Changing etiologies and outcome of liver failure in Southwest China

Figure 1 shows the enrollment of patients in this retrospective study. Firstly, we made a search in computerized diagnoses hospital registry for all patients admitted to department of infectious diseases, Southwest hospital of Chongqing, China from January 2000 to December 2012. A total of 25467 hospitalized patients were indexed during the 13 years period. Secondly, we screened out 4903 candidate cases for assumed liver failure according to the diagnostic records obtained from computerized diagnoses hospital registry, which included 5 cases of fulminant hepatic failure, 71 cases of liver failure, 52 cases of ALF, 48 cases of SALF, 62 cases of ACLF, 71 cases of fulminant viral hepatitis, 56 cases of subfulminant viral hepatitis, 4135 cases of chronic severe hepatitis B, 7 cases of chronic severe hepatitis C, 6 cases of severe acute hepatitis B, 8 cases of severe alcoholic hepatitis, 6 cases of severe drug hepatitis, 325 cases of severe chronic hepatitis B, 48 cases of Wilson’s disease and 13 cases of acute fatty liver of pregnancy (AFLP). Thirdly, each of 4903 cases with assumed liver failure was again determined to be whether or not fulfilled the diagnostic criteria of ALF, SALF and ACLF in China according to the following clinical data obtained from the electronic medical records, which included the levels of prothrombin activity (PTA) and serum total bilirubin (T-Bil), the length of illness, a history of underlying chronic liver disease, the grade of hepatic encephalopathy (HE) and the time from onset of illness to development of HE. Inclusion criteria for ALF included: ① serum T-Bil≧10 mg/dL or an increased T-Bil/d ≧ 1 mg/dL; ② PTA ≤40 %; ③ the occurrence of at least gradeII HE within 2 weeks of illness onset; ④ without pre-existing liver disease. Inclusion criteria for SALF included: ① serum T-Bil≧10 mg/dL; ②PTA ≤40 %; ③the length of illness <26 weeks with or without HE; ④ without pre-existing liver disease. Inclusion criteria for ACLF was an onset of acute liver decompensation within 12 weeks in a patient with previously diagnosed or undiagnosed chronic liver disease, and included the following evidences: ① serum T-Bil≧10 mg/dL; ②PTA ≤40 %. Finally, 3171 patients were enrolled in this study based on the above inclusion criteria, which included 75 cases of ALF, 174 cases of SALF and 2922 cases of ACLF. Among 3171 patients with liver failure, 3118 (98.33 %) cases were from Southwest areas of China, which included Chongqing (60.99 %), Sichuan (32.17 %), Guizhou (4.73 %), Yunnan province (0.28 %), Tibet (0.09 %) and Guangxi (0.06 %). Another 53 cases (1.67 %) were from other areas of China, which included Liaoning, Jilin, Anhui, Jiangsu, Jiangxi, Zhejiang, Fujian, Guangdong, Hainan, Hubei, Hunan, Shanxi, Henan, Shandong province and Xinjiang. After informed consent was obtained from the next of kin, detailed prospective clinical and laboratory data were collected in an anonymous fashion on admission to our hospital. The protocol was approved by the Ethics Committee of Southwest Hospital, Chongqing, China.

Viral infection was defined based on serum markers for hepatitis A-E, human immunodeficiency virus (HIV), herpes simplex virus (HSV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV). All 3171 patients were tested for serum anti-HAV IgM, HBsAg and HBV DNA, anti-HCV, HDAg and anti-HDV, anti-HEV IgM, and anti-HIV. Only patients who did not suffer from hepatitis A-E were tested for IgM antibody of HSV, EBV and CMV. Autoimmune hepatitis (AIH) was diagnosed based on descriptive clinical criteria reported by the International Autoimmune Hepatitis Group [10]. Alcoholic liver disease (ALD) was considered for patients who had taken alcohol at least 3 years, and a regular average consumption of ethanol >40 g/day for women and >60 g/day for men in this article [11]. Drug induced liver injury (DILI) was considered for patients who had taken any hepatotoxic drugs or Chinese herbs within 6 months before this illness onset. Wilson’s disease was diagnosed according to the criteria recommended by European Association for the Study of the Liver. The clinical diagnosis for other diseases was obtained from the electronic medical records, included hyperthyroidism, schistosomiasis japonica, AFLP, acute pancreatitis, septic cholangitis and tumors. The etiology of liver failure was considered to be indeterminate if no diagnostic clues were obtained from the patient’s history, serologic markers for HAV, HBV, HCV, HEV, CMV, EBV, HSV, HIV, anti-smooth-muscle or antinuclear antibodies and ceruloplasmin (or other signs of Wilsons disease). Trigger factors of liver failure included the following events: ① nucleos(t)ide analogues (NUCs) withdrawal, which was defined as HBV reactivation and abnormal liver function test within 52 weeks of withdrawal from NUCs therapy among patients who received at least 12 weeks NUC therapy; ② resistance to NUCs; ③ steroids use induced HBV reactivation; ④ interferon (IFN) therapy induced severe acute exacerbation (SAE) of chronic hepatitis B (CHB); ⑤ other factors, such as surgery and pregnancy. Bacterial infection was not defined as a trigger factor in HBV associated liver failure because that this infection was not identified to be existed prior to onset of liver failure or secondary to liver failure. We defined ACLF induced by NUCs withdrawal, resistance to NUCs and IFN therapy as antiviral therapy related ACLF (AVT-ACLF).

For processing the data, Microsoft Office Excel 2010(Microsoft, Redmond, WA) and IBM SPSS Statistics (IBM, Armonk, NY) were used. The data are shown in medians and interquartile ranges. Continuous variables were summarized as mean ± standard deviation (SD), median (range), or frequency (in percent). Categorical variables were compared with the chi-square test and Fisher’s exact test. A p value of <0.05 was considered statistically significant.

In this study, 3171 patients were enrolled to be analyzed for etiologies of liver failure, in which 3086 (97.3 %) cases were identified to be associated with at least one of several causal agents for hepatic injury, and 85 (2.7 %) cases were indeterminate etiology. A total of 25 precipitating factors were identified in 3171 patients, in which the 5 leading causes were HBV (91.6 %), alcohol (18.1 %), antiviral therapy (AVT) related hepatitis flares (6.7 %), drugs (5.4 %) and HEV (3.2 %), shown in Table 1. Among 171 patient with DILI, 107 (62.6 %) had received antituberculosis drugs, 41 (24.0 %) had received Chinese herbs and 23 (13.5 %) had received other drugs which included nonsteroidal anti-inflammatories drugs (3.5 %), acetaminophen (2.3 %), antibiotics (1.8 %), leflunomide (1.8 %), statins (1.2 %), methimazole (1.2 %), anticancer drug (0.6 %), cyclosporine A (0.6 %) and chlorpromazine (0.6 %). Among 164 ACLF induced by withdrawal of NUCs, the percentage of cases after the withdrawal from lamivudine was 53.7 %, adefovir 26.8 %, entecavir 9.8 %, telbivudine 4.9 %, lamivudine and adefovir 4.9 %. Among 37 patients with HBV resistance to NUCs, the percentage of cases with resistance to lamivudine was 67.6 %, adefovir 16.2 %, telbivudine 8.1 %, adefovir and lamivudine 5.4 %, adefovir and entecavir 2.7 %.

The distribution of etiologies showed wide variation in different clinical type of liver failure. The 3 leading causes were single HBV infection (46.7 %), indeterminate (20.0 %) and DILI (17.3 %) for ALF (Fig. 2), but being indeterminate (29.3 %), single HBV infection (25.3 %) and DILI (25.3 %) for SALF (Fig. 3). Among 2922 patients with ACLF, 2821 (96.5 %) cases were associated with HBV infection, but only 101 (3.5 %) cases being non-HBV associated ACLF. Among 2821 patients with HBV associated ACLF, 1057 (37.5 %) cases had more than one precipitating factor, in which the 3 leading trigger factors were alcohol, superinfection and NUCs withdrawal (Fig. 4). The percentages of patients with at least two precipitating factors were significantly higher in ACLF (36.7 %, 1071/2922) than those in ALF (6.7 %, 5/75) and SALF (1.7 %, 3/174), P = 0.000.

The distribution of etiologies for liver failure also showed wide variation during the 13 years periods. Figures 5–6 showed the trends of common etiologies. The etiologies with a declined trend included HAV, HCV, HDV, HEV infection, while those of having an increased trend included ALD, NUCs withdrawal and resistance to NUCs. For ACLF, the 3 leading etiologies were spontaneous SAE of CHB (58.2 %, 286/491), hepatotropic viruses superinfection (17.1 %, 82/491) and HBV plus alcohol (14.3 %, 70/491) between 2001 and 2003, but were spontaneous SAE of CHB (58.9 %, 989/1678), HBV plus alcohol (20.3 %, 341/1678) and medicinal factors (15.7 %, 264/1678) including 170 (10.1 %) cases of AVT-ACLF between 2007 and 2012. Cases induced by hepatotropic viruses superinfection and HBV plus drugs only accounted for 2.4 % and 3.0 % of all 1678 ACLF patients between 2007 and 2012.

Demographical characteristics of liver failure in different clinical types and etiologies are depicted in Table 2. The ratio of male to female was 5.6:1 in ACLF, which was significantly higher than that in ALF (1.3:1) and SALF (0.9:1), P = 0.000. Patients with ACLF tended to be older than those with SALF and ALF (P = 0.000). There were no significant difference with age (P = 0.122) and sex (P = 0.269) between SALF and ALF. The ratio of male to female was 5.9:1 in HBV associated liver failure, which was significantly higher than that (0.9:1) in non-HBV associated liver failure (P = 0.000), but having no significant difference with age between two groups (P = 0.258). Patients with liver failure induced by Chinese herbs tended to be older (P = 0.001) and more likely to be female (P = 0.000) than those with liver failure induced by antituberculosis drugs. Patients with indeterminate liver failure tended to be younger (P = 0.015) and more likely to be female (P = 0.000) than those of HBV associated liver failure. In HBV associated liver failure, male patients (41.5 ± 11.3 years) tended to be younger than female (45.3 ± 13.0 years) cases (P = 0.000). 81.1 % patients with HBV related liver failure were aged 25–54 years in male, while only 67.2 % cases were aged 25–54 years in female, the ratio of male to female reached 7.1:1 (Table 3).

In this study, only 66 (2.1 %) patients received a liver transplant, and 45 (68.2 %) survived within 1 year of post-transplant. During the 13 years, the average 3-month SS rates of liver failure were 31.4 % (996 of 3171), but showed a gradually increased trend (Table 4). SS rates were 41.1 % (401/976) in 3 years between 2010 and 2012, which were significantly higher than 32.4 % (344/1063) in 4 years between 2006 and 2009 (P = 0.000), and 22.2 % (251/1132) in 6 years between 2000 and 2005 (P = 0.000).

SS rate of ALF was 17.3 % (13/75), which was significantly lower than 29.3 % (51/174) of SALF and 31.9 % (932/2922) of ACLF (P = 0.047, 0.007). In SALF and ACLF group, SS rates of patients with HE were 6.3 % (6/95) and 8.0 % (100/1245), which were significantly lower than 57.0 % (45/79) and 49.6 % (832/1677) of patients without HE (P = 0.000). In fact, SS rate was significantly higher in ALF (17.3 %) than in SALF (6.3 %) and ACLF (8.0 %) with HE (P = 0.028, 0.010).

Figure 7 showed SS rates of patients according to the etiology amongst the major etiological groups of liver failure. There were significant difference with SS rates among different etiological groups (P = 0.000). In HBV associated ACLF, SS rate of patients induced by alcohol, drugs, NUCs withdrawal and resistance to NUCs was 29.1 % (223/766), which was significantly lower than those of spontaneous SAE (34.1 %, 601/1764) and hepatotropic viruses superinfection (38.5 %, 55/143), P = 0.014, 0.030. There were no significant difference with SS rates between spontaneous SAE and hepatotropic viruses superinfection groups (P = 0.314).

Spontaneous survivors (36.9 ± 17.3 years) tended to be younger than patients who were not spontaneous survivors whether in non-HBV (36.9 ± 17.3 versus 42.2 ± 18.7, P = 0.035) or HBV associated liver failure (38.6 ± 11.0 versus 43.6 ± 11.6, P = 0.000). There was no significant difference with SS rate between male (28.8 %, 36/125) and female (27.9 %, 39/140) patients (P = 0.865) in non-HBV associated liver failure. In HBV associated liver failure, SS rate was higher in female (35.4 %, 150/424) than 31.1 % (771/2482) of male patients, but having no statistically significant difference (P = 0.08). Table 3 showed the relationship of outcome with sex and age of patients in HBV associated liver failure. For male patients, there were significant difference with SS rates among different age groups (P = 0.000), which SS rate was the highest in those aged 20–24 years (63.1 %, 53/84), then decreased progressively with increasing age. For male, SS rate was significantly higher in patients aged 30–34 years (41.8 %) than 30.3 % of aged 35–39 years group (P = 0.001). For female, no significant difference was observed with SS rates among different age groups below 55 years (P = 0.564), and also among different age groups over 55 years (P = 0.322), but SS rate was significantly higher in patients aged <55 years group (42.5 %, 131/308) than 16.4 % (19/116) of aged ≥55 years group (P = 0.000). SS rates were higher in male than in female patients aged <25 years [59.8 % (73/122) versus 43.5 % (10/23)] and ≥55 years [18.7 % (65/347) versus 16.4 % (19/116)] group, though having no statistically significant difference (P = 0.154, 0.569). However, SS rates of female were all higher than those of male patients in each group of ages 25 to 54 years old. During ages of 40 to 44 years, SS rate was significantly higher in female (50.9 %, 29/57) than 27.6 % (118/427) of male patients, P = 0.001.