In this retrospective cohort study, first we found the onset of early hepatic injury within 48 hours on ICU admission was closely related to organ failure for patients with sepsis. Secondly, age, hypertriglyceridemia, serum total bile acid, hemoglobin and renal dysfunction were the independent predictors for early liver injury in sepsis by multiple regression analysis, while Kaplan-Meier survival analysis demonstrated similar survival time between early liver injury and non-early liver injury group. Third, age, organ failure of cardiovascular dysfunction, respiration dysfunction were independent risk factors for one year mortality of septic patients after discharge in the multivariate Cox hazard analysis.
The definition of liver injury of ours was different from traditional conception using bilirubin which can be explained as following. We demonstrated the percentage of septic patients with early hepatic injury within 48 h of admission was about 53.5%, which is not consistent with 11% occurrence showed in other study (14). Unlike using bilirubin as the only marker to define early liver injury, we choosed bilirubin > 2 mg/dL, or ALT or AST > twice the normal value representing early liver injury. Liver has powerful compensatory ability so early hepatic injury is latent. As bilirubin rises several days after hepatic dysfunction, we choose more sensitive indicators ALT or AST to define early liver injury. ALT was also identified as an independent predictive factor of critical illnesses (15). Moreover, hypoxia hepatitis, mainly histopathological changes in liver injury in sepsis (3), is characterized by marked increased ALT after insufficient oxygen uptake by hepatocytes (16). So we used the more sensitive indicators, ALT and AST, to present early and latent hepatic injury at the beginning of sepsis as liver has been ignored in sepsis compared to other organs. Our data have shown high incidence of 53.5% of early hepatic injury in septic patients. So, more attention should be paid to the liver, the guardian, modifier and target of sepsis (3).
Interestingly, we found younger septic patients were more prone to early liver damage in multivariate regression analysis (Table 3) which is at odds with results of Kramer’s study (14). One of causes is that Kramer research included all ICU patients while we choose only septic patients. A multiplecenter study from Japan demonstrated average age of septic patients is 69 ± 17 years (6). The underlying factor is that Japan is a population aging society than our country, and different regions, races and genetic background are important factors influencing sepsis epidemiology results, while our data is from Chinese Han population. Recently a cross continents epidemiology research of sepsis reported that average age of septic patients is 61.5 ± 17 years (2). Liver is a critical site to modify the immune response in sepsis. And younger patients may have a stronger immune response against infection attack than older ones. So younger patients are possible more prone to early liver injury in sepsis and this argument needs further in-depth research. While age was independent risk factor for mortality of septic patients after discharge for one year in multivariate Cox hazard analysis (Table 4), which was in line with previous detailed summary (17).
Our study showed ALT, AST, total bilirubin (TB), direct bilirubin (DB), gamma-glutamyl transpeptidase (GGT), TBA, triglyceride and lactate rise in septic patients with early liver injury (Table 1, 3, 4). Due to the great heterogeneity in clinical patients, the liver of individual has different tolerance ability to sepsis. Our clinical results hint at hepatitis, bile capillary obstruction, cholestasis, bile acid and lipid metabolism abnormity in septic patients with early liver injury. Sepsis influences both hepatic parenchymal and interstitial tissues and biliary tract. These results are consistent with the pathological change of liver in sepsis (18), 60% patients had “hepatitis” type including portal/lobular inflammation, hemorrhagic and necrosis, 40% patients had “mixed” liver injury by combinations of biliary lesions, like cholangitis, and portal/lobular inflammation, 73.3% patients had steatosis which was robust evidence and golden criteria. Further, we put forward hypoxia hepatitis, cholestasis, bile acid and lipid metabolism abnormity are main pathological and metabolic characteristics of early liver injury of sepsis.
There are few researches studied the correlation between early liver injury and severity of sepsis before. To our data, early liver injury is closely related to severity of sepsis as higher SOFA and APACHE II score, infectious indicators like PCT, prolonging length of vasopressor days, higher rates of CRRT and septic shock, some of which are typical indicators for exacerbation of sepsis (2, 19, 20). What’ more, few clinical studies have focused on the role of liver in organ failure in sepsis. We find, compared to non-early liver injury group, early liver injury group has widely worsening renal, coagulation and hemotological dyfunction judged by details from SOFA criteria. Liver and kidney interaction, namedly liver-kidney axis or hepatorenal syndrome are often referred in severe hepatic disease or other diseases situation (21, 22), but rarely has been discussed in sepsis. Our results prompt the underlying close interaction between liver and kidney at the beginning of sepsis, which may stimulate related further studies in the future. Though hemotological system is often ignored in sepsis, platelet, one member of blood system, can not be overlooked in sepsis. To our data, early liver injury group has significant lower platelet. Platelet plays key role in initial step to blood clotting and maintaining homeostasis among coagulation, vascular endothelium and cytokine network (23). Platelet is also found to have important functions like immune surveillance, co-working with immune cells to fight against invading pathogens (24). And thrombocytopenia is closely associated with dysregulated host response and increased 30 day mortality in recent research (25). Significant decreasing platelet in early liver injury group in our results suggest that early hepatic injury can break hemotological homeostasis in early phase of sepsis. Bleeding and coagulation disorder plays a crucial part in progress of sepsis and can lead to disseminated intravascular coagulation (DIC) in late stage of sepsis. To our data, worsening coagulation function in early liver injury group hints at turbulent coagulation function may come up in early stage of sepsis, which is reasonable due to close innate relationship between liver and coagulation function. Albeit not significantly, there were tendency of dampened cardiovascular and respiratory function in early liver injury group showned by faster respiratory rate and higher myocardial enzyme level (Table 1), which would be latent due to infectious fever and hyperdynamic circulation at the beginning of sepsis. Serum hemoglobin level shown as independent risk factor for early liver injury of sepsis (Table 3) is in line with previous study on non-alcoholic liver disease (26), indicating the mutual effect of hemoglobin and liver and requiring further study.
Our results are in line with some recent basic studies. Liver plays a central role in bacterias clearance, coagulating, modifying inflammatory and immune response, mediating a large number of the metabolism process in sepsis. These critical biological functions have important impact on other organs and systems including kidney, lung, cardiovascular and coagulation systems, acid-base balance and lipid metabolism (27). And Liver regulates inflammatory response to infection, generating plentiful inflammatory cytokines to spread to other vital organs by blood circulation to adapt to “inflammatory need” to help other organs to fight against pathogens. Liver is also a school to “re-education” circulating immune cells staying in hepatic sinusoid temporarily that thereafter recycle between different organs to fulfill demands to withstand attack from pathogens invaders (28). In some cases, this important adaptive function of liver can loss control and overreact thus producing redundant inflammatory cytokines to damage other organs.
However, there are no significant difference in hospital mortality, 180 days or 1 year after discharge between early liver injury group and non-early liver injury group shown by our results, which are not consistent with other studies (14, 29). Due to the two studies design is different from us, one is including all critically ill patients (14), the other is discussing the impact of liver trauma on sepsis. Early hepatic injury was closely related to organ failure but not mortality shown by our results (Table 2,4 and Fig. 1). We suppose liver is the first sentry and processor to face exogenous pathogen, toxin and etc, and quickly respond to re-educate immune cells and transfer attack signal to other organs, when this process is overreacted, liver itself and the connected organs can suffer injury, which aggravates sepsis at the beginning phase. This process can be reversible as liver has strong regeneration and compensatory ability to adapt to septic stress in most conditions, thus may probably not affect mortality of sepsis. Early cardiovascular and respiration dysfunction are independent risk factor for septic patients after discharge (Table 4) possibly because cardiovascular and respiratory organs are short of compensatory ability as liver.
Our research has substantial strengths. To our best knowledge, this is the first report that early liver injury is closely related to organ failure of sepsis in the world from clinical data. Second, we adopt transaminase as indicator for early hepatic injury which has high sensitivity to screening out latent liver injury cases in early stage of sepsis, we suppose this is objective and scientific. Third, we find younger people are prone to have early liver injury compared to older ones in sepsis in Chinese Han population which is different from other racial results.
There are several limitations to our study. First, the study design is retrospective and the sample size is relative small, so bias can not be eliminated. We have tried our best to strengthen data integrity and guarantee date equarlity by decreasing loss to follow-up and use multivariate regression analysis and multivariate Cox hazard analysis to reduce bias as much as possible. Secondly, the increasing sensisivity by using transaminase for detecting early hepatic injury also reduce specifity to recognize real liver injury thus brings bias. We think it’s double-edged sword which is unvoidable for losing perfection at present condition. We emphasis on highlighting the latent and early liver injury state of sepsis which is often overlooked in previous studies. Third, the single centered design limited the generalisability of our conclusion, while we carried out this study in different ICUs setting in our hospital to partially decrease generalisability reduction. Fourth, we have missing data but very few as we have tried our best to manage and control quarlity of all data from designing phase of this study.