Affiliated Hospital of Chongqing Hospital. The informed consent was obtained from the participants enrolled after January 1, 2019 and waived by the ethical committee due to the retrospective nature of the study for the patients recruited before Jan 1, 2019. Consent for publication Not applicable. Conflict of Interest The authors declare that they have no competing interests. References Balayan MS, Andjaparidze AG, Savinskaya SS, Ketiladze ES, Braginsky DM, Savinov AP, et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology. 1983;20(1):23-31. Wang B, Meng XJ. Structural and molecular biology of hepatitis E virus. Comput Struct Biotechnol J. 2021;19:1907-16. Pallerla SR, Harms D, Johne R, Todt D, Steinmann E, Schemmerer M, et al. Hepatitis E Virus Infection: Circulation, Molecular Epidemiology, and Impact on Global Health. Pathogens. 2020;9(10). Wang B, Meng XJ. Hepatitis E virus: host tropism and zoonotic infection. Curr Opin Microbiol. 2021;59:8-15. 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Masood I, Rafiq A, Majid Z. Hepatitis E presenting with thrombocytopaenia. Trop Doct. 2014;44(4):219-20. Additional Declarations No competing interests reported. Supplementary Files Additionalfile1.xlsx Additional files An additional movie file shows this in more detail [see Additional file 1]. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3863568","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":268491944,"identity":"eb610070-3265-41a0-98f3-2440875a4257","order_by":0,"name":"Xuemei Cao","email":"","orcid":"","institution":"the First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xuemei","middleName":"","lastName":"Cao","suffix":""},{"id":268491945,"identity":"f1e5ddce-a901-4a4f-8913-94677ee1e595","order_by":1,"name":"Jie Chen","email":"","orcid":"","institution":"the First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Chen","suffix":""},{"id":268491946,"identity":"058b03de-cab0-4a2c-ab76-e42c2bbe5857","order_by":2,"name":"Yushuang Liu","email":"","orcid":"","institution":"the First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yushuang","middleName":"","lastName":"Liu","suffix":""},{"id":268491947,"identity":"1e6f2e94-86e9-4bda-b1d8-3a64c8e324b1","order_by":3,"name":"Yuling Yang","email":"","orcid":"","institution":"the First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuling","middleName":"","lastName":"Yang","suffix":""},{"id":268491948,"identity":"1e8219aa-78f1-4946-b9c9-1e8548c2e790","order_by":4,"name":"Shujun Zhang","email":"data:image/png;base64,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","orcid":"","institution":"the First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Shujun","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2024-01-14 14:29:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3863568/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3863568/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50054622,"identity":"e0d6364a-5e25-4ef7-a6c8-2cf82f34cdda","added_by":"auto","created_at":"2024-01-23 17:24:48","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":57329,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in routine blood tests during hospitalization in a patient with HE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe horizontal axis represents the number of times blood routine tests were performed after admission, while the vertical axis represents the absolute value changes of white blood cell, red blood cell, and platelet. WBC: white blood cell; RBC: red blood cell; PLT: platelet;\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3863568/v1/cbd9ec7e78e83652fccdfb44.jpeg"},{"id":50054621,"identity":"9dca1c40-5c4f-4131-88c5-3182aa5eafa7","added_by":"auto","created_at":"2024-01-23 17:24:48","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":60704,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in routine blood tests during hospitalization in a patient with HE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe horizontal axis represents the number of times blood routine tests were performed after admission, while the vertical axis represents the absolute value changes of white blood cell, red blood cell, and platelet. WBC: white blood cell; RBC: red blood cell; PLT: platelet;\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3863568/v1/0dd1e074102ed0a28679090d.jpeg"},{"id":58558732,"identity":"aea0cce0-fc9e-4689-8639-041e64752c12","added_by":"auto","created_at":"2024-06-18 08:39:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":708699,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3863568/v1/779c4327-3af2-4522-a0d3-515c24b35a28.pdf"},{"id":50054623,"identity":"c7f5b429-9c70-46b5-8660-0aa51a9b3e70","added_by":"auto","created_at":"2024-01-23 17:24:48","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14837,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional files\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn additional movie file shows this in more detail [see Additional file 1].\u003c/p\u003e","description":"","filename":"Additionalfile1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3863568/v1/783fe1795f6fb0c07e4147f5.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hematologic system damage is common and related to severity in patients with acute hepatitis E","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eHepatitis E (HE) is an acute infectious disease caused by infection with the HE virus, which is mainly transmitted through the digestive tract. Most people with hepatitis E virus (HEV) infection are asymptomatic or self-limited. HEV, belonging to the family flavivirus, is a new pathogen discovered by investigators in an outbreak of unexplained hepatitis in 1983 that can circulate between multiple species and cause zoonotic diseases(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). It contains 4 open reading frames, ORF1 encodes non-structural polyproteins for viral replication and transcription, ORF2 encodes capsid proteins that elicit neutralizing antibodies, ORF3 fractions overlap ORF2, and encodes multifunctional proteins involved in virion morphogenesis and pathogenesis(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). At present, 8 genotypes have been identified, genotypes 1 and 2 only infect humans, transmitted by water, mainly causing pandemics or outbreaks in developing countries with poor sanitation(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e),genotypes 3 and 4 are zoonotic pathogens, generally infected by eating undercooked contaminated meat, often causing sporadic cases in developed countries(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e),genotypes 5 and 6 have been found in wild animals in Japan, Genotypes 7 and 8 were detected in camels. Previous studies have found that HE is an intrahepatic inflammatory disease caused by HEV infection, and recent studies have found that HE can lead to a variety of extrahepatic manifestations, mainly acute pancreatitis (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), nervous system diseases (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), kidney damage (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), blood system diseases (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) etc. Therefore, HEV infection should be considered a systemic disease, not just an inflammatory disease within the liver. Previous studies have reported that hematologic damage caused by HEV infection is mainly manifested by thrombocytopenia and anemia, Kemming et al (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) showed that chronic HEV infection is associated with specific CD8\u0026thinsp;+\u0026thinsp;T cell depletion, especially in immunosuppressed populations. While another study showed that increased reactive CD4\u0026thinsp;+\u0026thinsp;T cells and CD8\u0026thinsp;+\u0026thinsp;T cells could be detected in acute hepatitis E(AHE) infection (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). However, few studies have shown that AHE leads to a decrease in leukocytes. At present, thrombocytopenia caused by HE infection has been reported in France, Japan, India and other countries, mainly including genotypes 1 and 3, and these patients will have purpura, bleeding and other manifestations in addition to jaundice, poor feeding, elevated transaminases and other manifestations(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Similarly, Mu et al(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) found HEV infection leads to a decrease in platelets and can serve as a short-term prognostic marker for patients with acute HE liver failure. HE infection in patients with G-6-PD deficiency can lead to the development of hemolytic anemia(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). However, most of the previous studies on the extrahepatic manifestations of HE infection were limited to case report, and there was a lack of research on the clinical features and related complications of a large number of HE patients.\u003c/p\u003e \u003cp\u003eTherefore, we retrospectively investigated 170 patients diagnosed with acute HE and 49 patients with acute hepatitis A(AHA) to further elucidate the incidence and clinical significance of hematologic system damage in patients with acute HE.\u003c/p\u003e"},{"header":"2. Information and methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Definition of patients with acute HE and hematologic system damage\u003c/h2\u003e \u003cp\u003eA total of 170 patients diagnosed with sporadic AHE and 49 patients with AHA in the First Affiliated Hospital of Chongqing Medical University from January 2013 to March 2023 were included in the analysis. Patients who were discharged from hospital were followed up to six months, taking death as a clinical outcome.\u003c/p\u003e \u003cp\u003eAcute HE infection is defined as a marked elevation of aminotransferases (ALT\u0026thinsp;≧\u0026thinsp;2.5 \u0026times; upper limit of normal (ULN)) and positive anti-HEV IgM or HEV RNA(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eDefinition of anemia\u003c/strong\u003e \u003cp\u003eAccording to the World Health Organization's diagnostic criteria for anemia, hemoglobin (Hb)\u0026thinsp;\u0026lt;\u0026thinsp;120 g/L in premenopausal women and \u0026lt;\u0026thinsp;130 g/L in postmenopausal women and men of all ages are called anemia.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eThrombocytopenia\u003c/strong\u003e \u003cp\u003ePlatelet (PLT)\u0026thinsp;\u0026lt;\u0026thinsp;100\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L were defined as thrombocytopenia(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eLeukopenia\u003c/strong\u003e \u003cp\u003eThe normal reference range for total white blood cell (WBC) number is 4\u0026ndash;10\u0026times;10\u003csup\u003e12\u003c/sup\u003e/L. And if the WBC\u0026thinsp;\u0026lt;\u0026thinsp;4\u0026times;10\u003csup\u003e12\u003c/sup\u003e/L, it was defined as leukopenia (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) .\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eThe definition of suspicious drug\u003c/strong\u003e \u003cp\u003eIncluding proton pump inhibitors, antibiotics, antiviral drugs and so on.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Detection of anti-HEV IgM and IgG\u003c/h2\u003e \u003cp\u003eSerum anti-HEV-IgM and anti-HEV-IgG antibodies were detected by enzyme-linked immunosorbent kit (Beijing Hyundai Gundam 2012\u0026ndash;2019, Beijing Wantai Company 2019\u0026ndash;2022). The S/CO value\u0026thinsp;\u0026ge;\u0026thinsp;1 was positive.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistics\u003c/h2\u003e \u003cp\u003eQuantitative data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and qualitative data are expressed as absolute values and absolute percentages. The quantitative data were tested by T-test, and the qualitative data were tested by chi-square test or Fisher\u0026rsquo;s precision probability test. All tests are double-tailed tests. p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 is considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Outcomes","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Comparison of demographic characteristics between HE and HA\u003c/h2\u003e \u003cp\u003eComparative analysis of the demographic information of the two groups of hepatitis A(HA) and HE, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. HE patients did not differ from HA patients in terms of gender, but were older than HA patients, and there was no significant difference between HA and HE in terms of the use of suspected drugs. Patients with HE show no difference from those with HA in terms of decreased WBC and PLT counts, but HE patients are more commonly associated with anemia. In addition, patients with HE may experience more clinical complications and are more prone to death. Although there's no apparent statistical difference, it might also be due to a small sample size.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics of patients with HE and HA\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHAV(n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHEV(n\u0026thinsp;=\u0026thinsp;170)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29 (59.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e121 (71.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (40.80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49 (28.80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44.43\u0026thinsp;\u0026plusmn;\u0026thinsp;15.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54.26\u0026thinsp;\u0026plusmn;\u0026thinsp;15.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuspicious drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34(69.40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e113(66.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.702\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeucopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10(20.40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47(27.60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.309\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(16.30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22(12.90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.544\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(30.60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59(34.70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.594\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0(0.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(1.80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.349\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16(32.70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e94(55.30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6(12.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33(19.40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.248\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6(12.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24 (14.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.737\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous bacterial peritonitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (2.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (4.70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.675\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpper gastrointestinal hemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (2.40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.575\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic encephalopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (2.40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.575\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatorenal syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (3.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.342\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (3.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.342\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003e3.2 HE patients have lower hemoglobin and platelet levels\u003c/b\u003e\u003c/h2\u003e \u003cp\u003eTo understand the differences in laboratory indicators between HE and HA patients, a comparison was made between 170 cases of HE patients and 49 cases of HA patients. The results are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. HE patients experience more severe liver function damage compared to HA patients. However, unlike previous reports(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), our study suggests that HE patients have lower levels of hemoglobin and platelets. It's noteworthy that among WBC classifications, HE patients have lower levels of lymphocytes compared to HA patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of laboratory indicators of HA and HE\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHAV(n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHEV(n\u0026thinsp;=\u0026thinsp;170)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALB(g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e37.83\u0026thinsp;\u0026plusmn;\u0026thinsp;6.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e33.60\u0026thinsp;\u0026plusmn;\u0026thinsp;5.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTB (umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e100.08\u0026thinsp;\u0026plusmn;\u0026thinsp;101.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e154.74\u0026thinsp;\u0026plusmn;\u0026thinsp;133.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e928.46\u0026thinsp;\u0026plusmn;\u0026thinsp;1227.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1313.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1365.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e560.59\u0026thinsp;\u0026plusmn;\u0026thinsp;814.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1004.88\u0026thinsp;\u0026plusmn;\u0026thinsp;1226.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e165.20\u0026thinsp;\u0026plusmn;\u0026thinsp;74.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e210.41\u0026thinsp;\u0026plusmn;\u0026thinsp;146.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGGT(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e247.87\u0026thinsp;\u0026plusmn;\u0026thinsp;187.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e257.19\u0026thinsp;\u0026plusmn;\u0026thinsp;236.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.800\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e975.94\u0026thinsp;\u0026plusmn;\u0026thinsp;1620.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e661.59\u0026thinsp;\u0026plusmn;\u0026thinsp;653.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.190\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHE(U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e6133.09\u0026thinsp;\u0026plusmn;\u0026thinsp;2427.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4804.58\u0026thinsp;\u0026plusmn;\u0026thinsp;2013.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePTA(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e87.28\u0026thinsp;\u0026plusmn;\u0026thinsp;30.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e38.93\u0026thinsp;\u0026plusmn;\u0026thinsp;8.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.965\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e40.23\u0026thinsp;\u0026plusmn;\u0026thinsp;7.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e38.93\u0026thinsp;\u0026plusmn;\u0026thinsp;8.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.338\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC (\u0026times;10\u003csup\u003e12\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.45\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e5.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.654\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.13\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3.28\u0026thinsp;\u0026plusmn;\u0026thinsp;1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.621\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocyte\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonocyte\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.276\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosinophil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasophil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.161\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHB (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e130.80\u0026thinsp;\u0026plusmn;\u0026thinsp;15.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e118.91\u0026thinsp;\u0026plusmn;\u0026thinsp;21.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e198.78\u0026thinsp;\u0026plusmn;\u0026thinsp;89.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e166.75\u0026thinsp;\u0026plusmn;\u0026thinsp;79.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eALB: Albumin; TB: Total bilirubin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltranspeptidase; LDH: Lactate dehydrogenase; CHE: Cholinesterase; PTA: Prothrombin activity; INR: International normalized ratio; APTT: Activated partial thromboplastin time; WBC: White blood cells; HB: Hemoglobin; PLT: Platelet;\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Anemic patients exhibit more severe liver dysfunction and higher incidence of spontaneous bacterial peritonitis\u003c/h2\u003e \u003cp\u003eA total of 94 patients were diagnosed with anemia, resulting in an incidence rate of 55.29%. To explore the additional clinical significance of anemia in patients, we conducted a comparative analysis between the anemic group and the non-anemic group, as presented in [Additional file 1]. The results showed that patients in the anemic group were older and had longer hospital stay. Interestingly, patients in the anemic group exhibited decreased indicators of liver synthetic function, such as albumin (ALB) and cholinesterase (CHE). The anemic group experienced more severe liver dysfunction, with higher levels of total bilirubin (TB) and alkaline phosphatase (ALP), and lower levels of alanine aminotransferase (ALT), indicating cholestatic enzyme dissociation. Regarding complications, patients in the anemic group had a higher rate of spontaneous bacterial peritonitis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Thrombocytopenia indicates a more severe condition\u003c/h2\u003e \u003cp\u003eA total of 33 patients with HE exhibited thrombocytopenia, resulting in an incidence of 19.41%. The patients in the thrombocytopenia group were older. In laboratory tests, the levels of ALB and CHE, which reflect the synthetic function of the liver, were found to be decreased compared to the normal group. Patients with decreased PLT count have lower prothrombin activity (PTA) and higher international normalized ratio (INR), indicating impaired coagulation function. Regarding complications, [Additional file 1] demonstrates that the group with low PLT group exhibited a higher rate of experiencing mortality, spontaneous bacterial peritonitis, upper gastrointestinal bleeding, and hepatorenal syndrome.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Several representatives of patients with hepatitis E\u003c/h2\u003e \u003cp\u003eThe causes of changes affecting blood counts are more common, and hematologic disorders, drug effects, and hypersplenism cannot be excluded. Patients affected by hypersplenism have been excluded from this data, and there was no difference between the HA and HE groups in terms of the effect of medication. All patients are hospitalized and treated in the same way. Significantly, these patients with hematologic damage gradually normalized their baseline values as they recovered, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eHE is a group of diseases characterized by hepatocellular damage resulting from infection with the HE virus, which triggers inflammation. However, the HE virus can also disseminate to other tissues and cells, indicating that a more comprehensive understanding of HE should consider it as a multi-system damage disease. Several studies have reported that HE can cause damage to the hematologic system, but the frequency of these features has not been clearly indicated. This study conducted a retrospective analysis of 170 patients with acute HE to ascertain the incidence of hematologic damage and explore its additional clinical significance. The surprising finding is that hematologic system damage is very common.\u003c/p\u003e \u003cp\u003eIn this study, among the 170 patients with HE, 47 cases (27.64%) were found to have leukopenia. This marks the first time that leukopenia has been reported as a consequence of AHE infection. The study by Mu(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) et al suggested that leukocyte levels were higher in patients with hepatitis E acute liver failure (HE-ALF) compared to healthy controls, but our results found lower leukocytes in HE patients. However, their leukocyte levels may be associated with PCT and inflammatory factors. Studies have shown that HAV(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), HBV(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)and HCV(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) can lead to leukopenia. However, it should be noted that there are few previous studies reporting that HE infection causes leukopenia. These patients had no history of splenomegaly, autoimmune diseases, malignancies, or pregnancy. During hospitalization, the blood routine of HE patients showed a trough, with most of the parameters returning to normal either at admission or before discharge. The reason behind why HE infection causes leukopenia remains unclear. Previous studies have shown that the leukopenia caused by hepatitis C is related to antibodies(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Another study suggests that chronic HE infection may be associated with decreased lymphocytes(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). These studies suggest that hepatitis E-induced leukopenia may be related to immune factors.\u003c/p\u003e \u003cp\u003eAnemia occurs in both HA and HE. In patients with HA, aplastic anemia is the most common form of anemia, whereas in patients with HE, hemolytic anemia due to G-6-PD deficiency is the most common form of anemia. We found that hemoglobin levels were lower in HE patients. This could be due to the older age of patients with HE, leading to a decline in bodily functions. Significantly, patients in the anemia group exhibited more severe liver injury and a higher rate of spontaneous peritonitis. These results suggest that low Hb levels may indicate a more severe condition. Studies have shown that hypoxia plays a role in intestinal barrier function(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)and may lead to the occurrence of microecological disorder. This may result in a higher incidence of spontaneous bacterial peritonitis. The specific reason for this is not yet clear. Future large-sample studies may provide insights to help us address this question.\u003c/p\u003e \u003cp\u003e33 (19.41%) patients with HE had thrombocytopenia, with the lowest recorded PLT count being 47\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. Severe thrombocytopenia may be associated with genotypes 3(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). In this study, the majority of patients with thrombocytopenia had PLT values greater than 50\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, One possible reason for this observation could be that China is currently predominantly affected by genotype 4 of the virus. Different genotypes can have varying degrees of virulence, and over time, the infectivity and pathogenicity of the virus may decrease.(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The findings of this study revealed that patients in the low PLT group exhibited impaired liver synthetic function and were at a higher rate of mortality, spontaneous bacterial peritonitis, upper gastrointestinal bleeding, and hepatorenal syndrome. The study by Mu et al(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)showed that low PLT levels can be as effective as the model for end-stage Liver Disease (MELD) score in predicting mortality in patients with acute liver failure caused by HE, and may even outperform the king's college criteria (KCC) score. Therefore, the detection of PLT in patients with HE should be strengthened clinically. HE patients had lower mean PLT values than HA patients, but there was no difference in the proportion of patients with thrombocytopenia. Future studies with larger sample sizes are needed to confirm.\u003c/p\u003e \u003cp\u003eIn conclusion, our study highlights that HE can lead to damage in the hematologic system. Furthermore, the study by Sayed et al(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)suggests that the replication of HEV within human monocytes, macrophages, and bone marrow-derived macrophages has been implicated as a potential factor contributing to certain hematologic system diseases. Antibodies(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) or immune factors(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) may also mediate the mechanism of extrahepatic manifestations of HE. However, the specific mechanism still requires further investigation. It is worth noting that the decrease in WBC observed in patients with HE opens up new clinical avenues for research and exploration. Additionally, the decrease in Hb and PLT levels indicates a more severe condition, and clinicians should actively monitor changes in these indicators and intervene early.\u003c/p\u003e \u003cp\u003eHowever, this study was a small sample retrospective study, so the results may be biased. And future multicenter, large-sample prospective studies are needed to elucidate the mechanism of extrahepatic manifestations of HE hematologic damage and its clinical significance.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHE: Hepatitis E; HEV: Hepatitis E virus; AHE: Acute hepatitis E; HA: Hepatitis A; AHA: Acute hepatitis A; ALB: Albumin; TB: Total bilirubin; DB: Direct bilirubin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltranspeptidase; LDH: Lactate dehydrogenase; CHE: Cholinesterase; PTA: Prothrombin activity; INR: International normalized ratio; WBC: White blood cells; HB: Hemoglobin; PLT: Platelet;\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003e\u0026apos;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by XMC, JC, YLY and YSL. The first draft of the manuscript was written by XMC.\u0026nbsp;SJZ contributed to writing\u0026mdash;review \u0026amp; editing. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Joint Project of Chongqing Health Commission and Science and Technology Bureau (Nos. 2019MSXM076 and 2020FYYX007) and Senior Medical Talents Program of Chongqing for Young and Middle-aged (2019-181).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMedical Writing, Editorial, and Other Assistance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the protocol and the principles of the Declaration of Helsinki. The protocol was approved by the Ethical Committee of the First Affiliated Hospital of Chongqing Hospital. The informed consent was obtained from the participants enrolled after January 1, 2019 and waived by the ethical committee due to the retrospective nature of the study for the patients recruited before Jan 1, 2019.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBalayan MS, Andjaparidze AG, Savinskaya SS, Ketiladze ES, Braginsky DM, Savinov AP, et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. 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J Viral Hepat. 2016;23(4):305-15.\u003c/li\u003e\n\u003cli\u003eYamazaki Y, Naganuma A, Arai Y, Takeuchi S, Kobayashi T, Takakusagi S, et al. Clinical and virological features of acute hepatitis E in Gunma prefecture, Japan between 2004 and 2015. Hepatol Res. 2017;47(5):435-45.\u003c/li\u003e\n\u003cli\u003eMu X, Zou J, Chen J, Tong J, Ma L, Ning P, et al. Low platelets: a new and simple prognostic marker for patients with hepatitis E virus-related acute liver failure. Hepatol Int. 2022;16(5):1116-26.\u003c/li\u003e\n\u003cli\u003eKamani L, Shaikh H, Khemchandani AK. Fulminant Hepatic Failure in Glucose-6-Phosphate Dehydrogenase (G6PD) Deficient Patients Caused by Hepatitis E Infection: A Single Disease With Different Spectrums. Cureus. 2020;12(12):e12276.\u003c/li\u003e\n\u003cli\u003eDalton HR, Hazeldine S, Banks M, Ijaz S, Bendall R. Locally acquired hepatitis E in chronic liver disease. 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Transplant Proc. 2008;40(1):199-201.\u003c/li\u003e\n\u003cli\u003eUmumararungu E, Ntaganda F, Kagira J, Maina N. Prevalence of Hepatitis C Virus Infection and Its Risk Factors among Patients Attending Rwanda Military Hospital, Rwanda. Biomed Res Int. 2017;2017:5841272.\u003c/li\u003e\n\u003cli\u003eHuang CE, Chen WM, Wu YY, Shen CH, Hsu CC, Li CP, et al. Comparison of antiplatelet antibody profiles between hepatitis C virus-associated immune thrombocytopenia and primary immune thrombocytopenia. Platelets. 2021;32(8):1043-50.\u003c/li\u003e\n\u003cli\u003ePral LP, Fachi JL, Correa RO, Colonna M, Vinolo MAR. Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions. Trends Immunol. 2021;42(7):604-21.\u003c/li\u003e\n\u003cli\u003eColson P, Payraudeau E, Leonnet C, De Montigny S, Villeneuve L, Motte A, et al. Severe thrombocytopenia associated with acute hepatitis E virus infection. J Clin Microbiol. 2008;46(7):2450-2.\u003c/li\u003e\n\u003cli\u003eLi S, He Q, Yan L, Li M, Liang Z, Shu J, et al. Infectivity and pathogenicity of different hepatitis E virus genotypes/subtypes in rabbit model. Emerg Microbes Infect. 2020;9(1):2697-705.\u003c/li\u003e\n\u003cli\u003eSayed IM, Seddik MI, Gaber MA, Saber SH, Mandour SA, El-Mokhtar MA. Replication of Hepatitis E Virus (HEV) in Primary Human-Derived Monocytes and Macrophages In Vitro. Vaccines (Basel). 2020;8(2).\u003c/li\u003e\n\u003cli\u003eMasood I, Rafiq A, Majid Z. Hepatitis E presenting with thrombocytopaenia. Trop Doct. 2014;44(4):219-20.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"hepatitis E, hepatitis A, white blood cells, anemia, platelet","lastPublishedDoi":"10.21203/rs.3.rs-3863568/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3863568/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eExtrahepatic manifestations of hepatitis E have been extensively reported, yet there is a lack of comprehensive systematic studies on this aspect. This article is to report hematologic systemdamage caused by hepatitis E.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: A retrospective study enrolled 170 patients with acute hepatitis E. The study analyzed the proportion of patients with decreased white blood cell, hemoglobin, and platelet levels in their blood routine, along with their potential clinical significance. 49 patients with HA were also included as controls to compare and analyze the differences in biochemical indicators and hematologic damage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong the 170 patients with hepatitis E, 47 cases (27.64%) presented with leukopenia, 94 cases (55.29%) exhibited anemia, and 33 cases (19.41%) experienced thrombocytopenia. The findings indicated that hemoglobin and platelets are lower in patients with hepatitis E than in patients with hepatitis A, and anemia is more common in patients with hepatitis E. The anemia group had significantly lower levels of albumin, alanine aminotransferase, and cholinesterase compared to the normal group (p\u0026lt;0.001, p=0.005, p\u0026lt;0.001). Additionally, total bilirubin and alkaline phosphatase were significantly higher in the anemia group than in the normal group (p=0.031, p=0.003). Moreover, the anemia group showed a higher likelihood of experiencing spontaneous bacterial peritonitis (p=0.025). In comparison to the normal platelet group, the thrombocytopenia group exhibited significantly lower levels of albumin, cholinesterase, and prothrombin activity (p=0.036, p=0.015, p\u0026lt;0.001). Patients with decreased platelet have the higher incidence of death, spontaneous bacterial peritonitis, upper gastrointestinal bleeding and hepatorenal syndrome (p\u0026lt;0.001, p\u0026lt;0.001, p=0.027, p=0.014).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eHepatitis E patients with hematologic system damage are common. Patients with hepatitis Ehave lower levels of hemoglobin and platelets compared to patients with hepatitis A. The presence of anemia and low platelets in patients with hepatitis Eindicates a more severe condition.\u003c/p\u003e","manuscriptTitle":"Hematologic system damage is common and related to severity in patients with acute hepatitis E","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-23 17:24:43","doi":"10.21203/rs.3.rs-3863568/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8719c28d-9924-4d7f-910a-6602f39c5bd1","owner":[],"postedDate":"January 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-18T08:31:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-23 17:24:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3863568","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3863568","identity":"rs-3863568","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}