Clinical Features of Hepatitis C Virus-Related Acute-On-Chronic Liver Failure in a Korean Population

Acute-on-chronic liver failure (ACLF) is a widely recognized concept in which acute decompensation (AD) in patients with cirrhosis results in organ failures and high short-term mortality. However, few studies reecting the various etiologies of cirrhosis are available. We aimed to investigate the clinical features of patients with hepatitis C virus (HCV)-related ACLF.

In patients with HCV-related ACLF, the prevalence of liver failure was very low (17.1%), whereas that of kidney failure was very high (71.4%) compared to previous studies on hepatitis B virus-related ACLF and alcohol-related ACLF. Compared with all other prognostic scores, Chronic liver failure Consortium Organ Failure score most accurately predicted 90-day mortality, with an area under the receiver operator characteristic of 0.921.

Conclusions
HCV-related ACLF has unique clinical characteristics that are distinct from hepatitis B virus-related and alcohol-related ACLF. ACLF de ned by EASL can be useful in predicting short-term mortality in HCVrelated cirrhosis.

Background
Acute-on-chronic liver failure (ACLF) is a recently increasingly recognized syndrome in which acute decompensation (AD) leads to rapid liver and extra hepatic organ failure associated with high short-term mortality in patients with chronic liver disease [1][2][3][4]. Patients with ACLF have 28-day mortality rates of approximately 30% and 90-day mortality rates in exceeding 50% [5][6][7].
However, there is no diagnostic criteria for ACLF globally. Recently, two de nitions of ACLF proposed by the Asian Paci c Association for the Study of the Liver (APASL) and the European Association for the Study of the Liver (EASL) are currently widely accepted. APASL-ACLF was de ned rst in 2009 as a rapid deterioration manifesting as jaundice (serum bilirubin ≥5 mg/dL) and coagulopathy (prolonged international normalized ratio (INR) ≥1.5) complicated by clinical ascites and/or hepatic encephalopathy (HE) in patients with previously known or unknown chronic liver disease [6]. In contrast, the EASL-ACLF, from the CANONIC study, was de ned as AD (HE, gastrointestinal (GI) hemorrhage, ascites, or bacterial infection) in pre-existing cirrhosis patients followed by the development of multi-system organ failures [5].
Another important problem beyond the ongoing controversies surrounding diverse ACLF de nitions is that the data that have been studied do not re ect the various causes of cirrhosis. The de nition of APASL-ACLF was derived from a cohort consisting of patients predominantly infected by hepatitis B virus (HBV), whereas in the EASL-ACLF cohort, nearly 60% of patients had alcoholic liver disease.
Subsequently, the Chinese Group on the Study of Severe Hepatitis B (COSSH) developed a new de nition for HBV-related ACLF [8]. The Korean Acute-on-Chronic Liver Failure study cohort was proposed in cirrhosis patients from Korea, but this study had a population rate of alcoholic liver disease in excess of 60% [7,9]. Lee et al. recently investigated the ability of chronic liver failure sequential organ failure assessment (CLIF-SOFA) to predict short-term mortality in patients with alcohol-related ACLF [10].
However, to date, no studies have included patients with hepatitis C virus (HCV)-related ACLF. Therefore, we sought to identify the clinical features of patients of HCV-related ACLF in Korea, an HBV endemic area.

Study population
This retrospective cohort study included 1743 patients with HCV infection who visited the Gyeongsang National University Changwon Hospital and Gyeongsang National University Hospital from January 2005 to December 2018. The exclusion criteria were as follows: (1) a follow-up period of less than 6 months (n = 273); (2) presence of hepatocellular carcinoma (n = 143); (3) presence of extrahepatic malignancy or severe extrahepatic disease (n = 37); (4) HBV co-infection (n = 53); (5) human immunode ciency virus infection co-infection (n = 5); and (6) acute HCV infection (n = 10). Among the remaining 1222 patients with chronic hepatitis C, 1008 without cirrhosis and 214 with cirrhosis were initially analyzed for ACLF using the APASL criteria (total bilirubin ≥ 5 mg/dL and INR ≥ 1.5), applied to patients with chronic liver disease with or without cirrhosis. To apply the EASL-ACLF, after excluding 1008 patients without cirrhosis and 105 patients without AD events as de ned by the acute development of overt ascites, HE, GI hemorrhage, and bacterial infection, 109 patients with cirrhosis who developed AD were nally analyzed (Fig. 1). The study was approved by the Institutional Review Boards of Gyeongsang National University Changwon Hospital and Gyeongsang National University Hospital. The need for informed consent was waived due to the retrospective design of this study, as determined by the Institutional Review Boards of Gyeongsang National University Changwon Hospital and Gyeongsang National University Hospital.

Data collection and de nition
We collected data from the medical charts, including patient demographics, clinical and laboratory data on admission, types of AD events and organ failures, potential precipitating factors of AD and ACLF, and development of ACLF. Potential precipitating factors included bacterial infection, GI hemorrhage, active alcoholism, large volume paracentesis without albumin, transjugular intrahepatic portosystemic shunting, major surgery, hepatitis (including reactivation of viral hepatitis and toxic liver injury), and alcoholic hepatitis. Active alcoholism was de ned as > 14 drinks per week in women and > 21 drinks per week in men within the last three months [5]. AD events were de ned as acute onset of HE, ascites, GI hemorrhage, bacterial infection, or any combination of theses. Organ failure was de ned according to a modi ed CLIF Consortium Organ Failure score (CLIF-C OFs) [11], which is a simpli ed modi cation of the CLIF-SOFA score and entails the following: liver failure, de ned as total bilirubin level of ≥12 mg/dL; kidney failure, de ned as serum creatinine level of ≥2.0 mg/dL and/or requiring renal replacement therapy; cerebral failure, de ned as grade III or IV HE based on West Haven criteria; coagulation failure, de ned as INR > 2.5; circulation failure, de ned as treatment with vasoconstrictors to maintain the arterial blood pressure or inotropes to improve cardiac output; and respiratory failure, de ned as PaO 2 /FiO 2 ≤ 200 or SpO 2 /FiO 2 ≤ 214.
According to the EASL-ACLF criteria, the severity of ACLF was graded into ACLF grade 1 (ACLF-1), ACLF grade 2 (ACLF-2), or ACLF grade 3 (ACLF-3) according to the number of organ failures. ACLF-1 was de ned by the presence of a single kidney failure or any other organ failure when in combination with either kidney dysfunction (serum creatinine ranging 1.5 to 1.9 mg/dL) or grade I or II HE. ACLF-2 or 3 was de ned by the presence of 2 or ≥3 organ failures, respectively. We assessed the ACLF and ACLF grades, as de ned above, by investigating for any association of organ failure at admission.

Prognostic score
The performance of CLIF-C OFs in evaluating prognosis was comparable to that of the CLIF-SOFA score [11]. To predict short-term mortality in cirrhosis patients with AD, we compared the performance of CLLF-C OFs with that of Child-Pugh-Turcotte (CTP) scores, model for end-stage liver disease (MELD) score and MELD-sodium (MELD-Na) score. In addition, the CLIF-C ACLF score (CLIF-C ACLFs) was used to predict short-term mortality in ACLF patients [11], and the CLIF-C AD score (CLIF-C ADs) was used in AD patients without ACLF [12].

Statistical analysis
Fisher's exact and Pearson's chi-square tests to analyze the qualitative data and the Mann-Whitney U test to analyze the quantitative data were performed to assess the association between patient characteristics and ACLF at admission. Survival rates for the development of 90-day survival were estimated by the Kaplan-Meier method and compared using the log-rank test. The accuracy of the CLIF-OFs, CTP score, MELD score, and MELD-Na score in predicting survival was assessed by area under the receiver operating characteristic (AUROC) curve. A P-value < 0.05 was considered statistically signi cant for all analyses. All statistical operations were performed using PASW Statistics, version 18 (SPSS Inc., Chicago, IL, USA).

Patient characteristics
Patients with non-cirrhotic chronic hepatitis C did not exhibit ACLF as de ned by APASL (total bilirubin ≥ 5 mg/dL and INR ≥ 1.5). Thus, the EASL-ACLF criteria were chosen to de ne ACLF in this study. The baseline characteristics of 109 patients with HCV-related cirrhosis are shown in Table 1. Of cirrhosis patients with AD, ACLF developed in 35 patients (32.1%) on admission. Eight patients (7.3%) had ACLF-1, eight (7.3%) had ACLF-2, and 19 (17.4%) had ACLF-3. There was no signi cant difference in age, sex, HCV genotype, and sustained virologic response rate between patients with and without ACLF. Overt ascites was the most common type of AD, followed by bacterial infection, GI hemorrhage, and HE. GI hemorrhage, bacterial infection, and HE were more frequent in patients with ACLF than in patients without ACLF. History of AD was reported in 35 (32.1%) patients. Patients with ACLF more frequently had prior AD events. On admission, patients with ACLF had higher median white blood cell, total bilirubin, creatinine, and INR levels but lower median albumin and sodium levels than those without ACLF ( Table 2). Prognostic scores revealed that patients with ACLF had higher CTP scores, MELD scores, MELD-Na scores, and CLIF-OFs than those without ACLF.

Short-term mortality and prognostic scores
Kaplan-Meier curves of the probability of survival revealed that patients with ACLF had poorer outcomes than those with AD ( Fig. 2A). Mortality at 28 days, 90 days, and 1 year for patients without ACLF was 2.7%, 5.4%, and 9.5%, respectively while mortality at 28 days, 90 days, and 1 year for patients with ACLF was 60.0%, 74.3%, and 80.0%, respectively (Fig. 2B). Mortality at 28 days and 90 days was 2.7% and 5.4% for patients without ACLF, 0% and 37.5% for those with ACLF-1, 75.0% and 87.5% for those with ACLF-2, and 78.9% and 89.5% for those with ACLF-3, respectively ( Supplementary Fig. 1). In the survival curve according to prior AD, there was a signi cant difference in the survival rates of patients with or without ACLF, but there was no signi cant difference in the survival rates of patients according to prior AD ( Supplementary Fig. 2). Multiple organ failure without septic shock or hypovolemic shock was the most common cause of death at 90 days (53.3%), followed by septic shock (20.0%) and hypovolemic shock (16.7%) (Supplementary Table 2).

Discussion
In this study of 109 patients with HCV-related cirrhosis who were hospitalized for AD (ascites, HE, GI hemorrhage, and/or bacterial infection), 28-day and 90-day mortalities were higher in patients with ACLF at admission than in those without ACLF (60.0% and 74.3% vs. 2.7% and 5.4%, respectively). In addition, the CLIF-C OFs were the most accurate in predicting 90-day mortality for HCV-related cirrhosis patients who had AD compared with the CTP score, MELD score, and MELD-Na score.
Among the various de nitions of ACLF, no studies have been conducted in a cohort consisting only of patients with HCV-related chronic liver disease. In our chronic hepatitis C cohort of 1222 patients, no patient met the de nition of APASL-ACLF (total bilirubin ≥5 mg/dL and INR ≥1.5) in patients without cirrhosis. There are very few episodes of acute are-ups in chronic hepatitis C patients, even in immunocompromised patients. [13] Therefore, non-cirrhotic HCV-ACLF rarely occurs in chronic hepatitis C without cirrhosis, unlike in non-cirrhotic HBV-ACLF [8,14,15]. This suggests that the APASL-ACLF criteria or COSSH criteria cannot be applied to patients with non-cirrhotic chronic hepatitis C. Among 109 HCVrelated cirrhosis patients, eight had EASL-ACLF and APASL-ACLF, 27 had EASL-ACLF alone, and two had APASL-ACLF alone. Therefore, the EASL-ACLF criteria detected more ACLF patients even in the setting of chronic hepatitis with cirrhosis. In a previous study using data from the Veterans Health Administration, the incidence of ACLF for patients with hepatitis C was higher in EASL-ACLF criteria than in APASL-ACLF [16]. In our study, patients with EASL-ACLF on admission had a signi cantly higher 90-day mortality rate than patients without EASL-ACLF. In particular, patients with ACLF-2 and ACLF-3 on admission had extremely high 90-day mortality (87.5% and 89.5%, respectively), while patients with no ACLF had very low 90-day mortality (5.4%). These suggest that EASL-ACLF is a very useful tool for predicting the prognosis in HCV-related cirrhosis patients who were hospitalized for acute deterioration. To our knowledge, our study is the rst study on HCV-related ACLF that does not contain ACLF of other etiologies.
HCV-related ACLF showed distinctive characteristics that distinguished ACLF from other causes. The 90day mortality for patients ACLF was highest in our study, composed of HCV-related ACLF (74.3%), compared with the COSSH study (HBV-related ACLF, 69.7%), [8] the Korean study (alcohol-related ACLF, 67.2%) [10], and the CANONIC study, composed of various etiologies (51.2%) [5]. Comparing the prevalence of organ failure, liver failure in HCV-related ACLF was very low (17.1%) compared to HBVrelated ACLF (93.7%) and the CANONIC study (43.6%) [5,8]. On the other hand, the prevalence of kidney failure in HCV-related ACLF was very high (71.4%) compared to that of HBV-related ACLF (14.0%) and the CANONIC study (55.8%). Therefore, ACLF in HCV-related cirrhosis may be associated with kidney failure rather than liver failure, which is thought to be associated with high short-term mortality. These suggest that the mechanism for HCV-ACLF probably re ects an extrahepatic insult, such as bacterial infection and GI hemorrhage, while the mechanism for HBV-ACLF probably re ects a hepatic insult, such as HBV are. In a recent large-scale retrospective cohort study in the United States, patients with hepatitis C had the lowest ACLF incidence rate but had the highest short-term mortality compared with patients with HBVrelated ACLF and alcohol-related ACLF [16].
CLIF-C OFs displayed the best prognostic ability for cirrhosis patients with AD (AUROC = 0.921, 95% CI 0.855-0.986) compared to the CTP score, MELD score, and MELD-Na score. CTP, MELD, and MELD-Na scores are based only on liver failure (bilirubin), kidney failure (creatinine), coagulation failure (INR), and cerebral failure (HE), whereas CLIF-C OFs additionally re ect coagulation and respiratory failure to predict the prognosis more effectively. The CLIF-SOFA score is a widely used tool in predicting short-term mortality in ACLF and AD patients and is superior to MELD score in predicting prognosis [10,14,17,18].
Our study showed that short-term mortality can be effectively predicted using CLIF-C OFs, a simpli ed modi cation of the CLIF-SOFA score.
This study had some limitations. First, this was a retrospective study with a relatively small sample size. We were unable to accurately access HE grade 1 and 2 for measuring CLIF-C OFs through a retrospective chart review. Second, we excluded patients who were lost to follow-up within six months after transferring to other hospitals for liver transplantation because our institute cannot perform liver transplantation.
Third, most HCV-infected patients in this study did not receive antiviral therapy because they were enrolled before the direct acting agent era or consisted of severe decompensated cirrhosis. Despite these limitations, the strength of our study is that it is the rst study to identify the clinical features of patients HCV-related ACLF, especially in Korea, an HBV endemic area.

Conclusion
Applying the EASL-ACLF de nition to patients with HCV-related cirrhosis can be useful in predicting shortterm mortality, consistent with previous studies conducted on the other etiologies. Additionally, HCVrelated ACLF has unique clinical features that are distinct from HBV-related or alcohol-related ACLF.

Declarations
Ethics approval and consent to participate The project was approved by the Institutional Review Board of Gyeongsang National University Changwon Hospital (IRB No. 2019-08-030) and Gyeongsang National University Hospital (IRB No. 2014-04-028). Informed consent was waived given that all of the personal data obtained were anonymized before analysis, as determined by the Institutional Review Boards of Gyeongsang National University Changwon Hospital and Gyeongsang National University Hospital. All methods in this study were performed in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration.

Consent for publication
Not applicable.
Availability of data and material  Mortality at 28 days, 90 days, and 1 year of patients without or with ACLF. Figure 3