Abstract
Background
The present study is planned to assess etiologies, course, and outcome in patients with acute-on-chronic liver failure (ACLF).
Methods
Two hundred and eight (182 males and 26 females) patients of ACLF fulfilling modified Asia Pacific Association For Study Of Liver Consensus criteria 2009 admitted to the gastroenterology department of SMS Medical College and hospital, Jaipur, between October 2015 and December 2017 were included. We evaluated etiology of underlying chronic disease and the acute event precipitating decompensation in ACLF.
Results
Most common etiology of chronic liver disease (CLD) was alcohol with 133 (63.94 %) patients. Viral hepatitis, cryptogenic cirrhosis, autoimmunity, nonalcoholic steatohepatitis, and Wilson disease as causes of CLD were present in 32 (15.4%), 29 (13.94%), 9 (4.3%), 3 (1.4%), and 2 (1%) cases, respectively. Alcohol, sepsis, bleeding, reactivation of hepatitis B, hepatitis E, antitubercular drugs, and autoimmune hepatitis as the causes of acute event were present in 100 (48.08%), 34 (16.35%), 19 (9.1%), 17 (8.2 %), 15 (7.2%), 13 (6.25%), and 2 (0.96%) patients, respectively. In 8 (3.85%) patients, the precipitating event could not be known. Mortality (in-hospital) in this study was 37.5%. Higher model for end-stage liver disease score and high Child-Turcotte-Pugh score score were significantly associated with mortality (P <0.001). Patients with higher ACLF grade were associated with higher mortality. Alcohol as a cause of CLD was significantly associated with mortality (p=0.0146, 95% confidence interval between 3.802 and 30.979). There was no significant difference regarding acute precipitating events between survivors and nonsurvivors.
Conclusions
Alcohol was the most common cause for chronic etiology as well as acute precipitating event. Alcohol as a cause of CLD was significantly associated with mortality.
Keywords: ACLF, alcohol, precipitating factor, chronic etiology
Abbreviations: AASLD, American Association for Study of Liver Diasease; ACLF, Acute on Chronic Failure; AD, Acute Decompensation; AMA, Antimitochondrial Antibody; ANA, Antinuclear Antibody; APASL, Asia-Pacific Association for Study of Liver disease; ASMA, Antismooth Muscle Antibody; CLD, Chronic Liver Diase; CLIF-SOFA, Chronic Liver Failure-Sequential Organ Failure Assessment; CTP, Child Turcotte Pugh; EASL, European Association for Study of Liver; HBV, Hepatitis B Virus; HCV, Hepatitis C Virus; HEV, Hepatitis E Virus; INR, International Normalization Ratio; MELD, Model for Endstage Liver Disease
Acute-on-chronic liver failure (ACLF) is an acute event associated with high mortality. This term was first used in 1995, and it is associated with 50–90% mortality.1 There is difference between working definitions of ACLF in European Association for Study of Liver (EASL) and American Association for Study Of Liver Disease (AASLD) and Asia Pacific Association For Study Of Liver (APASL). APASL in 2009 defined ACLF as “acute hepatic insult manifesting as jaundice (bilirubin >5 mg/dl) and coagulopathy (international normalized ratio [INR] > 1.5), complicated within 4 weeks by ascites and/or hepatic encephalopathy (HE) in a patient with previously diagnosed or undiagnosed chronic liver disease”.2 Second definition was given by EASL-AASLD single-topic symposium in 2013 as “acute deterioration of preexisting, chronic liver disease, usually related to precipitating event and associated with increased mortality at 3 months due to multisystem organ failure”.3 EASL-AASLD definition includes only cirrhosis, whereas APASL definition includes both cirrhosis and noncirrhosis. The EASL-AASLD definition includes both hepatic and extrahepatic precipitating events (such as sepsis and upper gastrointestinal bleeding), whereas the APASL definition includes only hepatic insult as precipitating events. Alcohol and drugs are the major precipitating events in the West; reactivation of hepatitis B virus infection is one of the major causes of ACLF in Asia.4, 5 In India, most common etiology of ACLF is ethanol with 42% overall in-hospital mortality.6 Superadded infection with hepatitis E virus (HEV) is a common cause of ACLF in India.7, 8, 9 One study from East India observed high mortality in ACLF when the precipitating factor for acute decompensation (AD) is alcohol.10 There are chances of regional differences for epidemiology of ACLF. The present study was planned to assess etiologies, course, and outcome in ACLF patients in the northwestern region of India.
Methods
A total of 213 (187 men and 26 women) consecutive patients of ACLF fulfilling modified APASL Consensus criteria 2009, admitted to the gastroenterology department of SMS medical college and hospital, Jaipur, between October 2015 and December 2017 were included and prospectively evaluated. The study was approved by the ethical committee of this institution. Patients with pregnancy, age <18 years, portal vein thrombosis, hepatocellular carcinoma, and unwillingness to participate in the study were excluded from the study protocol. Of 213 patients, on subsequent investigations, 2 patients were found to have hepatocellular carcinoma (HCC), 1 patient had portal vein thrombosis (PVT), 1 patient had HCC with PVT, and 1 patient was positive for human immunodeficiency virus (HIV). So these patients were excluded from the study. A total of 208 patients (182 men and 26 women) were finally included in the study. The presence of cirrhosis was diagnosed by clinical examination, biochemical and hematological parameters, radiological parameters, and upper gastrointestinal endoscopy. All causes for AD were searched in a particular patient. Although, in this study, we recruited ACLF patients defined by APASL criteria, we took both hepatic and extrahepatic causes as precipitating factors as studies from western literature, and few Indian studies had taken both causes as precipitating factors.6, 11 Data of the following variables were collected at the baseline: age, sex, clinical presentation, complete blood counts, liver function tests, kidney function tests, cause of hepatic decompensation, etiology of underlying chronic liver disease (CLD), and outcomes. To determine the etiology of acute insult and underlying CLD, a detailed history regarding alcohol consumption, drug intake, hematemesis, or melena whether previously diagnosed as chronic hepatitis B virus (HBV) or hepatitis C virus infection was taken. We took alcohol as acute precipitating factor according to APASL 2009 consensus (active drinking within the last 4 weeks).2 Each patient was tested for hepatitis B surface antigen, immunoglobulin M (IgM) hepatitis B core antibody, and IgM antibody against hepatitis A or E. Patients without significant history of alcohol intake and negative viral markers were tested for fasting blood sugar, HBA1C, antineutrophilic antibodies titer by immunofluorescence method, total immunoglobulin, anti–smooth muscle antibody, antimitochondrial antibody, IgA antibodies to tissue transglutamate (IgA anti-tTG). All patients were managed by a standard protocol. Patient prognostic scores (model for end stage liver disease [MELD] and Child-Turcotte-Pugh score [CTP]) were calculated. We analyzed and compared all parameters such as age, sex, chronic etiology of CLD, acute precipitating event, ascites, renal failure, HE, bilirubin, total leukocyte count, MELD and CTP score, and organ failure between those who survived and died. Organ failure was defined by chronic liver failure (CLIF)–sequential organ failure assessment score which included renal failure (serum creatinine ≥ 2 mg/dl), liver failure (serum bilirubin ≥12 mg/dl), cerebral failure (HE grade 3 or 4 as per West Heaven criteria), circulatory failure (patient requiring ionotropic support to maintain blood pressure), coagulation failure (INR ≥ 2.5 mg/dl), and respiratory failure (SpO2/FiO2 ≤ 200 or requiring mechanical ventilation).
All the results were expressed as mean ± standard deviation or frequency (in percent). Normally distributed quantitative and categorical variables were compared using student's t-test and chi-square test, respectively. Nonparametric unpaired data were compared using Mann–Whitney U-test. All the analyses were performed using SPSS 17 software. P-value of <0.05 was considered statistically significant.
Results
Of 208 patients, 182(87.5%) were male and 26(12.5%) were female. The mean age of patients was 43.57 ± 10.855 years. Mean hemoglobin was 8.91 ± 2.31 g/dl, mean total leukocyte count was 10.18 ± 5.75 ✕103/mm3, mean platelet count was 71673.92 ± 54471.37/mm3, and mean INR was 2.37 ± 0.84. Mean creatinine, mean bilirubin, and mean albumin were 1.28 ± 0.72 mg/dl, 10.52 ± 0.72 mg/dl, 2.48 ± 0.63 g/dl, respectively. Mean MELD score and mean CTP score was 26.56 ± 5.95 and 12.52 ± 1.83, respectively (Table 1). In-hospital mortality in this study was 37.5% at median of 4 days (IQR 2–9). Four patients left against medical advice and were lost to follow-up. There was no significant difference between male and female mortality. Most common etiology of CLD was alcohol which was present in 133 (63.94%) patients. Viral, cryptogenic, autoimmune, nonalcoholic steatohepatitis, and Wilson disease as causes of CLD were present in 32 (15.4%), 29 (13.94%), 9 (4.3%), 3 (1.4%), and 2 (0.96%) patients, respectively (Figure 1). Most common precipitating event was alcohol, and it was present in 100 (48.08%) patients. Sepsis, bleeding, reactivation of hepatitis B, acute hepatitis E, antitubercular drugs, and autoimmune hepatitis as causes of acute event were present in 34 (16.35%), 19 (9.13%), 17 (8.2%), 15 (7.21%), 13 (6.25%), and 2 (0.96%) patients, respectively (Figure 2). Among the causes of sepsis, the most common cause was spontaneous bacterial peritonitis (SBP) which was present in 15 (44.11%) patients. The other causes of sepsis were urinary tract infection (UTI) in 14 (41.17%), lower respiratory tract infection (LRTI) in 3 (8.8%), and cellulitis in 2 (5.88%) patients. Eight patients of SBP were associated with UTI, whereas one patient had LRTI with SBP. In 8 (3.85%) patients, the precipitating event was not known. Ionotropic support was needed in 47 (22.6%) patients. The varices were absent, small, and large in 39 (18.8%), 96 (46.2%), and 73 (35.1%) patients, respectively. HE was present in 142 (68.26%) patients; of which, 56 (26.92%) patients had grade 1 to 2 HE, whereas 86 (41.34%) patients had grade 3 to 4 HE. Ascites was present in 192(92.23%) patients. Patients having encephalopathy had higher chances of mortality (P < 0.001). Alcohol as a cause of CLD was significantly associated with mortality (p = 0.04, 95% confidence interval between 1.007 and 3.391). The relative risk of alcohol as a chronic etiologic agent was 1.35. No other chronic etiologic agent was associated with mortality (Table 3). No specific etiology for acute precipitation was associated with mortality. The presence of high creatinine, high bilirubin, high INR, low albumin, and low hemoglobin were significantly associated with mortality (p < 0.001, p < 0.001, p < 0.001, p = 0.016, and p = 0.022, respectively). Organ failure (renal, hepatic, cerebral, coagulatory, circulatory, respiratory) was significantly associated with mortality (<0.001). Higher MELD score and high CTP score was significantly associated with mortality (P < 0.001) (Table 2). Patients who died during this study were younger than the survivors (mean age 41.71 ± 9.93 years vs 44.96 ± 11.08 years, respectively, p = 0.035), and this was independent of alcohol as the chronic etiologic agent (p = 0.39). Those patients who survived had higher hemoglobin level and albumin concentration, and this was statistically significant (P = 0.022 and 0.016, respectively). When the CLIF-ACLF criteria was applied, 113 (54.33%), 6 (2.88%), 46 (22.12%), and 43 (20.67%) patients had grade 0, 1, 2, and 3 ACLF, respectively. Patients with a higher ACLF grade were associated with higher mortality rate (p= < 0.001) (Figure 3) (Table 4).
Table 1.
Baseline Parameters of Patients.
| Baseline parameters | Mean |
|---|---|
| Age (years) | 43.57 ± 10.85 |
| Hb (g/dl) | 8.91 ± 2.31 |
| TLC (per mm3) | 10.18 ± 5.75 |
| Platelet (per mm3) | 71581.47 ± 54978.49 |
| INR | 2.37 ± 0.84 |
| Creatinin (mg/dl) | 1.286 ± 0.721 |
| Bilirubin (mg/dl) | 10.52 ± 5.63 |
| SGOT | 164 ± 111.85 |
| SGPT | 103.41 ± 110.05 |
| Albumin (g/dl) | 2.48 ± 0.613 |
| SAP | 122.36 ± 91.17 |
| MELD | 25.56 ± 5.95 |
| CTP | 12.60 ± 1.73 |
Hb, hemoglobulin; TLC, total leukocyte count; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; SAP, serum alkaline phosphatase; MELD, model for end-stage liver disease; CTP, Child-Turcotte-Pugh score.
Figure 1.
Etiology of chronic liver disease. NASH, nonalcoholic steatohepatitis.
Figure 2.
Acute precipitating factors. HBV, hepatitis B virus; HEV, hepatitis E virus; ATT, antitubercular drugs; AIH, autoimmune hepatitis; GI, Gastro-intestinal.
Table 3.
Outcome in Patients With Relation to Chronic Etiology of ACLF.
| Chronic | Outcome | Total | p-value | 95% CI | |||
|---|---|---|---|---|---|---|---|
| Survived | Nonsurvived | ||||||
| No. | % | No. | % | ||||
| Alcohol | 71 | 56.35% | 58 | 74.36% | 129 | 0.0146 | 3.802–30.979 |
| Viral | 23 | 18.25% | 9 | 11.54% | 32 | 0.2790 | 4.481–16.679 |
| Autoimmune | 7 | 5.56% | 2 | 2.56% | 9 | 0.5073 | 4.19–8.995 |
| Wilson | 2 | 1.59% | 0 | 0% | 2 | 0.6975 | 3.236–5.62 |
| Others | 21 | 16.67% | 8 | 10.26% | 29 | 0.2857 | 4.396–15.985 |
| NASH | 2 | 1.59% | 1 | 1.28% | 3 | 0.6748 | 5.514–4.529 |
NASH, nonalcoholic steatohepatitis; ACLF, acute-on-chronic liver failure; CI, confidence interval.
Table 2.
Basic Parameters Between Survivors and Nonsurvivors.
| Baseline parameters | Survivors (n = 126) | Nonsurvivors (n = 78) | P value |
|---|---|---|---|
| Age (years) | 44.96 ± 11.08 | 41.71 ± 9.93 | 0.035 |
| CTP Score | 11.63 ± 1.42 | 14 ± 1.39 | <0.001 |
| AST | 164.93 ± 112.26 | 163.01 ± 103.51 | 0.903 |
| ALT | 103.82 ± 110.68 | 103.03 ± 108.70 | 0.960 |
| SAP | 126.14 ± 99.01 | 117.77 ± 79.32 | 0.528 |
| MELD | 23.57 ± 3.04 | 31.37 ± 6.38 | <0.001 |
| INR | 2.06 ± 0.32 | 2.83 ± 1.12 | <0.001 |
| Bilurubin (mg/dl) | 9.38 ± 4.52 | 12.59 ± 6.68 | <0.001 |
| Albumin (g/dl) | 2.56 ± 0.57 | 2.35 ± 0.64 | 0.016 |
| Hb (g/dl) | 9.26 ± 2.24 | 8.51 ± 2.29 | 0.022 |
| TLC (✕103/mm3) | 9.83 ± 5.4 | 10.82 ± 6.34 | 0.235 |
| Platelet (✕103/mm3) | 69.326 ± 56.893 | 75.280 ± 51.845 | 0.461 |
| Creatinin (mg/dl) | 1.04 ± 0.41 | 1.67 ± 0.91 | <0.001 |
| HE | 71/126 | 70/78 | <0.001 |
| Renal failure | 5 | 22 | <0.001 |
| Liver failure | 23 | 31 | <0.001 |
| Circulatory failure | 22 | 31 | <0.001 |
| Respiratory failure | 6 | 19 | <0.001 |
| Cerebral failure | 25 | 61 | <0.001 |
| Coagulatory failure | 18 | 44 | <0.001 |
CTP, Child-Turcotte-Pugh score; SAP, serum alkaline phosphatase; MELD, model for end-stage liver disease; Hb, hemoglobulin; TLC, total leukocyte count; HE, hepatic encephalopathy.
Figure 3.
ACLF grade with respect to mortality. ACLF, acute-on-chronic liver failure.
Table 4.
Higher ACLF Grade is Associated With Increased Mortality.
| ACLF Grade | Died | Survived | Total | P value |
|---|---|---|---|---|
| Zero | 10(8.85%) | 103(91.15%) | 113(100%) | <0.0001 |
| One | 4(66.67%) | 2(33.33%) | 6(100%) | |
| Two | 28(60.87%) | 18(39.13%) | 46(100%) | |
| Three | 36(83.72%) | 7(16.28%) | 43(100%) |
ACLF, acute-on-chronic liver failure.
Discussion
In this single center study, alcohol was found to be the most common cause of CLD as well as an acute precipitating factor. In-hospital mortality in this study was 37.5%. Both hepatic as well as extra hepatic insults as precipitating factor were included in this study. In the CANONIC study, the common precipitating factors for ACLF were bacterial infection (32.6%), gastrointestinal bleeding (13.2%), and active alcoholism (24.5%), and in 43.6% of patients, precipitating factors were not found.12 In another single-center study, alcohol (42.27%) was the most common cause for an acute precipitating event.10 In a multicentre study from India, alcohol was the most common etiology found in 35% patients, followed by sepsis (16.6%), hepatotrophic viruses (hepatitis B, A, and E [21.4%]), variceal bleed (8.4%), and drugs (5.7%).6 In our study, causes for precipitating factors were similar to this study except sepsis was more common and there was no hepatitis A virus (HAV) infection identified.
A prospective study of 52 patients from our institute found hepatotropic viruses as the most common cause for precipitation in ACLF followed by bacterial infection after excluding patients with active alcoholism.13 They also found dual etiology for acute precipitation in 9 patients. However, except one patient (Plasmodium falciparum + HEV), all other patients had bacterial infection/sepsis as the second etiology in causes of dual precipitation. Sepsis can be a cause or complication of ACLF. We determined sepsis as a cause of acute precipitation only after ruling out other causes of precipitation.
Most common etiology for CLD was found to be alcohol (72.1%). In a multicentre study from India and in CANONIC study, the most common cause of CLD was alcohol.6, 12 Study by Shalimar et al6 had taken nonalcoholic steatohepatitis as a cause of cryptogenic cirrhosis. Their findings regarding chronic etiology were similar to our study. However studies from north India, China, and Taiwan found HBV infection as the most common etiological agent for CLD.14, 15, 16, 17 This may be due to increased alcohol consumption in the society and increased awareness of preventative measures and vaccination for HBV infection.
There was a higher mortality in patients with alcoholic CLD as compared with nonalcoholic cause of CLD. However, alcohol as a precipitating factor was not significantly associated with increased mortality. In the CANONIC study, there was increased risk of developing ACLF in patients with alcoholic CLD and alcohol as precipitating factor. In addition, there was increased leukocyte count and C-reactive protein in alcoholics. However, there was no significantly increased risk of mortality in them. A study from a single center in Delhi found no increased risk of mortality in alcoholic than nonalcoholic CLD.14
In our study, no precipitating factors were associated with increased short term mortality. In CANONIC study, precipitating factors were not the major determinants of the number of failing organs and increased mortality. The study by Shalimar et al showed better survival rates in viral super infection/reactivation group. In multisystem involvement, cerebral failure was the most common organ failure (41.34%) in our study followed by coagulatory failure (29.80%), liver failure (25.96%), circulatory failure (25.48%), renal failure (12.9%), and respiratory failure (12.01%). Patients with organ failure had higher mortality (<0.001). Patients with a higher ACLF grade had a higher mortality (p= < 0.001). The importance of organ failure as defining criteria of ACLF was highlighted in the CANONIC study.12 Although in CANONIC study, they did not assess the in-hospital mortality; 28- and 90-day mortalities showed an increasing pattern with increasing grades of ACLF. The grades of ACLF were assessed depending on the number of organ failures. In CANONIC study, liver failure was present in 43.6% patients as compared with 25.96% in our study. In INASL Consortium for ACLF Research in the East (ICARE) cohort, liver failure was seen in 68% patients.6 In our study, mortality was more common in younger patients. This finding is similar to CANONIC study in which patients with higher grade of ACLF were younger than lower grade of ACLF and no ACLF. Higher grade of ACLF was associated with increased mortality. In our study, increased mortality in younger patients was found to be independent of alcohol as chronic etiology (p = 0.39).
Our study has limitations inherent to lack of follow-up as we assessed only in-hospital mortality; 28- and 90-day mortalities were not assessed. Patients were diagnosed as ACLF according to the APASL criteria, so there would have been cases that did not satisfy the APASL criteria but might have had organ failure with increased mortality, and these patients were excluded from the analysis. In addition, ACLF grading is dependent on number of organ failures (CLIF-ACLF), and some patients fall in category of ACLF grade 0, that is, no ACLF.
In conclusion, this study showed that alcohol is the most common cause of CLD as well as acute precipitating factor in ACLF. Mortality was significantly more common in patients with alcoholic CLD, in younger patients, with low albumin, low hemoglobin, with organ failure, with higher grades of ACLF, with high MELD and CTP score, with HE and increased creatinine level.
Conflicts of interest
The authors have none to declare.
References
- 1.Jalan R., Yurdaydin C., Bajaj J.S. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology. 2014;147:4–10. doi: 10.1053/j.gastro.2014.05.005. [DOI] [PubMed] [Google Scholar]
- 2.Sarin S.K., Kumar A., Almeida J.A. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL) Hepatol Int. 2009;3:269–282. doi: 10.1007/s12072-008-9106-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Jalan R., Gines P., Olson J.C. Acute-on chronic liver failure. J Hepatol. 2012;57:1336–1348. doi: 10.1016/j.jhep.2012.06.026. [DOI] [PubMed] [Google Scholar]
- 4.Olson J.C., Wendon J.A., Kramer D.J. Intensive care of the patient with cirrhosis. Hepatology. 2011;54:1864–1872. doi: 10.1002/hep.24622. [DOI] [PubMed] [Google Scholar]
- 5.Kohrt H.E., Ouyang D.L., Keeffe E.B. Antiviral prophylaxis for chemotherapy- induced reactivation of chronic hepatitis B virus infection. Clin Liver Dis. 2007;11:965–991. doi: 10.1016/j.cld.2007.08.006. [DOI] [PubMed] [Google Scholar]
- 6.Shalimar Saraswat V., Singh S.P. J Gastroenterol Hepatol. 2016 Oct;31:1742–1749. doi: 10.1111/jgh.13340. [DOI] [PubMed] [Google Scholar]
- 7.Ramachandran J., Eapen C.E., Kang G. Hepatitis E superinfection produces severe decompensation in patients with chronic liver disease. J Gastroenterol Hepatol. 2004;19:134–138. doi: 10.1111/j.1440-1746.2004.03188.x. [DOI] [PubMed] [Google Scholar]
- 8.Monga R., Garg S., Tyagi P., Kumar N. Superimposed acute hepatitis E infection in patients with chronic liver disease. Indian J Gastroenterol. 2004;23:50–52. [PubMed] [Google Scholar]
- 9.Kumar M., Sharma B.C., Sarin S.K. Hepatitis E virus as an etiology of acute exacerbation of previously unrecognized asymptomatic patients with hepatitis B virus-related chronic liver disease. J Gastroenterol Hepatol. 2008;23:83–88. doi: 10.1111/j.1440-1746.2007.05243.x. [DOI] [PubMed] [Google Scholar]
- 10.Pati Girish Kumar, Singh Ayaskanta, Misra Bijay. J Clin Exp Hepatol. 2016 Mar;6:26–32. doi: 10.1016/j.jceh.2015.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Gupta T., Dhiman R.K., Rathi S. Impact of hepatic and extrahepatic insults on the outcome of acute-on-chronic liver failure. J Clin Exp Hepatol. 2017 Mar;7:9–15. doi: 10.1016/j.jceh.2016.10.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Moreau R., Jalan R., Gines P. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144:1426–1437. doi: 10.1053/j.gastro.2013.02.042. [DOI] [PubMed] [Google Scholar]
- 13.Jha A.K., Nijhawan S., Rai R.R., Nepalia S., Jain P., Suchismita A. Etiology, clinical profile, and in hospital mortality of acute-on-chronic liver failure: a prospective study. Mar. 2013;32:108–114. doi: 10.1007/s12664-012-0295-9. [DOI] [PubMed] [Google Scholar]
- 14.Garg Hitendra, Kumar Ashish, Garg Vishal. Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure digestive and Liver. Disease. 2012;44:166–171. doi: 10.1016/j.dld.2011.08.029. [DOI] [PubMed] [Google Scholar]
- 15.Radha Krishna Y., Saraswat V.A., Das K., Himanshu G. Clinical features and predictors of outcome in acute hepatitis A and hepatitis E virus hepatitis on cirrhosis. Liver Int. 2009 Mar;29:392–398. doi: 10.1111/j.1478-3231.2008.01887.x. [DOI] [PubMed] [Google Scholar]
- 16.Huang K., Hu J.H., Wang H.F. Survival and prognostic factors in hepatitis B virus-related acute-on-chronic liver failure. World J Gastroenterol. 2011;17:3448–3452. doi: 10.3748/wjg.v17.i29.3448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Zhihui X., Xiaoqiang R., Yan L. Association of hepatitis B virus mutations in basal core promoter and precore regions with severity of liver disease: an investigation of 793 Chinese patients with mild and severe chronic hepatitis B and acute-on-chronic liver failure. J Gastroenterol. 2011;46:391–400. doi: 10.1007/s00535-010-0315-4. [DOI] [PMC free article] [PubMed] [Google Scholar]