Multiple bacterial infections increase the risk of hepatic encephalopathy in patients with cirrhosis
Multiple bacterial infections increase the risk of hepatic encephalopathy in patients with cirrhosis
Lan-Ting Yuan 0 1 2
Seng-Kee Chuah 0 2
Shih-Cheng Yang 0 2
Chih-Ming Liang 0 2
Cheng- Kun Wu 0 2
Wei-Chen Tai 0 2
Tsung-Hsing Hung 0 2
Seng-Howe Nguang 0 2
Jiunn-Wei Wang 0 2
Kuo-Lun Tseng 0 2
Ming-Kun Ku 0 2
Pin-I Hsu 0 2
Deng-Chyang Wu 0 2
Chien-Ning Hsu 0 2
0 Abbreviations: CI , Confidence interval; H. pylori, Helicobacter pylori; HE, Hepatic encephalopathy; ICD-9-CM , International Classification of Diseases
1 Division of Gastroenterology, Yuan General Hospital , Kaohsiung, Taiwan , 2 Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan , 3 Chang Gung University, College of Medicine, Kaohsiung, Taiwan, 4 Division of Hepatogastroenterology, Department of Internal Medicine, Buddist Tzu Chi General Hospital , Dalin Branch, Chia-Yi, Taiwan , 5 Division of Gastroenterology, Pin-Tung Christian Hospital , Pin-Tung, Taiwan , 6 Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University , Kaohsiung, Taiwan , 7 Division of Gastroenterology, Kaohsiung Municipal TaTung Hospital , Kaohsiung, Taiwan , 8 Division of Gastroenterology, Cishan Hospital , Kaohsiung, Taiwan , 9 Division of Gastroenterology, FooYin University Hospital , Pin-Tung, Taiwan , 10 Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, National Yang-Ming University , Kaohsiung, Taiwan , 11 Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan , 12 School of Pharmacy, Kaohsiung Medical University , Kaohsiung , Taiwan
2 Editor: Gianfranco D. Alpini, Texas A&M University , UNITED STATES
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Patients with liver cirrhosis (LC) are at increased risk for bacterial infections. It is not fully
understood how exposure to infections induces further development of hepatic
encephalopathy (HE). This study estimated risks of infection associated with HE among patients with
A nested case-control study of 14,428 adult patients with LC was performed using the
population-based Longitudinal Health Insurance Database 2000 in Taiwan. Cases were cirrhotic
patients who developed HE during follow-up. Controls were matched to each case by age at
LC diagnosis (±2 years), sex, Charlson Comorbid index score, year of LC, and follow-up time
with a 1:1 ratio. A multivariate logistic regression model was used to determine and compare
the odds of developing HE based on exposure to various risk factors, including site of
infection, cirrhosis-related complications, Helicobacter pylori eradication therapy, and peptic ulcer
bleeding. Patient survival was evaluated using the time-dependent Cox regression model.
Cirrhotic patients with HE (n = 714) and without HE (n = 714) were matched to compare
risks. Infections and more frequent yearly infections were significantly associated with
Ninth Revision, Clinical Modification; LC, liver
cirrhosis; LHID 2000, Longitudinal Health
Insurance Database 2000; NHI, National Health
Insurance; OR, Odds ratio; PPI, Proton pump
inhibitor; SBP, Spontaneous bacterial peritonitis;
UTI, urinary tract infections.
increased risk of HE. Independent predictors of HE included spontaneous bacterial
peritonitis (aOR, 5.13; 95% CI, 3.03±8.69), sepsis (aOR, 2.54; 95% CI, 1.82±-3.53), and
biliary tract infection (aOR, 2.03; 95% CI, 1.2±3.46), controlling for confounders.
Frequent infections are associated with increased risk of HE in cirrhotic patients. More
frequent exposure to infection increases the risk of HE and mortality rates. Appropriate
prevention of infection and the use of antibiotics for cirrhotic patients at risk for HE are needed.
Hepatic encephalopathy (HE) is a commonly encountered complication in cirrhotic patients
with advanced liver disease or portosystemic shunts. The incidence of HE ranges from 2% to
20% per year in patients with liver cirrhosis.[1±3] HE is associated with increased morbidity
and mortality as well as significant utilization of health care resources.[4±6] Identifying risk
factors for HE would be paramount for implementing preventive measures to improve overall
outcomes for cirrhotic patients. When HE is diagnosed, underlying precipitating factors
should be sought and treated first. Common culprits include gastrointestinal bleeding,
infection, constipation, excessive dietary protein, hypovolemia, shock, hypokalemia, alkalosis,
surgical portosystemic shunts or transjugular intrahepatic portosystemic shunts, hyponatremia,
and medications such as opiates and benzodiazepines.[
HE is a reversible neuropsychiatric condition, and elevated ammonia level in the serum has
been considered the primary pathophysiologic cause. It is widely accepted that ammonia is
derived primarily from enteric bacterial flora.[
] Bacterial infection is present at admission
(community-acquired infections) or develops during hospitalization in patients with liver
cirrhosis (nosocomial and health care±related infections), and it occurs in more than 50% of
hospitalized cirrhotic patients.[
] Spontaneous bacterial peritonitis (SBP), urinary tract infections
(UTI), pneumonia, and cellulitis are the most frequent infections among cirrhotic patients in
] Furthermore, ammonia toxicity is greatly attributed to fecal bacteria.
Helicobacter pylori (H. pylori) in the stomach hydrolyzes urea and converts it to ammonia,
which can be rapidly absorbed and increases blood ammonia concentrations in H. pylori–
infected patients with cirrhosis.[10±12] However, ammonia levels are not related to severity of
HE. Whether eradication therapy for H. pylori–infected patients can lower ammonia levels
and the risk of HE development remains inconclusive.[
Infections in cirrhotic patients are detrimental to hepatic functions and increase mortality
fourfold.[15±17] To date, there is not enough empirical evidence of risk factors for HE in
cirrhotic patients to support a prevention strategy for HE. To determine the independent effect
of infections on the development of HE, we used a nested case-control design to avoid
incorrect sampling of cases and controls and compared individual infections according to system
Materials and methods
The study was reviewed and approved by the Institutional Review Board and Ethics
Committee of Chang Gung Medical Foundation in Taoyuan, Taiwan (IRB #201601548B1). All
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personal identifying information for patients was anonymized; therefore, the need for
informed consent was waived for the study.
Data were extracted from the Longitudinal Health Insurance Database 2000 (LHID 2000) of 1
million individuals who were randomly sampled from the year 2000 Registry for Beneficences
of 23.75 million individuals involved in Taiwan's National Health Insurance (NHI) program.
] The Taiwan NHI is a single-payer health insurance program that covers 99.9% of Taiwan's
population. The LHID 2000 contains demographic information, diagnostics, medical
treatments, prescriptions, and total costs from January 1, 1997 to December 31, 2012. Data
analysts were staff members of the Center for Medical Informatics and Statistics at Kaohsiung
Medical University, a site of the Application of Health and Welfare Informatics of the Ministry
of Health and Welfare in Taiwan.
Study design and population
The population-based case study involved a cohort of patients aged older than 18 years with a
hospital discharge diagnosis of liver cirrhosis (LC) (International Classification of Diseases,
9th edition [ICD-9], codes 571.5, 571.2, 571.6) recorded in the LHID 2000 between 1997 and
2012 (Fig 1). The study index date was defined as the date of the first ICD-9 code for LC was
assigned. Patients were excluded if they had prior peptic ulcer disease (ICD-9 531, 532, 533,
534), malignancy (140±239), HE (572.2), ever underwent a transjugular intrahepatic
portosystemic shunt procedure (33113A, 3313B), or had infections including antimicrobial
combination therapy or a diagnosis of H. pylori (041.86), pneumonia (481±487), spontaneous bacterial
peritonitis (SBP) (567.2, 567.8, 567.9), sepsis (038, 020.0, 790.7, 112.81), UTI (590.1, 595.0,
595.9, 599.0), biliary tract infection (574.00, 574.01, 574.1, 574.30, 574.31, 574.4, 574.60,
574.61, 574.80, 574.81, 576.1, 575.0), cellulitis (681, 682, 728.86), inflammatory disease of the
central nervous system (324, 320), septic arthritis (711), endocarditis (421), perianal abscess
(566), or liver abscess (572.0) recorded as both inpatient and outpatient claims within 365 days
before the index date. H. pylori infection and eradication triple or quadruple therapy was
defined as proton-pump inhibitor (PPI) or histamine type 2 receptor antagonists (H2RA) plus
clarithromycin or metronidazole plus amoxicillin or tetracycline, with or without bismuth for
All patients were followed from the first date of LC until death, withdrawal from the NHI
program, or the last date used for the dataset (December 31, 2012). Patients in the case group
who developed overt HE with more severe symptoms (Grade III-IV) requiring hospital
admission for treatment during the follow-up period were defined by an ICD-9 code (572.2) for HE
at hospital discharge.[
] For controls, the LC group without HE during follow-up was
identified and subsequently matched to each HE case. The 1:1 exact matching for age at the
index date within a 2-year difference, sex, and propensity score (including age at the index
date, sex, Charlson comorbidity index [CCI] score, year of the index date, and length of
follow-up in months) was performed for cases and controls.
Patients' demographic information, time at HE diagnosis, length of follow-up, comorbidities,
liver diseases, and liver transplantation (LT) (ICD9, V427) were identified within 365 days
prior to the index date. Comorbidities were assessed by the CCI using ICD-9 codes with at
least two records from inpatient, emergency, and outpatient claims. Prevalent liver diseases
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Fig 1. All-cause mortality among cirrhotic patients by frequency of infection episodes.
were hepatitis B virus (HBV) infection (070.2, 070.3, V0261), hepatitis C virus (HCV) infection
(070.41, 070.44, 070.51, 070.54, 070.70, 070.71, V0262), other viral hepatitis (V0269),
alcoholrelated liver disease (ALD) (571.0±571.3), decompensated cirrhosis with esophageal variceal
bleeding (456.0, 456.20, 530.82), ascites (789.5, 567.2,567.8, 567.9, ICD-9 procedure 54.91),
and others such as jaundice (782.4), portal hypertension (572.3), hepatorenal syndrome
(572.4), other sequelae of chronic liver disease (572.8), and hepatic cellular carcinoma (HCC)
(1550) within 1 year before the index date.
During follow-up, ICD-9 codes for infections recorded on inpatient claims were obtained.
To investigate the dose relationship between infection and HE risk, the number of infections
during hospitalization was categorized as 0, 1±3, and more than 3. Undergoing endoscopy for
upper gastroenterology bleeding (billing code 47043B with the exclusion of ICD-9 44.43) and
developing HCC and decompensated cirrhosis were accounted for by all-cause mortality
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Descriptive statistics and counts with proportions were presented as the mean (standard
deviation [SD]) for categorical data and as the median (25th-75th percentile) for continuous data.
Categorical variables were compared between groups using the χ2 test. Multiple logistic
regression models were used to calculate adjusted odds ratios (aOR) with 95% confidence intervals
(CI) for development of HE among cirrhotic patients. Model 1 included exposure to any
infection, model 2 included frequency of infection, and model 3 included individual infections. All
three models included patient demographic characteristics, CCI scores, H. pylori therapy
initiation, HCC, and decompensated cirrhosis development that may predispose to HE. The
timedependent Cox proportional hazards regression model was used to calculate the adjusted
hazard ratio (aHR) with 95% CI for all-cause mortality and accounted for potential time-varying
] The independent effect of HE in the model was adjusted according to
infection, patient demographic characteristics, CCI score, H. pylori therapy, HCC, and
decompensated cirrhosis development. The level of statistical significance was 5%, and a two-sided
P<0.05 was considered significant. All statistical analyses were performed using SAS software
version 9.4 (SAS Institute Inc., Cary, NC).
Baseline patient characteristics
In the study cohort, 6078 cirrhotic patients (42%) who ever had an infection before
development of HE were excluded (S1 Fig). The incidence of HE among patients with liver cirrhosis
was 11.3% (2136 of 18824 cirrhotic patients). The demographic characteristics of the LC
patients with and without HE are shown in S1 Table. Using the predefined matching criteria,
714 patients with HE during hospitalization (cases) and 714 randomly selected patients
without HE (controls) were analyzed. In the LC-matched cohort, the mean age was 55.74±13.35
years and 548 (76.75%) patients were male. The demographic characteristics of the
LCmatched cohort are shown in Table 1.
Ascertainment of risk factors
The potential risk factors for HE were categorized from the study index date to the first event
of HE during hospitalization. As shown in Table 2, a higher proportion of patients in the case
group (58.82%) than in the control group (30.81%) was exposed to any type of infection. H.
pylori infection (13.31% vs. 8.68%; p<0.01), pneumonia (14.99% vs. 10.50%; p = 0.01),
spontaneous bacterial peritonitis (SBP) or peritonitis (14.29% vs. 2.52%; p 0.001), sepsis (25.63% vs.
9.52%; p<0.001), UTI (18.77% vs. 11.20%; p<0.0001), biliary tract infection (7.14% vs. 3.22%;
p<0.001), and cellulitis (11.62% vs. 3.98%; p = 0.02) increased the risk of HE. Hospitalization
due to infection occurred for 6.44±42.26 of the case group and 0.87±1.27 of the control group.
Risk factors associated with hepatic encephalopathy
The proportion of the case group ever exposed to infection was higher than that of the control
group (69.19% vs. 41.18%; p<0.001). Tables 3 and 4 show risk factors associated with HE.
Infections were associated with hepatic encephalopathy development (aOR, 3.04; 95% CI,
2.44±3.78; p<0.0001). Compared to patients without any infection, patients with 1 to 3
episodes of any type of infection had approximately threefold odds of developing HE (aOR, 2.68;
95% CI, 2.13±3.37; p<0.001), and the odds increased for patients with more frequent
infections (aOR, 10.27; 95% CI, 5.17±20.4; p<0.001) when controlling for age at LC diagnosis,
gender, CCI score, and severity of liver diseases.
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LC, liver cirrhosis; CCI, Charlson comorbid index; SD, standard deviation; HCC, hepatic cellular carcinoma; PPI = proton pump inhibitors,
Case: patients with HE, control: patient without HE, Patient's comorbid conditions were identified within 1 year prior to the date of LC diagnosis
In model 3 (Table 4), an independent effect associated with HE development was observed
among patients who ever had SBP (aOR, 5.13; 95% CI, 3.03±8.69; p<0.0001), sepsis (aOR,
2.54; 95% CI, 1.82±3.53; p<0.0001), or biliary tract infection (aOR, 2.03; 95% CI, 1.20±3.46;
p = 0.009). Although UTI was associated with an additional 38% risk for HE, its effect did not
reach statistical significance in this study cohort.
Risk factors associated with all-cause mortality
The overall mortality rate was 43.1% (n = 615) for the matched study cohort and 76% for those
who ever had an infection before HE development. The overall survival rate was not
statistically different between patients with and without development of HE (48.6% vs. 37.54%;
P = 0.081) (S2 Fig)
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SBP, spontaneous bacterial peritonitis; LC, liver cirrhosis; SD, standard deviation; PUB, peptic ulcer bleeding, EV, esophageal varices;
The exposure of risk factors for hepatic encephalopathy was categorized from the date of LC diagnosis to the first event of hospitalized HE.
HE is one of the most debilitating complications of cirrhosis because it greatly affects society
and individual patients and their caregivers.[
] Bacterial infections are common in patients
with LC; however, the epidemiological features of infection associated with HE have not been
clearly demonstrated. In the present study, we found the following. First, infection was an
independent risk for HE, requiring hospitalization among cirrhotic patients. Second, more
frequent infections significantly increased the dose-response risk of HE development and
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H. Pylori therapy
SBP and unspecified peritonitis
Sepsis without infection focus
Urinary tract infection
Biliary tract infection
Age at LC, years
50±59 vs 49
60±69 vs 49
70 vs 49
Male vs Female
Prior to HE development
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mortality. In addition, prevalent infections such as SBP and unspecified peritonitis were strong
risk predictors of HE among cirrhotic patients.
Intestinal bacterial overgrowth is associated with higher ammonia production and higher
serum ammonia concentrations, resulting in the induction of encephalopathy through the
promotion of cerebral edema, modulation of the blood±brain barrier, and neuro-inhibition.
] The present population-based epidemiological study confirmed that prior to the
development of HE, cirrhotic patients with HE were more likely to have been exposed to infection
than those without HE (58.81 vs. 30.81%; p<0.0001). The significant predictive factors of HE
development for cirrhotic patients were SBP and unspecified peritonitis, sepsis, and biliary
tract infection. UTI (30%) and pneumonia (25%) were the common sites of infection among
cirrhotic patients, which is consistent with previous cirrhotic cohorts.[
] However, the
individual predictive value of HE was not confirmed in the present study cohort. When the intensity
of exposure to infection associated with HE development was examined, our data showed that
a subgroup of cirrhotic patients with 3 infectious episodes per year is at higher risk for HE
than those with fewer exposures.
More frequent exposure to infection ( 3 episodes per year) was a strong predictive factor
for all-cause mortality in cirrhotic patients. The adjusted morality (aHR, 1.03; 95% CI, 0.87±
1.22; p = 0.711) revealed no statistical difference between patients with and without HE.
Although the therapeutic effectiveness of cirrhotic encephalopathy needs further
investigations, these findings suggest that HE occurrence was not independent of survival outcome. In
the present study, effect of HE occurrence on overall mortality among cirrhotic patients was
assessed in time-dependent Cox model to justify cirrhosis complications that occurred before
end of the study period. Future applications in survival research, it is important to consider the
presence of competing events during follow-up, i.e. receiving liver transplantation, death on
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first HE event that might influence the results and interpretations in conventional Cox
proportional hazard model.
As previously reported, a history of infection in the past 12 months, advanced liver disease
(model of end-stage liver disease score 15), and diagnosis of malnutrition were independent
predictors of infection and sepsis.[
] The present study results support that routine screening
and identifying who is at risk for bacterial infections among hospitalized cirrhotic patients
would facilitate compliance with empirical antibiotic therapy and may prevent resistance and
The results of the present study support that H. pylori is more prevalent in cirrhotic patients
with HE than in those without HE (13.31% vs. 8.68%; p = 0.005); however, the administration
of standard combinations of H. pylori eradication regimens (22%) did not benefit HE
prevention (aOR, 1.34; 95% CI, 0.88±2.04; p = 0.178) after adjusting for other sites of infection and
deterioration of liver cirrhosis. It is worth noting that eradication of H. pylori was significantly
associated with a 28% lower risk of mortality for patients with liver cirrhosis. Similarly, Dasani
et al observed that symptoms in infected encephalopathic patients improved following H.
pylori eradication therapy.[
Based on these study results and previous evidence,[
] the beneficial effects of eradication
therapy for H. pylori are insufficient for recommending the use of this therapy in clinical
practice. Because there are geographic differences in the incidence and prevalence of H. pylori
infection and antimicrobial resistance and in the availability of medications and endoscopy,
cirrhotic patients with a history of peptic ulcer, gastric mucosa±associated lymphoid tissue
lymphoma, or history of endoscopic resection of early gastric cancer should be tested for H.
pylori infection and administered the most appropriate combination of antibiotic regimens
recommended in the clinical setting.[
Bajaj et al report the recent results of an open-label, randomized, standard of care (SOC)
controlled study using fecal microbiota transplantation (FMT) in patients with recurrent HE.
Twenty patients received a single FMT enema in combination with SOC and a 5-day antibiotic
pre-treatment or SOC-only were followed for 150 days. During the follow-up, none of the HE
episodes developed in the FMT group, compared with 5 (50%) in the SOC-only group.[
The FMT group had cognitive function improvement and a lower rate of serious adverse event
(20% vs 80%) than the SOC-only group. [
] Although FMT has shown promising results in
the treatment of overt HE, stronger evidence on efficacy, long-term safety and which patients
with HE should be considered are needed. A registry assessing short- and long-term patient
outcomes after FMT has been developed in this regard. [
A systematic review with meta-analysis synthesized 21 trials, 1420 participants and suggest
that probiotics has a beneficial effect on HE symptoms recovery (10 trials, 574 participants, RR
0.67, 95% CI 0.56±0.79) and development of overt HE (10 trials, 585 participants, RR 0.29,
95% CI 0.16±0.51) comparing to no intervention. [
] Serum ammonia level was lower (10
trials, 705 participants, mean difference -8.29 umol/L, 95% CI -13.7± -3.41) and slightly
imporved quality of life for pariticipants with probiotcs. There were no reliable difference
between probiotics and lactulose.[
] Considerable efforts of research in the field of gut
microbiota are needed for the future therapeutic use in overt HE.
The overall mortality rate was high among cirrhotic patients with HE (48.6% of matched
cases of HE and 51.26% of all HE cases) in the present study cohort, and 76% of them were
exposed to infection before HE development. The present findings support other studies that
have shown infections in cirrhotic patients with HE present additional risks of worsening
outcomes.[33±35] For example, acquisition of infection during the mild stage of HE was
significantly associated with progression to the advanced stage.[
] Moreover, recent reports have
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shown that bacterial infections were significantly associated with increased overall mortality
among patients with HE.[
Most previous studies regarding the influence of the microbiota on LC were highly diverse
in design and involved small numbers of patients in single-center settings.[
] One of the
strengths of the present study was its relatively large sample size derived from a
populationbased cohort, thus allowing for the investigation of independent associations between
individual sites of infection and HE development. The advantages of longitudinal data have enabled
us to further investigate the dose-response association between infection and risk of HE
To date, the mechanism that could further induce HE development and deterioration of
patient outcomes among those with LC remains unclear. Our data focusing on exposure to
infection and the probability of the first episode of HE have relevant clinical implications for
the detection and prevention of cirrhosis for high-risk patients. First, a synergistic effect of
infections is likely to be important in developing HE. Prior exposure to infection and
medication history is easy to obtain and should be identified during routine practice for those
cirrhotic patients at higher risk for HE.
In addition, recommended empirical therapy for bacterial infections should be closely
monitored and justified according to the prevalence of resistant pathogens.[
prophylactic therapy strategies are recommended for patients with previous episodes of SBP and variceal
] Studies focusing on who will benefit from prevention of the first HE episode and
what should be included in the standard of care therapy are needed. Despite the diverse range
of bacterial pathogens, it has been suggested that interactions between gut microbiota, etiology
of chronic LC, and host-related precipitating factors (e.g., malnutrition, low protein ascites
<1.5 g/dL, and alcohol consumption)[
] should be incorporated into an algorithm for
standard of care therapy.[
It is worthy to noting that acute kidney injury (AKI) is a recognized mortality predictor in
cirrhotic patients with infection. The 30-day mortality was 10-fold higher in cirrhotic patients
admitted with infection who developed AKI than those who did not. Advancing stages of AKI
in cirrhotic patients were associated with a higher incidence of bacteremia, pneumonia and
UTI, and cirrhosis-related encephalopathy and spontaneous bacterial peritonitis (SBP). [
For caring cirrhotic patients with infection, factors associated with worsening HE should
be identified and closely monitored, including diuretic therapy and hypokalemia which may
facilitate the conversion of ammonium (NH4) to ammonia (+NH3) and lead to acute mental
] Furthermore, due to kidney involved both excretion and production of
ammonia, early detection of hypovolemia and AKI, and prevention of patients affected by this
disease (e.g., infection, diuretic therapy) are imperative to better survival outcome.[
This study was subject to certain limitations common to studies using claims data. First,
laboratory results regarding the severity of LC and index HE are not available in the NHI
dataset. Using the liver disease diagnosis as a proxy for the presence of decompensated cirrhosis
(esophageal varices bleeding, ascites) at baseline and during years of follow-up can minimize
the potential bias when estimating risk factors for the development of HE. In addition, there is
a lack of bacterial culture results to determine microbial diversity and the effects of
antimicrobial therapy for HE. We used the advanced stage HE diagnosis at hospital discharge, which
could underestimate the incidence of mild infections without hospitalization; however, it
ensured diagnostic infection specificity. Furthermore, other unmeasured or unknown health
factors for HE development, including actual alcohol use, dietary protein intake, and
medication use, among cirrhotic patients may result in a biased estimate of exposure to infection, thus
limiting the generalizability of the current study results to different cirrhotic populations.
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In conclusion, bacterial infections, especially SBP and unspecified peritonitis, sepsis, and
biliary tract infection, are common and important predictors of the development of HE.
Furthermore, a dose-response effect associated with an increased risk of HE highlights the need to
promote appropriate infection prevention strategies and the use of antibiotic therapy for
cirrhotic patients with different precipitating risks for HE. Additional research is needed
regarding the associations between antibiotic therapy and the occurrence of HE or changes in its
S1 Fig. Schematic flowchart of study design.
S2 Fig. All-cause mortality among cirrhotic patients by occurrence of hepatic
S1 Table. Baseline characteristics of cirrhotic patient cohort before matching.
The authors thank Professor Yi-Hsin Yang and the staff of the Center for Medical Informatics
and Statistics at Kaohsiung Medical University, a site of the Application of Health and Welfare
Informatics, Ministry of Health and Welfare, in Taiwan for their suggestions and help with
Conceptualization: Lan-Ting Yuan, Seng-Kee Chuah, Chien-Ning Hsu.
Data curation: Seng-Kee Chuah, Shih-Cheng Yang, Chih-Ming Liang, Cheng-Kun Wu,
WeiChen Tai, Tsung-Hsing Hung, Seng-Howe Nguang, Jiunn-Wei Wang, Kuo-Lun Tseng,
Ming-Kun Ku, Pin-I Hsu, Deng-Chyang Wu, Chien-Ning Hsu.
Formal analysis: Chien-Ning Hsu.
Investigation: Seng-Kee Chuah, Shih-Cheng Yang, Chih-Ming Liang, Cheng-Kun Wu,
Methodology: Chien-Ning Hsu.
Project administration: Seng-Kee Chuah, Pin-I Hsu, Deng-Chyang Wu.
Resources: Shih-Cheng Yang, Chih-Ming Liang, Cheng-Kun Wu, Wei-Chen Tai,
TsungHsing Hung, Seng-Howe Nguang, Jiunn-Wei Wang, Kuo-Lun Tseng, Ming-Kun Ku, Pin-I
Hsu, Deng-Chyang Wu.
Supervision: Chien-Ning Hsu.
Validation: Seng-Kee Chuah, Shih-Cheng Yang, Chih-Ming Liang, Cheng-Kun Wu,
WeiChen Tai, Tsung-Hsing Hung, Seng-Howe Nguang, Jiunn-Wei Wang, Kuo-Lun Tseng,
Ming-Kun Ku, Pin-I Hsu, Deng-Chyang Wu.
Visualization: Shih-Cheng Yang, Chih-Ming Liang, Cheng-Kun Wu, Wei-Chen Tai,
Hsing Hung, Seng-Howe Nguang, Jiunn-Wei Wang, Kuo-Lun Tseng, Ming-Kun Ku.
12 / 14
Writing ± original draft: Lan-Ting Yuan.
Writing ± review & editing: Seng-Kee Chuah, Pin-I Hsu, Deng-Chyang Wu, Chien-Ning
13 / 14
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