ACLF is a clinical syndrome characterized by acute deterioration of liver function based on chronic liver disease which is associated with poor outcome in response to an acute insult. At present, there is no consistent definition of ACLF owing to the different etiology of chronic liver disease between the Asian and European populations. Chronic hepatitis B is the main cause of chronic liver disease in Asia, especially in China, while alcoholic liver disease is the most common cause in Europe and USA[22, 23]. In addition, the prognosis of ACLF with various PEs and different underlying chronic in this study were enrolled according to the APASL criteria of ACLF, from three medical centers of China. Among all PEs, HBV reactivation was the leading one (39.9%), followed by infection (29.6%). For patients with HBV-ACLF, acute liver deterioration induced by hepatitis B virus exacerbation was still the predominant factor and the mechanism of liver injury was different from other factors, which should be analyzed separately.
There have been previous studies on the PEs of ACLF, in which PEs were divided into hepatic-ACLF and extrahepatic-ACLF groups. The former was induced by hepatic insults such as acute exacerbation or flare-up of CHB, superimposed infection of HAV or HEV, active drinking of alcohol, and use of hepatotoxic drugs; whereas, the extra hepatotropic insults were considered as bacterial infection, UGIB, and other surgical factors. However, it was difficult to simply divide the PEs into hepatic and extrahepatic insults, because the extent of alcohol consumption and duration of active drinking to be included as acute insult was unclear. With prolonged drinking time, autoimmune injury will gradually manifest besides direct liver injury[8, 25]. The proportion of drug insult was 10.3% in our study, which was consistent with a previous report of the AARC database. Although drugs have been listed as a precipitating factor in ACLF, different types of drugs have heterogeneous effects on liver injury. In this study, bacterial infection as a PE also accounted for a higher proportion, whereas various bacterial and fungal infections may directly affect the liver in addition to spreading from extrahepatic organs. It remains to be discussed whether hemorrhage or manifestation of liver failure is the PE[27, 28]. In our study, both cases of hemorrhagic events occurred before liver function damage, which may be related to acute hepatic ischemia and subsequent bacterial infection. Overwork was included as a precipitating event in this study, which was not mentioned in previous studies. 7.9% of all patients had a definite history of overwork in the last month before admission, as shown by a retrospective investigation, wherein overwork was manifested as physical work in excess of normal time and intensity, mental stress, and sleep disorders. In previous studies, overwork is a serious public health problem and links to cardiovascular and cerebrovascular illnesses and deaths[29, 30]. Overwork may also be a cause for disease progression by mental stress and fatigue in CHB patients, and the likely potential for liver injury may be related to psychological stress and changes in the internal environment. The effects of these heterogeneous factors on liver deterioration in patients with underling hepatitis B or cirrhosis were varied, but they were distinguished from hepatitis B virus reactivation. Therefore, we classified them as NVIs.
ACLF cases in the HVI group were related to recurrence and flare-up of HBV after withdrawal of antiviral drugs, immunosuppressive drugs, and viral mutations. There were no significant intergroup differences in the proportion of ACLF patients with respect to cirrhosis and non-cirrhosis. However, exacerbation time in the HVI group was significantly longer than in the NVI group. It took longer for liver deterioration induced by reactivation of HBV in the HVI group than in that NVI group. At the time of ACLF diagnosis, there was no significant difference in parameters of liver function between the two groups except that serum albumin level was lower in the NVI than HVI group. Jaundice and coagulopathy, which define liver failure, were the main manifestations of organ failure, and the proportion of extrahepatic organ failure was similar in the two groups.
The 90-day and 1-year survival in the HVI group was lower than that in NVI group; there was no difference in the 28-day mortality. The results of this study are inconsistent with those published by Shi et al., which may likely be due to the different ACLF diagnostic criteria and study population. Our study only focused on the HBV-ACLF patients with the ACLF criteria of APASL. The 90-day and long prognosis of liver failure induced by HVI were worse in this study. For HBV-ACLF, effective control of HBV replication makes sense for the recovery of liver injury induced by HBV reactivation. Early and rapid reduction of HBV titer is the essence of therapy, which is related to the suppression of hepatocyte inflammatory necrosis. However, it is suggested that for HBV-ACLF patients, the basic liver function at the start of antiviral treatment is more important for prognosis than the antiviral regimens. Some studies suggested that antiviral therapy was beneficial to ACLF patients with MELD scores of 20–30. Therefore, baseline liver status may have a positive impact on the prognosis of ACLF patients with HBV reactivation. In this study, cirrhosis, bilirubin, PTA, age, and serum creatinine at baseline were independent predictors for the 28- and 90-day mortality.
Patients with non-virus precipitants such as bacterial infection, alcohol consumption, hepatotoxic drugs, and bleeding could benefit from elimination of these causative factors, by considering antibiotic therapy, quitting drinking, taking drugs for interruption of liver damage, or undergoing hemostasis therapy. Therefore, the short-term therapy may have an impact on the survival and death of patients. A previous study reported that the patient’s condition during the first 3–7 days after ACLF diagnosis determined their prognosis; therefore, we focused on the parameter changes within one week after diagnosis due to their positive predictive prognosis. In this study, there were significant dynamic changes in bilirubin, PTA, INR, creatinine, and blood sodium within 14 days between the patients who survived and those that died in the non-HBV insult group, but there was no significance seen in the HBV insult group. We speculated that the dynamic changes of liver and renal function in the NVI group within 14 days after admission might be related to the prognosis.
We attempted to compare the predictive scoring model for HBV-ACLF patients induced by hepatotropic virus insult. The MELD score, which is used to assess end-stage liver disease, had good predictive value both for short- and long-term mortality in the two groups. The results revealed that MELD score was superior to the other five models in predicting the prognosis of patients in the NVI group. Lactate-free AARC score showed higher predictive value than for the existing models for the 28-day, 90-day, and 1-year mortality in the NVI group. The AARC score, which included TBil, INR, grade of HE, plasma lactate, and serum creatinine, could reliably predict the severity and outcome for ACLF patients. However, serum lactate test is not a routine test in some countries. A study on the predictive value of lactate-free AARC score among 749 patients with alcoholic liver disease and liver failure (from the AARC database) suggested that the AUC prediction values for 90-day mortality is similar to that of other models. The lactate-free AARC score could also reflect liver failure to some extent, which is at the core of ACLF, based on APASL criteria. In the HVI group, we found that the lactate-free AARC score had an ideal AUROC and could better predict the 28-day, 90-day, and 1-year mortality than MELD and CLIF-ACLF.
There are some limitations in this study. First, although patients were enrolled from three Chinese hospitals, the sample size was still relatively small. In this study, part of the screened HBV-ACLF patients lacked the PE, and some patients had ambiguous insults; both these categories of patients were excluded. Consequently, there are some deviations in the results of this study. Second, owing to the lack of lactate data, we scored both groups using lactate-free AARC. Therefore, it is necessary to expand the sample size to validate the results reported.
In summary, HBV reactivation is still the most common PE in HBV-ACLF patients, and the 90-day and 1-year prognosis of patients with HBV-reactivation–induced HBV-ACLF was worse than that induced by non-virus insult. It is necessary to pay attention to the liver damage caused by HBV reactivation during the management of patients with chronic HBV infection. Lactate-free AARC score and MELD scores are valuable predictors of short- and long-term prognosis in patients with HVI-induced HBV-ACLF.