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Clinical course of sporadic acute hepatitis E in a hepatitis B virus endemic region
Accepted Manuscript Title: Clinical course of sporadic acute hepatitis E in a hepatitis B virus endemic region Authors: Li Liu, Di Xiao, Jin-Hong Yu, Rui Shen, Meng Wang, Qiang Li PII: DOI: Reference:
S1201-9712(18)30067-5 https://doi.org/10.1016/j.ijid.2018.03.008 IJID 3195
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
5-2-2018 3-3-2018 9-3-2018
Please cite this article as: Liu Li, Xiao Di, Yu Jin-Hong, Shen Rui, Wang Meng, Li Qiang.Clinical course of sporadic acute hepatitis E in a hepatitis B virus endemic region.International Journal of Infectious Diseases https://doi.org/10.1016/j.ijid.2018.03.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Clinical course of sporadic acute hepatitis E in a hepatitis B virus endemic region
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Authors: Li Liu1, Di Xiao1, Jin-Hong Yu1, Rui Shen1, Meng Wang1,2, Qiang Li1
1. Division of Liver Diseases, Jinan Infectious Disease Hospital, Shandong University,
2. Division of Infectious Diseases, Jinan Central Hospital, Shandong
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Jinan, China.
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University, Jinan, China.
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Corresponding author: Qiang Li, M.D., Ph.D., Division of Liver Diseases, Jinan
China
Tel:+86-531-87935971
Email:
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Abstract
Fax:+86-531-87932070
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[email protected]
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250021,
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Infectious Disease Hospital, Shandong University, 22029# Jingshi Road, Jinan ,
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Objectives: In China, the epidemic pattern of acute hepatitis E virus (HEV) infection has changed from waterborne outbreaks to foodborne sporadic cases. However, the clinical course of sporadic acute hepatitis E has not been well defined.
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Methods: Consecutive AHE inpatients who were admitted to the Jinan Infectious Disease Hospital, Jinan, Shandong Province, between January 2003 and December 2014 were evaluated and followed. Demographic data, clinical manifestations, results of laboratory tests，and outcomes were recorded. Risk factors of liver failure and 1
death were analyzed. Results: A total of 680 AHE inpatients were identified during the study period. The incidence was high in February, March, and April, accounting for about 41% of the cases. The male to female ratio was 5.1:1(574/106). The average age was 50.9 ±
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12.8 years old. The prevalence of prodromal fever, fatigue, loss of appetite, and jaundice was 25.6%, 85.6%, 83.8%, and 92.8%, respectively. The median (range)
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serum ALT, AST, bilirubin, albumin, and platelet levels was 727(8-6270)U/L,
300(17-6226)U/L, 196.8(8.0-1083)µmol/L, 33.0(15.2-45.8)g/L, and 162 (10-589)×
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109/L, respectively. The prevalence of HBsAg and liver cirrhosis was 18.5% (126/680)
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and 9.4% (64/680), respectively. 13.1% (89/680) of the cases progressed to liver
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failure, including 4.1% (28/680) acute liver failure (ALF) and 9.0% (61/680)
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acute-on-chronic liver failure (ACLF). Among patients with HBsAg or cirrhosis, 28.6%
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(36/126) and 36.0% (23/64) progressed to ACLF, respectively. Multiple logistic regressions indicated that age>53yesrs, prodromal fever, HBsAg positive, cirrhosis,
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and thrombocytopenia (PLT<150×109/L) were independently associated with the
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development of liver failure with an odds ratio (95% confidence interval) of 2.5(1.5-4.3), 1.9(1.1-3.2), 3.7(2.0-6.7), 2.1(1.1-4.2), and 5.9 (3.3-10.4), respectively. The overall mortality was 5.6% (38/680), and the mortality in patients with and without
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underlying liver diseases were 3.3% (15/442) and 8.8% (21/238), respectively. Multiple
logistic
regressions
indicated
that
hepatic
encephalopathy,
bilirubin>500(µmol/L), INR>2, and severe thrombocytopenia (PLT<100×109/L) were independently associated with death with an odds ratio (95% confidence interval) of 2
7.2(2.4-21.8), 5.8(1.9-17.2), 24.1(7.9-73.3), and 10.8(3.6-32.9), respectively. Conclusions: In HBV and HEV dual endemic areas, the HEV vaccine for patients with obvious liver diseases is of significance. Thrombocytopenia is an important
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predictor of liver failure and mortality in sporadic AHE.
Keywords: acute hepatitis E; sporadic; liver failure; hepatitis B surface antigen; liver
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cirrhosis; platelet; thrombocytopenia
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Globally, hepatitis E virus (HEV) is the most common cause of acute viral hepatitis 1.
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Four genotypes of HEV have been associated with human infections. HEV genotype
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1 (HEV1) occurs mainly in Asia and HEV genotype 2 (HEV2) in Africa and Mexico,
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and they are responsible for water-borne epidemics in developing countries. HEV
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genotype 3 (HEV3) and HEV genotype 4 (HEV4) infect human beings, pigs, and other mammalian species and are responsible for sporadic cases of acute hepatitis E (AHE)
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in both developing and developed countries. HEV3 has a worldwide distribution. By
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contrast, HEV4 mostly occurs in Southeast Asia. HEV3 and HEV4 have been linked to the consumption of raw and undercooked pork or game meat2. China is an endemic area of HEV. Even though, there were waterborne outbreaks
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of AHE in China in last century, which were caused by HEV1, with social economic development, the epidemic pattern has changed from waterborne outbreaks to sporadic foodborne cases1. Several investigations showed that sporadic hepatitis E in China is mainly caused by HEV43-5. In China, sporadic cases of hepatitis E have 3
doubled in last decades5. Water-borne epidemics of hepatitis E mainly affect young adults. Mortality rates are general under 0.5% but may reach up to 25% in pregnant women. Several investigations indicated that the mortality is higher in AHE patients with underlying 6-9.
The clinical features and outcome of sporadic
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chronic liver diseases (CLD)
foodborne AHE cases may differ from water-borne epidemic AHE. What is more, in
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China, in a hepatitis B virus (HBV) endemic area, the clinical features and outcome may differ from a low HBV endemic region. The prevalence of HBsAg in AHE patients
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and the influence of chronic HBV infection on the outcome of AHE are still largely
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unclear. The predictors associated with death of sporadic AHE still need to be
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clarified.
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The aim of the present study was to investigate the clinical course of sporadic AHE
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in HBV high endemic regions in China. Patients and Methods
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Study Design and Population.
The present study was performed in the Jinan
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Infectious Disease Hospital, a tertiary and teaching hospital of Shandong University located in Jinan, Shandong Province. This study is part of a hospital-based prospective investigation to study the natural history of acute HEV infection that was
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conducted in the hospital，in which all inpatients with confirmed acute hepatitis E (AHE) between January 2003 and December 2014 were included and followed. The study was approved by the hospital ethics committee, and written informed consent for participation was obtained from each study participant or their next of kins. 4
Upon entry to the hospital, all patients and/or their attendants were interviewed by trained physicians. Physical examinations, blood counts, serum biochemical parameters, prothrombin time, serum alpha-fetoprotein (AFP), anti-HEV IgM and IgG antibody (Wantai Pharmaceutical Co. Beijing, China), anti-HAV IgM (Beijing Kewei
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Clinical Diagnostic Regent INC, Beijing China), anti-HCV (AxSYM HCV, Abbott Laboratories, Abbott Park, IL, USA), HBsAg, anti-HBs, HBeAg, anti-HBe, and
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anti-HBc (Abbott Laboratories) were measured. HBV DNA quantification (Applied
Biosystems® 7500 Real-Time PCR Systems, Thermo Fisher Scientific Inc.),
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ultrasound examinations, and gastrointestinal barium meal X-ray examinations were
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also performed. Serum samples were collected at admission and stored at -80℃. The
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previously described 10-12.
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details of general information collection and other laboratory measurements were
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The diagnosis of AHE was based on a discrete onset of symptoms, jaundice, elevated serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
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levels, detection of HEV IgM antibodies, or a rising HEV IgG or HEV RNA positive,
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and compatible clinical history13. In this study, AHE with evidence of coagulation abnormality (international normalized ratio [INR]≥1.5) and hepatic encephalopathy (HE),
and without pre-existing liver diseases was diagnosed as acute liver failure
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(ALF)14. The diagnosis of acute-on-chronic liver failure (ACLF) was according to the APASL
consensus
recommendations
(2014):
AHE
patients
with
serum
bilirubin>85µmol/L and INR≥1.5 complicated within 4 weeks by clinical ascites and/or encephalopathy in patients with underlying chronic liver diseases15. 5
Study Variables and Definitions.
The variables analyzed in this study included
demographic data, prodromal signs and symptoms, serum biochemical parameters, liver failure, and mortality. Underlying liver diseases included hepatitis B, hepatitis C, alcoholic liver disease,
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non-alcoholic fatty liver disease, and other CLD with known or unknown etiologies. The diagnosis of CLD in AHE was made by history, physical examination, and
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previously available or recent laboratory, B ultrasonography, endoscopic or radiological investigations15.
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The diagnosis of cirrhosis was based on clinical and morphological criteria,
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ultrasound or computed tomography or magnetic resonance imaging, according to
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standard definitions16. These included the presence of clinical manifestations of portal
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hypertension (e.g., esophageal varices, encephalopathy, or ascites), biochemical
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abnormalities (e.g., decreased serum albumin and platelets or prolonged prothrombin time), and obvious morphological changes in the liver detected by hepatic imaging.
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Ultrasonography was performed by experienced radiologists for every patient upon
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entry to the hospital17.
For patients with jaundice, prodromal manifestations were defined as signs or
symptoms occurring in the 1-10 days before onset of icterus (prodromal period). For
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patients without jaundice, prodromal manifestations were defined as signs or symptoms occurring in the 1-10 days before diagnosis of hepatitis or hospital admission. Prodromal signs and symptoms analyzed in this study included fever, loss of 6
appetite, fatigue. Prodromal fever was defined in 2 different ways: patients reporting a measured fever ≥37.5℃ during the prodromal period or any fever (measured or subjective) during the prodromal period
18, 19.
Loss of appetite during the prodromal
period was classified into 3 categories: mild: reduction of daily food intake less than
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1/3 of normal, medium: reduction of daily food intake between 1/3-1/2 of normal, and severe: reduction of daily food intake more than 1/2 of normal with anorexia or
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vomiting. Fatigue during the prodromal period was also classified into 3 categories: mild: mildly sick but not influencing daily activity, medium: sick and influencing daily
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activity, and severe: sick and influencing daily activity and need to lie on bed.
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Jaundice referred to measured serum total bilirubin>25µmol/L at admission.
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Hepatic encephalopathy (HE) was classified into four grades as previously
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described 14, 20. The presence of ascites was evaluated using B ultrasonography.
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Blood platelet (PLT)< 150 × 109/L and 100 × 109/L were defined as thrombocytopenia and severe thrombocytopenia, respectively.
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In this study, subjects with an ethanol intake of 40 g/d or more for men and 20 g/d
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or more for women for longer than 5 years were considered to have a positive history of alcohol consumption. Statistical Analyses. Clinical parameters were evaluated using the chi-squared
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test for discrete variables and the t test, Mann-Whitney U test, or Kruskal-Wallis test for continuous variables, as appropriate. Multiple logistic regression analyses were performed to identify the factors associated with liver failure in AHE. For all tests, a P value of less than 0.05 was considered significant. All data analyses were performed 7
using SPSS v. 16.0 (SPSS Inc., Chicago, IL, USA). Results Epidemic and demographic characteristics of sporadic AHE A total of 680 inpatients were diagnosed with AHE during the study period. As shown in Figure 1,
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there was an AHE epidemic throughout the year, with high incidences in February, March, and April, accounting for about 41% of the cases. The male to female ratio
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was 5.1:1(574/106). The average age was 50.9 year±12.8 years. The cases in <30,
31-40, 41-50, 51-60, >60 year old age groups were 6.8%(46/680), 13.7% (93/680),
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25.9%(176/680), 30.7%(209/680), and 22.9%(156/680), respectively.
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34.6% (237/680) of the patients had underlying chronic liver diseases, including
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chronic HBV infection (18.5%, 126/680), chronic hepatitis C (7.4%, 5/680), ALD
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(13.4%, 91/680), NAFLD (1.5%), and others (7.4%, 5/680, including 1 schistosomal
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cirrhosis, 1 hepatolenticular degeneration, 1 autoimmune hepatitis, and 2 cryptogenic diseases). The prevalence of HBsAg and liver cirrhosis was 18.5% (126/680) and
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8.8% (60/680), respectively. 4.9% (5/102) of female patients were pregnant. All
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pregnant patients were in the third trimester of pregnancy (pregnant week 28-31). (Table 1)
Symptoms，Signs, Complications, and Outcome of sporadic acute hepatitis E.
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As shown in Table 2, the prevalence of prodromal fever, fatigue, loss of appetite,
jaundice, and cholestasis was 25.6%, 85.6%, 83.8%, 92.6%, and 8.4%, respectively. The occurrence of ascites, encephalopathy, and cholestasis was 11.6% (79/680), 7.4% 50/680), and 8.4% (57/680), respectively. 8
13.1% (89/680) of the patients progressed to liver failure, including 4.1% (28/680) ALF and 9.0% (61/680) ACLF. The overall mortality was 5.6%, 2.2% died of ALF, 9.0% (61/680) died of ACLF, and 2 cases died of infection and renal failure. Biochemical changes in sporadic AHE.
The median (range) serum ALT, AST,
196.8(8.0-1083)µmol/L,
33.0(15.2-45.8)g/L,162
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bilirubin, albumin, platelet, and INR levels were 727(8-6270)U/L, 300(17-6226)U/L, (10-589) × 109/L,
1.15,
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respectively. (Table 3)
and
Features of patients from urban or rural areas
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Table 9 showed the feature of sporadic AHE patients from urban or rural areas.
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Risk factors of Patients With Liver Failure in Sporadic AHE
As shown in Table 4,
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the mean age of the patients with liver failure was older than that of those without liver
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failure (53.8±13.6 vs. 50.5±12.6, P=0.025). The occurrence of liver failure increased with age and severity of thrombocytopenia (Figure 2A, Figure 3A). The liver failure
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rate was higher in patients with underlying liver diseases or HBsAg or cirrhosis. Of 5
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pregnant patients, 2 progressed to liver failure, including 1 ALF and 1 ACLF with chronic HBV infection. The occurrence of
prodromal fever, loss of appetite, jaundice, ascites,
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encephalopathy, and mortality were significantly higher in patients with liver failure than in those without liver failure.(Table 5) The mortality among ALF and ACLF was 53.6%(15/28) and 34.4%(21/61), respectively. The serum bilirubin and INR level were higher in the patients with liver failure than 9
in those without liver failure. The PLT, albumin, GGT, and AKP levels were lower in patients with liver failure than in those without liver failure (Table 6). Multiple logistic regressions indicated that age>53yesrs, prodromal fever, HBsAg positive, liver cirrhosis, and thrombocytopenia were independently associated with
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the development of liver failure with an odds ratio (95% confidence interval) of 2.5 (1.5-4.3), 1.9(1.1-3.2), 3.7 (2.0-6.7), and 5.9 (3.3-10.4), respectively (Table 7).
The overall in hospital mortality was 5.6%
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Risk factors of Death in Sporadic AHE
(38/680), the mortality in patients with and without underlying liver diseases were
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3.6% (16/443) and 9.3% (22/237), respectively (P=0.002), and the mortality in
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patients with HBsAg positive, liver cirrhosis, severe thrombocytopenia, INR<2, or HE
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were 10.3% (13/126, P=0.01), 20.3%(13/64, P<0.001), 25%(26/104, P<0.001),
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47.5% (29/61, P<0.001), and 50% (25/50, P<0.001 ), respectively. Mortality increased
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with age and the severity of thrombocytopenia (Figure 2B, Figure 3B). 1 pregnant patient with ACLF died from liver failure.
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Multiple logistic regressions indicated that HE, bilirubin>500µmol/L, INR>2, and
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severe thrombocytopenia were independently associated with death in sporadic AHE with an odds ratio of (95% confidence interval) 7.2(2.4-21.8), 5.8(1.9-17.2), 24.1(7.9-73.3), and 10.8(3.6-32.8), respectively. (Table 8) The association of liver
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cirrhosis with death was adjusted by severe thrombocytopenia and INR>2. Discussion The transmission of sporadic AHE caused by HEV3 and HEV4 is primarily through the consumption of undercooked food products1. There is no clear epidemic season 10
for sporadic AHE. In the present study, we noticed that there was a sporadic AHE epidemic throughout the year, with high incidences in February, March, and April, accounting for about 41% of the cases. The traditional Chinese New Year begins around February. During the Festival people usually eat much more pork, pork
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products, and game meat than usual. So, the high incidences of sporadic AHE in China from February to April may be closely related to the increased consumption of
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pork and pork products. This is consistent with several investigations in China4, 5, 21. However, a study from England also reported a seasonal variation of sporadic AHE,
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with a peak in the spring22. So, whether the spring season is suitable for HEV
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transmission needs further investigation.
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Compared to waterborne epidemic AHE, the sporadic AHE cases are strongly
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predominantly male and older. In our study cohort, the male to female ratio was
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5.1:1(574/106), and the average age was 50.9 year±12.8 years. These are in agreement with several studies from the developing and developed world4, 5, 21-23. The
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occurrence of liver failure increased with older age (Figure 2A). The association
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between liver failure and age are both significant in ALF and ACLF. Among those older than 60 years, the occurrence of ALF and ACLF was 12.5% (14/112) and 50% (22/44), respectively. These may be related to a possible weakened immune
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response to HEV infection and high percentage of underlying liver diseases in older patients. All of the patients in the study were symptomatic. Jaundice, fatigue, and loss of appetites were the most common symptoms. 92 .8% of the cases were icteric. It is 11
worth noting that 25.6% of the case had prodromal fever. Similar to that of acute hepatitis B, fever prodrome is associated with severity of liver injuries and liver failure in sporadic AHE24. 34.9% of the cases had underlying liver diseases, including chronic hepatitis B
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infection, ALD, NFALD, and chronic hepatitis C. We noticed a very high prevalence of HBsAg (18.5%) and liver cirrhosis (9.4%) in our cohorts. 53.4% (38/64) of the liver
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cirrhosis was HBV-related. A recent survey in Shandong Province showed that the
prevalence of HBsAg was 2.49% among the population aged 1-59 years, and was at
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a peak among 40-49 years at about 4%25. So, the HBsAg prevalence was much
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higher in our study cohort than in the general population. This indicates that HEV
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infection in these populations more easily becomes symptomatic. Furthermore, both
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HBsAg positive and liver cirrhosis are independently associated with occurrence of
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liver failure. Among patients with HBsAg or cirrhosis, 28.6% (36/126) and 36.0% (23/64) progressed to ACLF.
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Overall, 13.1% (89/680) of the cases progressed to liver failure, including 4.1%
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(28/680) ALF and 9.0% (61/680) ACLF. In addition to fever prodrome, HBsAg, liver cirrhosis, old age, and thrombocytopenia (PLT<150×109/L) are also independently associated with the occurrence of liver failure. The occurrence of liver failure
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increased with the severity of thrombocytopenia (Figure 3A). The association between liver failure and thrombocytopenia is both significant both in ALF and ACLF. Among patients with thrombocytopenia, the occurrence of ALF and ACLF was 13.6% (21/154) and 40.3% (50/124), respectively. 12
Platelets have important roles at every stage during the continuum of viral clearance, liver injury, and healing26, 27. In addition to being an indicator of severity of underlying liver diseases or liver cirrhosis, thrombocytopenia may be a result of HEV clearance, liver inflammation, anti-inflammation, and liver regeneration in sporadic
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AHE. The value of platelet level in estimating the severity of liver diseases need to be study further. In our study cohorts, thrombocytopenia was also associated with
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mortality.
The overall mortality was 5.6% (38/680), and the mortality in patients with and
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without underlying liver diseases was 3.3% (15/442) and 8.8% (21/238), respectively.
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Also, HE, bilirubin>500µmol/L, INR>2, and severe thrombocytopenia (PLT<100×
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109/L) were independently associated with death in sporadic AHE with an odds ratio
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(95% confidence interval) of 11.6 (3.7-36.3). The mortality in patients with a normal
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platelet level, thrombocytopenia, and severe thrombocytopenia was 1.74% (7/402), 2.9% (5/174), and 25% (26/104), respectively (Figure 3B). The association between
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liver cirrhosis and mortality is adjusted by severe thrombocytopenia and INR.
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In the present cohort, two of the five pregnant patients developed to ALF and ACLF, respectively. Because of the small sample, we cannot draw any conclusions about the outcome of sporadic AHE in pregnancy.
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In our study, the patients from rural areas tended to have more severe liver
diseases and higher mortality. One possible reason is that more patients with mild disease were treated in local hospitals than those with severe disease. Delayed proper medical care may be another reason. The days from disease onset to hospital 13
admission of patients from rural areas were longer than those from urbal areas (15.4±9.3 vs. 11.8±8.4, P<0.001). After disease onset, more patients from rural areas were treated as common cold with antipyretic drugs and Chinese herbs which have poetinal hepatotoxicity (23.8% vs. 14.6%, P=0.002).
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The clinical course of sporadic AHE is also related to HEV genotypes. In recent years autochthonous HEV3 infection have been reported in Europe, North American,
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and Japan1. HEV3 infection usually runs a mild course and is often asymptomatic.
study from Japan showed that the patients with genotype 4 tended to have more severe clinical manifestations than those with genotype 3 infection 28. However, in the
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immunocompromised, about 60% of these patients go on to develop chronic HEV infection29. On the contrary, only one chronic infection with HVE 4 case has been
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reported to date30. Worth noting is that , in a hospital in Germany, about 10%-15% of
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patients with ALF had evidence for HEV infection31, 32.
There is a concern that whether HEV genotype is revelant to the clinical course in
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our study cohort. All the tested blood samples of AHE patients from our hospital belong to HEV genotype 4. Several epidemiology study have investigated HEV 33-36.
The results of these studies also
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genotypes in Shandong province, China5,
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showed that all HEV strains belong to genotype 4 both in human beings and animals.
In conclusion, we have documented 680 cases of symptomatic sporadic AHE in
Shandong Province, China. Sporadic AHE mainly occurs in middle aged males.
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There are sporadic AHE epidemics throughout the year, with high incidences in February, March, and April. Jaundice, fatigue, and loss of appetites are the most common symptoms. Age>53yesrs, prodromal fever, HBsAg positive, cirrhosis, and thrombocytopenia are independently associated with the development of liver failure.
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High mortality is observed in patients with underlying liver diseases. In addition to parameters defining liver failure, old age and severe thrombocytopenia are predictors of death in sporadic AHE.
In HBV and HEV dual endemic areas, the HEV vaccine
for patients with obvious liver diseases is of significance. Thrombocytopenia is an
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important predictor for liver failure and mortality.
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Funding
This work was supported by the Jinan Clinical Medicine Innovation Program and Technology Development Projects [201503012] and the 5th Quancheng Outstanding
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Medical Scholar Research Fund.
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Acknowledgement
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Conflict of interest statement
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Thanks to Dr. Edward C. Mignot, Shandong University, for linguistic advice.
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All authors have none conflicts of interest to disclose.
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Du WJ, Liu L, Sun C, Yu JH, Xiao D, Li Q. Prodromal fever indicates a high risk of liver failure in acute
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Liu J, Lv J, Yan B, Feng Y, Song L, Xu A, Zhang L, Yan Y. Comparison between two population-based hepatitis B serosurveys with an 8-year interval in Shandong Province, China. Int J Infect Dis;61:13-9. Chauhan A, Adams DH, Watson SP, Lalor PF. Platelets: No longer bystanders in liver disease.
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Wang XJ, Zhao Q, Jiang FL, Liu BY, Zhao JN, Dang L, Sun YN, Mu Y, Xiao SQ, Wang CB, Hsu WH, Liu L, Widen F, Zhou EM. Genetic characterization and serological prevalence of swine hepatitis E virus in Shandong province, China. Vet Microbiol;172:415-24.
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Xia J, Zeng H, Liu L, Zhang Y, Liu P, Geng J, Wang L, Zhuang H. Swine and rabbits are the main reservoirs of hepatitis E virus in China: detection of HEV RNA in feces of farmed and wild animals. Arch Virol;160:2791-8. Gong LF, Liu J, Han WQ, Cui WH, Sun ZL, Jiang M. [The coastal areas of Yantai human and swine
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36.
A
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PT
ED
M
A
N
U
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hepatitis E virus genotyping analysis]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi;26:31-3.
18
19
A ED
PT
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SC R
U
N
A
M
Age distribution of acute hepatitis E patients with and without liver failure
A
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PT
Figure 2A.
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M
A
N
U
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Figure 1. Seasonal distribution of hepatitis E from 2003 to 2014 (n=680)
20
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Age distribution of survivors and deceased patients with acute hepatitis E
A
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PT
Figure 2B.
21
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Liver failure in different platelet grades
A
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PT
Figure 3A.
22
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PT
Survivors and deceased patients in different platelet grades
A
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Figure 3B.
23
Table 1. Demographics of sporadic acute hepatitis E N=680
Age (years)
50.9±12.8
Sex(male)
574 (84.4%)
Residence 377 (55.4%)
Rural
303(44.6%)
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Urban
5(0.7%)
U
Pregnancy
54(7.9%)
N
Type 2 diabetes
M
HBsAg positive
A
Underlying chronic liver diseases
ED
Anti-HCV positive
PT
Alcohol NAFLD
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Schistosomal cirrhosis,
237(34.9%) 126(53.2%) 5(2.1%) 91(38.4%) 10(4.2%) 1(0.15%) 1(0.15%)
Autoimmune hepatitis,
1(0.15%)
A
Hepatolenticular degeneration
Cryptogenic disease
2(0.29%)
Cirrhosis
64(9.4%)
Days of stay in hospital
29.6±17.2
NOTE.
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Variables
Data are expressed as mean±SD or n (%) of patients .NAFLD, nonalcoholic fatty liver disease.
24
Prodromal Fever
174(25.6%)
Fatigue
582(85.6%)
Loss of appetite
570(83.8%)
Jaundice
631(92.8%)
Ascites
79(11.6%)
Hepatic encephalopathy
50 (7.4%)
Cholestasis
N
57(8.4%)
Acute liver failure
Mortality
PT
Acute liver failure
ED
Acute-on-chronic liver failure
Acute-on-chronic liver failure
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M
A
Liver Failure
Without liver failure
89(13.1%) 28 (4.1%) 61(9.0%) 38(5.6%) 15(2.2%) 21(3.1%) 2(0.3%)
Data are expressed as n (%) of patients.
A
NOTE.
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N=680 (%)
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Variables
U
Table 2. Symptoms， Signs, and Complications of sporadic acute hepatitis E
25
N=680
ALT(IU/L)
727(8-6270)
AST( IU/L)
300(17-6226)
Bilirubin(µmol/L)
196.8(8.0-1083)
Bilirubin>85µmol/L
540(79.4%)
Albumin(g/L)
33.0(15.2-45.8)
GGT(IU/L)
160(10-3784)
AKP(IU/L)
154(47-2369)
N
U
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Variables
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Table 3. Biochemical Data of sporadic acute hepatitis E
1.15(0.81-41.9)
A
INR
M
PLT(×109/L)
162(10-589)
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NOTE. Data are expressed as median (min-max) or n(%) of patients. ALT, alanine aminotransferase; AST, aspartate transaminase; GGT,
A
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PT
gamma-glutmyltransferase; AKP, alkaline phosphatase; INR, international normalized ratio; PLT, platelet.
26
Table 4. Demographics of sporadic acute hepatitis E with and without liver failure Without Liver Failure
With Liver Failure P
Variables N=591
N=89 53.8±13.6
0.368
Sex 496 (83.9%)
78(87.6%)
Female
95(16.1%)
11(12.4%)
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Male
Rural
254(43.0%) 39(6.6%)
Underlying liver diseases
175(29.6%)
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Liver cirrhosis
PT
Anti-HCV positive
Days of stay in hospital
0.006
62(69.7%)
<0.001
89(15.1%)
37(41.6%)
<0.001
4(0.68%)
1(1.1%)
0.38
40(6.8%)
24(27.0%)
<0.001
29.2±14.9
32.2±28.0
0.128
ED
HBsAg positive
49(55.0%) 15(16.9%)
M
Type 2 diabetes
40(45.0%)
N
337(57.0%)
A
Urban
0.033
U
Residence
Data are expressed as mean±SD or n (%) of patients; .
A
NOTE.
0.025
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50.5±12.6
Age (years)
27
Table 5. Symptoms， Signs, and Complications of sporadic acute hepatitis E with and without liver failure Without Liver Failure
With Liver Failure P
Variables N=89
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N=591 142(24.0%)
32(36.0%)
Fatigue
498(84.3%)
84(94.4%)
Loss of appetite
497(84.1%)
73(82.0%)
0.621
Jaundice
542(91.7%)
102(100%)
0.005
Ascites
36(6.1%)
Hepatic encephalopathy
2(0.34%)
Cholestasis
52(8.8%)
Mortality
2(0.34%)
0.016 0.011
43(48.3%)
<0.001
48(53.9%)
<0.001
5(5.6%)
0.305
36(40.4%)
<0.001
ED
M
A
N
U
SC R
Prodromal fever
A
CC E
PT
NOTE. Data are expressed n (%) of patients.
28
Table 6. Biochemical Data in of sporadic acute hepatitis E with and without liver failure Without Liver Failure
With Liver Failure P
Variables N=591
N=89
731(21-6270)
571(8-6226)
0.075
AST(IU/L)
307(17-3904)
242(22-6226)
Bilirubin(µmol/L)
179(8-956)
506(77-1083)
Albumin(g/L)
33.6(18-45.8)
30.2(15.2-39.0)
<0.001
GGT(IU/L)
169(10-3784)
87(17-508)
<0.001
AKP(IU/L)
158(49-2369)
INR
1.11(0.81-41.9)
PLT(×109/L)
175(10-589)
2.19(1.11-25.4)
<0.001
108(23-279)
<0.001
N A
<0.001
0.012
142(47-474)
M
0.827
U
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ALT(IU/L)
ED
NOTE. Data are expressed as median (min-max) of patients. ALT, alanine aminotransferase; AST, aspartate transaminase; GGT,
A
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PT
gamma-glutmyltransferase; AKP, alkaline phosphatase; INR, international normalized ratio; PLT, platelet.
29
Table 7. Risk factors associated with liver failure in patients with sporadic acute hepatitis E: Multivariate logistic regression Variables
Odds ratio
95%CI
P
No
1(reference)
Yes
2.5
Prodromal fever 1(reference)
Yes
1.9
2.0-6.7
<0.001
1.1-4.2
0.025
3.3-10.4
<0.001
N
0.02
1(reference)
M
No
3.7
ED
Yes
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PT
Liver cirrhosis
Yes
1.1-3.2
A
HBsAg
No
U
No
0.01
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1.5-4.3
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Age>53yesrs
1(reference) 2.1
Platelet<150×109/L
A
No
Yes
1(reference) 5.9
NOTE: multivariate logistic regression adjusted for age, type 2 diabetes, prodromal fever, fatigue, liver cirrhosis, HBsAg, and platelet
30
Table 8. Risk factors associated with death in sporadic acute hepatitis E: Multivariate logistic regression Variables
Odds ratio
95%CI
P
No
1(reference)
Yes
7.2
Bilirubin>500µmol/L 1(reference)
Yes
5.8
7.9-73.3
<0.001
3.6-32.9
<0.001
N
0.002
1(reference)
M
No
24.1
1(reference) 10.8
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PT
PLT<100×109/L
ED
Yes
Yes
1.9-17.2
A
INR>2
No
U
No
<0.001
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2.4-21.8
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Hepatic encephalopathy
NOTE: multivariate logistic regression adjusted for,HBsAg, liver cirrhosis, hepatic encephalopathy, bilirubin, INR, and PLT. INR, international
A
normalized ratio; PLT, platelet.
31
Table 9. Features of sporadic acute hepatitis E from urban or rural areas Urban
Rural P
Variables N=377
N=303
Age (years)
51.2±12.9
50.6±12.6
Male
313(83.0%)
261(86.1%)
Type 2 diabetes
37(9.8%)
Underlying liver diseases
121(32.1%)
HBsAg positive
57(15.1%)
Liver cirrhosis
29(7.7%)
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Demographics 0.579 0.266 0.044
116(38.3%)
0.092
U
17(5.6%)
0.011
35(11.2%)
0.087
11.8±8.4
15.4±9.3
<0.001
343(91.0%)
288(95.0%)
0.041
32(8.5%)
47(15.5%)
0.004
Hepatic encephalopathy
20(5.3%)
30(9.9%)
0.022
Liver Failure
40(10.7%)
49(16.2%)
0.033
Acute liver failure
10 (2.7%)
18(5.9%)
0.032
Acute-on-chronic liver failure
30(8.0%)
31(10.2%)
0.302
Mortality
14(3.7%)
24(7.9%)
0.018
M
Days from disease onset to hospital
A
N
69(22.8%)
ED
admission
Jaundice
A
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Ascites
PT
Complications and outcome
Biochemical Data 32
890(8-6270)
576(25-6226)
<0.001
AST(IU/L)
341(17-5022)
234(29-6226)
0.028
Bilirubin(µmol/L)
179(8-957)
228(9.3-1083)
<0.001
Albumin(g/L)
34(17.3-45.8)
32.2(15.2-45.4)
<0.001
INR
1.14(0.81-41.9)
1.16(0.87-25.4)
0.148
PLT(×109/L)
165(10-510)
160(23-589)
Thrombocytopenia
141(37.4%)
137(45.2%)
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Data are expressed as mean±SD or median (min-max) o or n (%) of patients; .
0.145 0.039
A
CC E
PT
ED
M
A
N
U
NOTE.
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ALT(IU/L)
33
S1201-9712(18)30067-5 https://doi.org/10.1016/j.ijid.2018.03.008 IJID 3195
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
5-2-2018 3-3-2018 9-3-2018
Please cite this article as: Liu Li, Xiao Di, Yu Jin-Hong, Shen Rui, Wang Meng, Li Qiang.Clinical course of sporadic acute hepatitis E in a hepatitis B virus endemic region.International Journal of Infectious Diseases https://doi.org/10.1016/j.ijid.2018.03.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Clinical course of sporadic acute hepatitis E in a hepatitis B virus endemic region
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Authors: Li Liu1, Di Xiao1, Jin-Hong Yu1, Rui Shen1, Meng Wang1,2, Qiang Li1
1. Division of Liver Diseases, Jinan Infectious Disease Hospital, Shandong University,
2. Division of Infectious Diseases, Jinan Central Hospital, Shandong
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Jinan, China.
U
University, Jinan, China.
N
Corresponding author: Qiang Li, M.D., Ph.D., Division of Liver Diseases, Jinan
China
Tel:+86-531-87935971
Email:
PT
Abstract
Fax:+86-531-87932070
ED
[email protected]
M
250021,
A
Infectious Disease Hospital, Shandong University, 22029# Jingshi Road, Jinan ,
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Objectives: In China, the epidemic pattern of acute hepatitis E virus (HEV) infection has changed from waterborne outbreaks to foodborne sporadic cases. However, the clinical course of sporadic acute hepatitis E has not been well defined.
A
Methods: Consecutive AHE inpatients who were admitted to the Jinan Infectious Disease Hospital, Jinan, Shandong Province, between January 2003 and December 2014 were evaluated and followed. Demographic data, clinical manifestations, results of laboratory tests，and outcomes were recorded. Risk factors of liver failure and 1
death were analyzed. Results: A total of 680 AHE inpatients were identified during the study period. The incidence was high in February, March, and April, accounting for about 41% of the cases. The male to female ratio was 5.1:1(574/106). The average age was 50.9 ±
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12.8 years old. The prevalence of prodromal fever, fatigue, loss of appetite, and jaundice was 25.6%, 85.6%, 83.8%, and 92.8%, respectively. The median (range)
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serum ALT, AST, bilirubin, albumin, and platelet levels was 727(8-6270)U/L,
300(17-6226)U/L, 196.8(8.0-1083)µmol/L, 33.0(15.2-45.8)g/L, and 162 (10-589)×
U
109/L, respectively. The prevalence of HBsAg and liver cirrhosis was 18.5% (126/680)
N
and 9.4% (64/680), respectively. 13.1% (89/680) of the cases progressed to liver
A
failure, including 4.1% (28/680) acute liver failure (ALF) and 9.0% (61/680)
M
acute-on-chronic liver failure (ACLF). Among patients with HBsAg or cirrhosis, 28.6%
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(36/126) and 36.0% (23/64) progressed to ACLF, respectively. Multiple logistic regressions indicated that age>53yesrs, prodromal fever, HBsAg positive, cirrhosis,
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and thrombocytopenia (PLT<150×109/L) were independently associated with the
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development of liver failure with an odds ratio (95% confidence interval) of 2.5(1.5-4.3), 1.9(1.1-3.2), 3.7(2.0-6.7), 2.1(1.1-4.2), and 5.9 (3.3-10.4), respectively. The overall mortality was 5.6% (38/680), and the mortality in patients with and without
A
underlying liver diseases were 3.3% (15/442) and 8.8% (21/238), respectively. Multiple
logistic
regressions
indicated
that
hepatic
encephalopathy,
bilirubin>500(µmol/L), INR>2, and severe thrombocytopenia (PLT<100×109/L) were independently associated with death with an odds ratio (95% confidence interval) of 2
7.2(2.4-21.8), 5.8(1.9-17.2), 24.1(7.9-73.3), and 10.8(3.6-32.9), respectively. Conclusions: In HBV and HEV dual endemic areas, the HEV vaccine for patients with obvious liver diseases is of significance. Thrombocytopenia is an important
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predictor of liver failure and mortality in sporadic AHE.
Keywords: acute hepatitis E; sporadic; liver failure; hepatitis B surface antigen; liver
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cirrhosis; platelet; thrombocytopenia
U
Globally, hepatitis E virus (HEV) is the most common cause of acute viral hepatitis 1.
N
Four genotypes of HEV have been associated with human infections. HEV genotype
A
1 (HEV1) occurs mainly in Asia and HEV genotype 2 (HEV2) in Africa and Mexico,
M
and they are responsible for water-borne epidemics in developing countries. HEV
ED
genotype 3 (HEV3) and HEV genotype 4 (HEV4) infect human beings, pigs, and other mammalian species and are responsible for sporadic cases of acute hepatitis E (AHE)
PT
in both developing and developed countries. HEV3 has a worldwide distribution. By
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contrast, HEV4 mostly occurs in Southeast Asia. HEV3 and HEV4 have been linked to the consumption of raw and undercooked pork or game meat2. China is an endemic area of HEV. Even though, there were waterborne outbreaks
A
of AHE in China in last century, which were caused by HEV1, with social economic development, the epidemic pattern has changed from waterborne outbreaks to sporadic foodborne cases1. Several investigations showed that sporadic hepatitis E in China is mainly caused by HEV43-5. In China, sporadic cases of hepatitis E have 3
doubled in last decades5. Water-borne epidemics of hepatitis E mainly affect young adults. Mortality rates are general under 0.5% but may reach up to 25% in pregnant women. Several investigations indicated that the mortality is higher in AHE patients with underlying 6-9.
The clinical features and outcome of sporadic
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chronic liver diseases (CLD)
foodborne AHE cases may differ from water-borne epidemic AHE. What is more, in
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China, in a hepatitis B virus (HBV) endemic area, the clinical features and outcome may differ from a low HBV endemic region. The prevalence of HBsAg in AHE patients
U
and the influence of chronic HBV infection on the outcome of AHE are still largely
N
unclear. The predictors associated with death of sporadic AHE still need to be
A
clarified.
M
The aim of the present study was to investigate the clinical course of sporadic AHE
ED
in HBV high endemic regions in China. Patients and Methods
PT
Study Design and Population.
The present study was performed in the Jinan
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Infectious Disease Hospital, a tertiary and teaching hospital of Shandong University located in Jinan, Shandong Province. This study is part of a hospital-based prospective investigation to study the natural history of acute HEV infection that was
A
conducted in the hospital，in which all inpatients with confirmed acute hepatitis E (AHE) between January 2003 and December 2014 were included and followed. The study was approved by the hospital ethics committee, and written informed consent for participation was obtained from each study participant or their next of kins. 4
Upon entry to the hospital, all patients and/or their attendants were interviewed by trained physicians. Physical examinations, blood counts, serum biochemical parameters, prothrombin time, serum alpha-fetoprotein (AFP), anti-HEV IgM and IgG antibody (Wantai Pharmaceutical Co. Beijing, China), anti-HAV IgM (Beijing Kewei
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Clinical Diagnostic Regent INC, Beijing China), anti-HCV (AxSYM HCV, Abbott Laboratories, Abbott Park, IL, USA), HBsAg, anti-HBs, HBeAg, anti-HBe, and
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anti-HBc (Abbott Laboratories) were measured. HBV DNA quantification (Applied
Biosystems® 7500 Real-Time PCR Systems, Thermo Fisher Scientific Inc.),
U
ultrasound examinations, and gastrointestinal barium meal X-ray examinations were
N
also performed. Serum samples were collected at admission and stored at -80℃. The
M
previously described 10-12.
A
details of general information collection and other laboratory measurements were
ED
The diagnosis of AHE was based on a discrete onset of symptoms, jaundice, elevated serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
PT
levels, detection of HEV IgM antibodies, or a rising HEV IgG or HEV RNA positive,
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and compatible clinical history13. In this study, AHE with evidence of coagulation abnormality (international normalized ratio [INR]≥1.5) and hepatic encephalopathy (HE),
and without pre-existing liver diseases was diagnosed as acute liver failure
A
(ALF)14. The diagnosis of acute-on-chronic liver failure (ACLF) was according to the APASL
consensus
recommendations
(2014):
AHE
patients
with
serum
bilirubin>85µmol/L and INR≥1.5 complicated within 4 weeks by clinical ascites and/or encephalopathy in patients with underlying chronic liver diseases15. 5
Study Variables and Definitions.
The variables analyzed in this study included
demographic data, prodromal signs and symptoms, serum biochemical parameters, liver failure, and mortality. Underlying liver diseases included hepatitis B, hepatitis C, alcoholic liver disease,
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non-alcoholic fatty liver disease, and other CLD with known or unknown etiologies. The diagnosis of CLD in AHE was made by history, physical examination, and
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previously available or recent laboratory, B ultrasonography, endoscopic or radiological investigations15.
U
The diagnosis of cirrhosis was based on clinical and morphological criteria,
N
ultrasound or computed tomography or magnetic resonance imaging, according to
A
standard definitions16. These included the presence of clinical manifestations of portal
M
hypertension (e.g., esophageal varices, encephalopathy, or ascites), biochemical
ED
abnormalities (e.g., decreased serum albumin and platelets or prolonged prothrombin time), and obvious morphological changes in the liver detected by hepatic imaging.
PT
Ultrasonography was performed by experienced radiologists for every patient upon
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entry to the hospital17.
For patients with jaundice, prodromal manifestations were defined as signs or
symptoms occurring in the 1-10 days before onset of icterus (prodromal period). For
A
patients without jaundice, prodromal manifestations were defined as signs or symptoms occurring in the 1-10 days before diagnosis of hepatitis or hospital admission. Prodromal signs and symptoms analyzed in this study included fever, loss of 6
appetite, fatigue. Prodromal fever was defined in 2 different ways: patients reporting a measured fever ≥37.5℃ during the prodromal period or any fever (measured or subjective) during the prodromal period
18, 19.
Loss of appetite during the prodromal
period was classified into 3 categories: mild: reduction of daily food intake less than
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1/3 of normal, medium: reduction of daily food intake between 1/3-1/2 of normal, and severe: reduction of daily food intake more than 1/2 of normal with anorexia or
SC R
vomiting. Fatigue during the prodromal period was also classified into 3 categories: mild: mildly sick but not influencing daily activity, medium: sick and influencing daily
U
activity, and severe: sick and influencing daily activity and need to lie on bed.
N
Jaundice referred to measured serum total bilirubin>25µmol/L at admission.
A
Hepatic encephalopathy (HE) was classified into four grades as previously
M
described 14, 20. The presence of ascites was evaluated using B ultrasonography.
ED
Blood platelet (PLT)< 150 × 109/L and 100 × 109/L were defined as thrombocytopenia and severe thrombocytopenia, respectively.
PT
In this study, subjects with an ethanol intake of 40 g/d or more for men and 20 g/d
CC E
or more for women for longer than 5 years were considered to have a positive history of alcohol consumption. Statistical Analyses. Clinical parameters were evaluated using the chi-squared
A
test for discrete variables and the t test, Mann-Whitney U test, or Kruskal-Wallis test for continuous variables, as appropriate. Multiple logistic regression analyses were performed to identify the factors associated with liver failure in AHE. For all tests, a P value of less than 0.05 was considered significant. All data analyses were performed 7
using SPSS v. 16.0 (SPSS Inc., Chicago, IL, USA). Results Epidemic and demographic characteristics of sporadic AHE A total of 680 inpatients were diagnosed with AHE during the study period. As shown in Figure 1,
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there was an AHE epidemic throughout the year, with high incidences in February, March, and April, accounting for about 41% of the cases. The male to female ratio
SC R
was 5.1:1(574/106). The average age was 50.9 year±12.8 years. The cases in <30,
31-40, 41-50, 51-60, >60 year old age groups were 6.8%(46/680), 13.7% (93/680),
U
25.9%(176/680), 30.7%(209/680), and 22.9%(156/680), respectively.
N
34.6% (237/680) of the patients had underlying chronic liver diseases, including
A
chronic HBV infection (18.5%, 126/680), chronic hepatitis C (7.4%, 5/680), ALD
M
(13.4%, 91/680), NAFLD (1.5%), and others (7.4%, 5/680, including 1 schistosomal
ED
cirrhosis, 1 hepatolenticular degeneration, 1 autoimmune hepatitis, and 2 cryptogenic diseases). The prevalence of HBsAg and liver cirrhosis was 18.5% (126/680) and
PT
8.8% (60/680), respectively. 4.9% (5/102) of female patients were pregnant. All
CC E
pregnant patients were in the third trimester of pregnancy (pregnant week 28-31). (Table 1)
Symptoms，Signs, Complications, and Outcome of sporadic acute hepatitis E.
A
As shown in Table 2, the prevalence of prodromal fever, fatigue, loss of appetite,
jaundice, and cholestasis was 25.6%, 85.6%, 83.8%, 92.6%, and 8.4%, respectively. The occurrence of ascites, encephalopathy, and cholestasis was 11.6% (79/680), 7.4% 50/680), and 8.4% (57/680), respectively. 8
13.1% (89/680) of the patients progressed to liver failure, including 4.1% (28/680) ALF and 9.0% (61/680) ACLF. The overall mortality was 5.6%, 2.2% died of ALF, 9.0% (61/680) died of ACLF, and 2 cases died of infection and renal failure. Biochemical changes in sporadic AHE.
The median (range) serum ALT, AST,
196.8(8.0-1083)µmol/L,
33.0(15.2-45.8)g/L,162
IP T
bilirubin, albumin, platelet, and INR levels were 727(8-6270)U/L, 300(17-6226)U/L, (10-589) × 109/L,
1.15,
SC R
respectively. (Table 3)
and
Features of patients from urban or rural areas
N
U
Table 9 showed the feature of sporadic AHE patients from urban or rural areas.
A
Risk factors of Patients With Liver Failure in Sporadic AHE
As shown in Table 4,
M
the mean age of the patients with liver failure was older than that of those without liver
ED
failure (53.8±13.6 vs. 50.5±12.6, P=0.025). The occurrence of liver failure increased with age and severity of thrombocytopenia (Figure 2A, Figure 3A). The liver failure
PT
rate was higher in patients with underlying liver diseases or HBsAg or cirrhosis. Of 5
CC E
pregnant patients, 2 progressed to liver failure, including 1 ALF and 1 ACLF with chronic HBV infection. The occurrence of
prodromal fever, loss of appetite, jaundice, ascites,
A
encephalopathy, and mortality were significantly higher in patients with liver failure than in those without liver failure.(Table 5) The mortality among ALF and ACLF was 53.6%(15/28) and 34.4%(21/61), respectively. The serum bilirubin and INR level were higher in the patients with liver failure than 9
in those without liver failure. The PLT, albumin, GGT, and AKP levels were lower in patients with liver failure than in those without liver failure (Table 6). Multiple logistic regressions indicated that age>53yesrs, prodromal fever, HBsAg positive, liver cirrhosis, and thrombocytopenia were independently associated with
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the development of liver failure with an odds ratio (95% confidence interval) of 2.5 (1.5-4.3), 1.9(1.1-3.2), 3.7 (2.0-6.7), and 5.9 (3.3-10.4), respectively (Table 7).
The overall in hospital mortality was 5.6%
SC R
Risk factors of Death in Sporadic AHE
(38/680), the mortality in patients with and without underlying liver diseases were
U
3.6% (16/443) and 9.3% (22/237), respectively (P=0.002), and the mortality in
N
patients with HBsAg positive, liver cirrhosis, severe thrombocytopenia, INR<2, or HE
A
were 10.3% (13/126, P=0.01), 20.3%(13/64, P<0.001), 25%(26/104, P<0.001),
M
47.5% (29/61, P<0.001), and 50% (25/50, P<0.001 ), respectively. Mortality increased
ED
with age and the severity of thrombocytopenia (Figure 2B, Figure 3B). 1 pregnant patient with ACLF died from liver failure.
PT
Multiple logistic regressions indicated that HE, bilirubin>500µmol/L, INR>2, and
CC E
severe thrombocytopenia were independently associated with death in sporadic AHE with an odds ratio of (95% confidence interval) 7.2(2.4-21.8), 5.8(1.9-17.2), 24.1(7.9-73.3), and 10.8(3.6-32.8), respectively. (Table 8) The association of liver
A
cirrhosis with death was adjusted by severe thrombocytopenia and INR>2. Discussion The transmission of sporadic AHE caused by HEV3 and HEV4 is primarily through the consumption of undercooked food products1. There is no clear epidemic season 10
for sporadic AHE. In the present study, we noticed that there was a sporadic AHE epidemic throughout the year, with high incidences in February, March, and April, accounting for about 41% of the cases. The traditional Chinese New Year begins around February. During the Festival people usually eat much more pork, pork
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products, and game meat than usual. So, the high incidences of sporadic AHE in China from February to April may be closely related to the increased consumption of
SC R
pork and pork products. This is consistent with several investigations in China4, 5, 21. However, a study from England also reported a seasonal variation of sporadic AHE,
U
with a peak in the spring22. So, whether the spring season is suitable for HEV
N
transmission needs further investigation.
A
Compared to waterborne epidemic AHE, the sporadic AHE cases are strongly
M
predominantly male and older. In our study cohort, the male to female ratio was
ED
5.1:1(574/106), and the average age was 50.9 year±12.8 years. These are in agreement with several studies from the developing and developed world4, 5, 21-23. The
PT
occurrence of liver failure increased with older age (Figure 2A). The association
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between liver failure and age are both significant in ALF and ACLF. Among those older than 60 years, the occurrence of ALF and ACLF was 12.5% (14/112) and 50% (22/44), respectively. These may be related to a possible weakened immune
A
response to HEV infection and high percentage of underlying liver diseases in older patients. All of the patients in the study were symptomatic. Jaundice, fatigue, and loss of appetites were the most common symptoms. 92 .8% of the cases were icteric. It is 11
worth noting that 25.6% of the case had prodromal fever. Similar to that of acute hepatitis B, fever prodrome is associated with severity of liver injuries and liver failure in sporadic AHE24. 34.9% of the cases had underlying liver diseases, including chronic hepatitis B
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infection, ALD, NFALD, and chronic hepatitis C. We noticed a very high prevalence of HBsAg (18.5%) and liver cirrhosis (9.4%) in our cohorts. 53.4% (38/64) of the liver
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cirrhosis was HBV-related. A recent survey in Shandong Province showed that the
prevalence of HBsAg was 2.49% among the population aged 1-59 years, and was at
U
a peak among 40-49 years at about 4%25. So, the HBsAg prevalence was much
N
higher in our study cohort than in the general population. This indicates that HEV
A
infection in these populations more easily becomes symptomatic. Furthermore, both
M
HBsAg positive and liver cirrhosis are independently associated with occurrence of
ED
liver failure. Among patients with HBsAg or cirrhosis, 28.6% (36/126) and 36.0% (23/64) progressed to ACLF.
PT
Overall, 13.1% (89/680) of the cases progressed to liver failure, including 4.1%
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(28/680) ALF and 9.0% (61/680) ACLF. In addition to fever prodrome, HBsAg, liver cirrhosis, old age, and thrombocytopenia (PLT<150×109/L) are also independently associated with the occurrence of liver failure. The occurrence of liver failure
A
increased with the severity of thrombocytopenia (Figure 3A). The association between liver failure and thrombocytopenia is both significant both in ALF and ACLF. Among patients with thrombocytopenia, the occurrence of ALF and ACLF was 13.6% (21/154) and 40.3% (50/124), respectively. 12
Platelets have important roles at every stage during the continuum of viral clearance, liver injury, and healing26, 27. In addition to being an indicator of severity of underlying liver diseases or liver cirrhosis, thrombocytopenia may be a result of HEV clearance, liver inflammation, anti-inflammation, and liver regeneration in sporadic
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AHE. The value of platelet level in estimating the severity of liver diseases need to be study further. In our study cohorts, thrombocytopenia was also associated with
SC R
mortality.
The overall mortality was 5.6% (38/680), and the mortality in patients with and
U
without underlying liver diseases was 3.3% (15/442) and 8.8% (21/238), respectively.
N
Also, HE, bilirubin>500µmol/L, INR>2, and severe thrombocytopenia (PLT<100×
A
109/L) were independently associated with death in sporadic AHE with an odds ratio
M
(95% confidence interval) of 11.6 (3.7-36.3). The mortality in patients with a normal
ED
platelet level, thrombocytopenia, and severe thrombocytopenia was 1.74% (7/402), 2.9% (5/174), and 25% (26/104), respectively (Figure 3B). The association between
PT
liver cirrhosis and mortality is adjusted by severe thrombocytopenia and INR.
CC E
In the present cohort, two of the five pregnant patients developed to ALF and ACLF, respectively. Because of the small sample, we cannot draw any conclusions about the outcome of sporadic AHE in pregnancy.
A
In our study, the patients from rural areas tended to have more severe liver
diseases and higher mortality. One possible reason is that more patients with mild disease were treated in local hospitals than those with severe disease. Delayed proper medical care may be another reason. The days from disease onset to hospital 13
admission of patients from rural areas were longer than those from urbal areas (15.4±9.3 vs. 11.8±8.4, P<0.001). After disease onset, more patients from rural areas were treated as common cold with antipyretic drugs and Chinese herbs which have poetinal hepatotoxicity (23.8% vs. 14.6%, P=0.002).
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The clinical course of sporadic AHE is also related to HEV genotypes. In recent years autochthonous HEV3 infection have been reported in Europe, North American,
A
SC R
and Japan1. HEV3 infection usually runs a mild course and is often asymptomatic.
study from Japan showed that the patients with genotype 4 tended to have more severe clinical manifestations than those with genotype 3 infection 28. However, in the
U
immunocompromised, about 60% of these patients go on to develop chronic HEV infection29. On the contrary, only one chronic infection with HVE 4 case has been
N
reported to date30. Worth noting is that , in a hospital in Germany, about 10%-15% of
M
A
patients with ALF had evidence for HEV infection31, 32.
There is a concern that whether HEV genotype is revelant to the clinical course in
ED
our study cohort. All the tested blood samples of AHE patients from our hospital belong to HEV genotype 4. Several epidemiology study have investigated HEV 33-36.
The results of these studies also
PT
genotypes in Shandong province, China5,
CC E
showed that all HEV strains belong to genotype 4 both in human beings and animals.
In conclusion, we have documented 680 cases of symptomatic sporadic AHE in
Shandong Province, China. Sporadic AHE mainly occurs in middle aged males.
A
There are sporadic AHE epidemics throughout the year, with high incidences in February, March, and April. Jaundice, fatigue, and loss of appetites are the most common symptoms. Age>53yesrs, prodromal fever, HBsAg positive, cirrhosis, and thrombocytopenia are independently associated with the development of liver failure.
14
High mortality is observed in patients with underlying liver diseases. In addition to parameters defining liver failure, old age and severe thrombocytopenia are predictors of death in sporadic AHE.
In HBV and HEV dual endemic areas, the HEV vaccine
for patients with obvious liver diseases is of significance. Thrombocytopenia is an
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important predictor for liver failure and mortality.
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Funding
This work was supported by the Jinan Clinical Medicine Innovation Program and Technology Development Projects [201503012] and the 5th Quancheng Outstanding
N
U
Medical Scholar Research Fund.
A
Acknowledgement
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Conflict of interest statement
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Thanks to Dr. Edward C. Mignot, Shandong University, for linguistic advice.
A
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PT
All authors have none conflicts of interest to disclose.
15
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36.
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A
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U
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hepatitis E virus genotyping analysis]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi;26:31-3.
18
19
A ED
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U
N
A
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Age distribution of acute hepatitis E patients with and without liver failure
A
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Figure 2A.
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A
N
U
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Figure 1. Seasonal distribution of hepatitis E from 2003 to 2014 (n=680)
20
IP T SC R U N A M ED
Age distribution of survivors and deceased patients with acute hepatitis E
A
CC E
PT
Figure 2B.
21
IP T SC R U N A M ED
Liver failure in different platelet grades
A
CC E
PT
Figure 3A.
22
IP T SC R U N A M ED
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Survivors and deceased patients in different platelet grades
A
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Figure 3B.
23
Table 1. Demographics of sporadic acute hepatitis E N=680
Age (years)
50.9±12.8
Sex(male)
574 (84.4%)
Residence 377 (55.4%)
Rural
303(44.6%)
SC R
Urban
5(0.7%)
U
Pregnancy
54(7.9%)
N
Type 2 diabetes
M
HBsAg positive
A
Underlying chronic liver diseases
ED
Anti-HCV positive
PT
Alcohol NAFLD
CC E
Schistosomal cirrhosis,
237(34.9%) 126(53.2%) 5(2.1%) 91(38.4%) 10(4.2%) 1(0.15%) 1(0.15%)
Autoimmune hepatitis,
1(0.15%)
A
Hepatolenticular degeneration
Cryptogenic disease
2(0.29%)
Cirrhosis
64(9.4%)
Days of stay in hospital
29.6±17.2
NOTE.
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Variables
Data are expressed as mean±SD or n (%) of patients .NAFLD, nonalcoholic fatty liver disease.
24
Prodromal Fever
174(25.6%)
Fatigue
582(85.6%)
Loss of appetite
570(83.8%)
Jaundice
631(92.8%)
Ascites
79(11.6%)
Hepatic encephalopathy
50 (7.4%)
Cholestasis
N
57(8.4%)
Acute liver failure
Mortality
PT
Acute liver failure
ED
Acute-on-chronic liver failure
Acute-on-chronic liver failure
CC E
M
A
Liver Failure
Without liver failure
89(13.1%) 28 (4.1%) 61(9.0%) 38(5.6%) 15(2.2%) 21(3.1%) 2(0.3%)
Data are expressed as n (%) of patients.
A
NOTE.
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N=680 (%)
SC R
Variables
U
Table 2. Symptoms， Signs, and Complications of sporadic acute hepatitis E
25
N=680
ALT(IU/L)
727(8-6270)
AST( IU/L)
300(17-6226)
Bilirubin(µmol/L)
196.8(8.0-1083)
Bilirubin>85µmol/L
540(79.4%)
Albumin(g/L)
33.0(15.2-45.8)
GGT(IU/L)
160(10-3784)
AKP(IU/L)
154(47-2369)
N
U
SC R
Variables
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Table 3. Biochemical Data of sporadic acute hepatitis E
1.15(0.81-41.9)
A
INR
M
PLT(×109/L)
162(10-589)
ED
NOTE. Data are expressed as median (min-max) or n(%) of patients. ALT, alanine aminotransferase; AST, aspartate transaminase; GGT,
A
CC E
PT
gamma-glutmyltransferase; AKP, alkaline phosphatase; INR, international normalized ratio; PLT, platelet.
26
Table 4. Demographics of sporadic acute hepatitis E with and without liver failure Without Liver Failure
With Liver Failure P
Variables N=591
N=89 53.8±13.6
0.368
Sex 496 (83.9%)
78(87.6%)
Female
95(16.1%)
11(12.4%)
SC R
Male
Rural
254(43.0%) 39(6.6%)
Underlying liver diseases
175(29.6%)
CC E
Liver cirrhosis
PT
Anti-HCV positive
Days of stay in hospital
0.006
62(69.7%)
<0.001
89(15.1%)
37(41.6%)
<0.001
4(0.68%)
1(1.1%)
0.38
40(6.8%)
24(27.0%)
<0.001
29.2±14.9
32.2±28.0
0.128
ED
HBsAg positive
49(55.0%) 15(16.9%)
M
Type 2 diabetes
40(45.0%)
N
337(57.0%)
A
Urban
0.033
U
Residence
Data are expressed as mean±SD or n (%) of patients; .
A
NOTE.
0.025
IP T
50.5±12.6
Age (years)
27
Table 5. Symptoms， Signs, and Complications of sporadic acute hepatitis E with and without liver failure Without Liver Failure
With Liver Failure P
Variables N=89
IP T
N=591 142(24.0%)
32(36.0%)
Fatigue
498(84.3%)
84(94.4%)
Loss of appetite
497(84.1%)
73(82.0%)
0.621
Jaundice
542(91.7%)
102(100%)
0.005
Ascites
36(6.1%)
Hepatic encephalopathy
2(0.34%)
Cholestasis
52(8.8%)
Mortality
2(0.34%)
0.016 0.011
43(48.3%)
<0.001
48(53.9%)
<0.001
5(5.6%)
0.305
36(40.4%)
<0.001
ED
M
A
N
U
SC R
Prodromal fever
A
CC E
PT
NOTE. Data are expressed n (%) of patients.
28
Table 6. Biochemical Data in of sporadic acute hepatitis E with and without liver failure Without Liver Failure
With Liver Failure P
Variables N=591
N=89
731(21-6270)
571(8-6226)
0.075
AST(IU/L)
307(17-3904)
242(22-6226)
Bilirubin(µmol/L)
179(8-956)
506(77-1083)
Albumin(g/L)
33.6(18-45.8)
30.2(15.2-39.0)
<0.001
GGT(IU/L)
169(10-3784)
87(17-508)
<0.001
AKP(IU/L)
158(49-2369)
INR
1.11(0.81-41.9)
PLT(×109/L)
175(10-589)
2.19(1.11-25.4)
<0.001
108(23-279)
<0.001
N A
<0.001
0.012
142(47-474)
M
0.827
U
SC R
IP T
ALT(IU/L)
ED
NOTE. Data are expressed as median (min-max) of patients. ALT, alanine aminotransferase; AST, aspartate transaminase; GGT,
A
CC E
PT
gamma-glutmyltransferase; AKP, alkaline phosphatase; INR, international normalized ratio; PLT, platelet.
29
Table 7. Risk factors associated with liver failure in patients with sporadic acute hepatitis E: Multivariate logistic regression Variables
Odds ratio
95%CI
P
No
1(reference)
Yes
2.5
Prodromal fever 1(reference)
Yes
1.9
2.0-6.7
<0.001
1.1-4.2
0.025
3.3-10.4
<0.001
N
0.02
1(reference)
M
No
3.7
ED
Yes
CC E
PT
Liver cirrhosis
Yes
1.1-3.2
A
HBsAg
No
U
No
0.01
SC R
1.5-4.3
IP T
Age>53yesrs
1(reference) 2.1
Platelet<150×109/L
A
No
Yes
1(reference) 5.9
NOTE: multivariate logistic regression adjusted for age, type 2 diabetes, prodromal fever, fatigue, liver cirrhosis, HBsAg, and platelet
30
Table 8. Risk factors associated with death in sporadic acute hepatitis E: Multivariate logistic regression Variables
Odds ratio
95%CI
P
No
1(reference)
Yes
7.2
Bilirubin>500µmol/L 1(reference)
Yes
5.8
7.9-73.3
<0.001
3.6-32.9
<0.001
N
0.002
1(reference)
M
No
24.1
1(reference) 10.8
CC E
PT
PLT<100×109/L
ED
Yes
Yes
1.9-17.2
A
INR>2
No
U
No
<0.001
SC R
2.4-21.8
IP T
Hepatic encephalopathy
NOTE: multivariate logistic regression adjusted for,HBsAg, liver cirrhosis, hepatic encephalopathy, bilirubin, INR, and PLT. INR, international
A
normalized ratio; PLT, platelet.
31
Table 9. Features of sporadic acute hepatitis E from urban or rural areas Urban
Rural P
Variables N=377
N=303
Age (years)
51.2±12.9
50.6±12.6
Male
313(83.0%)
261(86.1%)
Type 2 diabetes
37(9.8%)
Underlying liver diseases
121(32.1%)
HBsAg positive
57(15.1%)
Liver cirrhosis
29(7.7%)
SC R
IP T
Demographics 0.579 0.266 0.044
116(38.3%)
0.092
U
17(5.6%)
0.011
35(11.2%)
0.087
11.8±8.4
15.4±9.3
<0.001
343(91.0%)
288(95.0%)
0.041
32(8.5%)
47(15.5%)
0.004
Hepatic encephalopathy
20(5.3%)
30(9.9%)
0.022
Liver Failure
40(10.7%)
49(16.2%)
0.033
Acute liver failure
10 (2.7%)
18(5.9%)
0.032
Acute-on-chronic liver failure
30(8.0%)
31(10.2%)
0.302
Mortality
14(3.7%)
24(7.9%)
0.018
M
Days from disease onset to hospital
A
N
69(22.8%)
ED
admission
Jaundice
A
CC E
Ascites
PT
Complications and outcome
Biochemical Data 32
890(8-6270)
576(25-6226)
<0.001
AST(IU/L)
341(17-5022)
234(29-6226)
0.028
Bilirubin(µmol/L)
179(8-957)
228(9.3-1083)
<0.001
Albumin(g/L)
34(17.3-45.8)
32.2(15.2-45.4)
<0.001
INR
1.14(0.81-41.9)
1.16(0.87-25.4)
0.148
PLT(×109/L)
165(10-510)
160(23-589)
Thrombocytopenia
141(37.4%)
137(45.2%)
SC R
Data are expressed as mean±SD or median (min-max) o or n (%) of patients; .
0.145 0.039
A
CC E
PT
ED
M
A
N
U
NOTE.
IP T
ALT(IU/L)
33