Severe damage to liver function results in LF, which manifests as coagulation dysfunction, hepatic encephalopathy, and other pathological conditions²⁵. In China, LF make up most of the ~ 1 million/year liver disease deaths²⁶. As LF is hard to treat²⁷, effective and comprehensive prognosis assessment of LF patients, to facilitate early intervention, has become an issue of significant interest for clinicians. In this study, 861 Hepatitis B-related ACLF patients were recruited and found, consistent with ACLF diagnoses, to have worse liver and coagulative functional indicators, compared to healthy controls and patients with chronic Hepatitis B. We then conducted univariate logistic regression analysis of patient characteristics and found 13 significant indicators for adverse ACLF prognoses. Univariate logistic regression analysis was followed by multivariate logistic regression analysis, as well as the 3 machine-learning analyses LASSO, RF, and SVM; there, the number of indicators identified were, respectively, 8, 6, 9, and 12. Among those 4 analyses, age, GSP, HDL-c, and INR were common to all of them. These indicators were then incorporated into a predictive nomogram, in which they were highly predictive and possess great clinical utility for identifying patients prone to adverse ACLF prognoses after both 28- and 90-day examination periods. We also found that patients with higher GHR also had worse ACLF outcomes after those examination periods, as well as increased gastrointestinal bleeding, hepatorenal syndrome, plus MELD and i-MELD scores. In fact, this study is one of the first to link the glucose metabolism indicator GSP, and the lipid metabolism indicator HDL-c, to MELD score, which has long been used to predict adverse prognoses and mortality among ACLF patients. For instance, a study showed that Child-Turcotte-Pugh grade > 12 and MELD > 28 were independent predictors of ACLF mortality²⁸. MELD-Na and i-MELD scores were then derived from MELD by other researchers after additional optimization²⁹. As for age and INR, they have been widely accepted as key predictive indicators for adverse ACLF prognoses.

With respect to GSP and HDL-c, the liver has been noted to play an important role in glucose metabolism, and excess liver damage could disrupt proper glucose homeostasis, leading to hypoglycemia, impaired glucose tolerance, and diabetes in patients with severe liver disease³⁰. Additionally, hypoglycemia and transient hyperglycemia can also occur in patients with severe acute hepatitis and acute LF³¹. However, the impact of these metabolism disorders on ACLF prognosis is still largely unknown^32,33, though Hu et al. noted that glucose metabolism disorders in ACLF patients may be different than in cirrhosis, in that such disorders in ACLF may be caused by the stress response of liver function loss and acute systemic inflammation³⁴. Additionally, in chronic Hepatitis B virus (HBV)-related ACLF, diabetes was associated with high mortality³⁴. All these findings indicated that ACLF patients also tend to have complex glucose homeostasis disorders; for instance, hyperglycemia could increase mortality, but its strict control could result in hypoglycemia, which also increases mortality³⁵. In line with those observations, our investigations found that ACLF patients had lower FBG levels compared to CH and healthy controls, which may be owed to short-term hypoglycemia upon initial admission. On the other hand, their GSP level, which reflects their longer-term blood glucose status, is significantly higher than for CH and healthy individuals. Therefore, ACLF patients, compared to CH or healthy ones, have greater instability in blood glucose levels, pointing to them developing complex glucose homeostasis disorders, which otherwise may be overlooked from just examining FBG levels. In fact, GSP was found to be more valuable than FBG in determining 28-day adverse prognosis likelihoods for HBV-ACLF patients. Therefore, GSP is more reliable as an indicator of the longer-term glucose metabolic state of a patient, compared to merely testing FBG at a specific time point, for predicting HBV-ACLF prognoses.

Lipid metabolism, compared to glucose, has been more documented as a subject of analysis for evaluating ACLF prognosis. Indeed, our study found that compared to healthy individuals, HBV-ACLF patients had lower TC and TG, which may be related to malnutrition. Furthermore, we found that HDL-c levels were an independent risk factor for ACLF prognosis, in which lower levels were associated with worse prognoses, which were in accordance with previous studies, such as one involving 530 HBV-ACLF patients, which showed that HDL-c levels had some prognostic potential, where higher levels were associated with higher survival rates³⁶. Similarly, in a retrospective cohort study of 200 HBV-ACLF patients, significant differences in HDL-c levels were found between dead patients versus those who survived the 28-day examination period³⁷. All these findings have led to the likes of Trieb et al.³⁸ to conclude that HDL-c is a powerful predictor of LF progression and survival, which may be due to it being involved in regulating ACLF patient immune function and infection responses^39,40. More specifically, another study has shown that HDL-c regulates cell membrane cholesterol levels by removing excess cholesterol and other lipid substances, leading to reductions in inflammatory receptor signaling⁴¹. HDL-c could also lower cytokine production by binding to LPS. All this evidence indicates that reducing HDL-c levels could result in decreased anti-inflammatory activity, which may serve as the underlying basis behind HBV-ACLF patients having poor prognoses^42,43,44.

Based on the wealth of previous findings, we thus examined whether any connections between both pathological glucose and lipid metabolism, with respect to ACLF prognosis, may be present. In fact, we found that higher GHR, obtained from the GSP to HDL-c ratio, was associated with worse laboratory indicators, higher incidence of complications, and poor prognosis after 28- and 90-days of examination, all of which contributes to the higher cumulative mortality risk found in the Kaplan-Meier analysis. Therefore, the combination of higher long-term blood glucose levels, as indicated by GSP, coupled with lower HDL-c, is a major predictive factor for more adverse HBV-ACLF prognoses.

There are a number of limitations in this study, one of which is that it is a single-center, retrospective one, which may not be fully representative of all ACLF patients; thus, future prospective studies, with larger sample sizes and multiple centers, should be carried out to verify the present findings. Another limitation is the lack of longer-term follow-up data, particularly in terms of the changes in indicators after 90-days. This is owed to HBV-ACLF having a high mortality rate during the short-term periods of 28- and 90-day follow-up periods, meaning that those who survive afterwards are more likely to have favorable prognoses. Indeed, Xiao et al. found that HBV-ACLF survival rates after 90 days was 48.8%; this rate only slightly decreased after 1, 5, and 8 years, with survival rates being, respectively, 46.1%, 43.8%, and 42.2%⁴⁵, indicating that if an individual survives after 90 days, they are still likely to be alive afterwards, for up to 8 years. As a result, little change would be present for longer-term follow-up with respect to survival rates, and consequently their correlations with clinical indicators. Nevertheless, future studies should examine the associations between alterations in clinical indicators with longer-term HBV-ACLF prognoses. Additionally, the study did not fully investigate the role of cardiometabolic risk factors, such as insulin resistance, on HBV-ACLF prognoses, though it had been noted by Hu et al. that in a group of 96 ACLF patients, those with diabetics had significantly higher 90-day mortality rates³⁴. Further studies should therefore be conducted to elucidate the influence of such cardiometabolic disturbances on ACLF prognoses. Likewise, the postulation that lower FBG levels reflect short-term hypoglycemia upon admission, while higher GSP reflects the longer-term metabolic state of an HBV-ACLF patient, requires further confirmation. Consequently, future studies should increase the number of cases for both control and CH groups, as well as monitor changes of glucose and lipid indexes at different times in the follow-up, thereby providing more matched comparisons among control, CH, and ACLF groups to minimize the influence of errors.