In our study, we have observed that liver involvement in sepsis is common and characterized by either a hepatitic-like injury, observed in 60% of our patients, or a mixed, hepatitic and cholestatic, pattern of injury. Furthermore, steatosis was a common finding observed in 74% of our patients. Bacteriaemia and sepsis have been associated with abnormal liver biochemistry[2–4,8–10
]. In the current study, elevated serum ALP and γGT levels were observed in 70% and 93% of our cases before death compared to 13% and 40% at admission, respectively. Similarly, increased bilirubin levels were seen in 53% of our cases before death compared to 13% at admission. In this respect, serum bilirubin, γGT and ALP may serve as indicators of clinical deterioration in septic critically ill patients. Other studies, however, have showed conflicting data regarding the prevalence of abnormal liver tests in patients with bacteraemia[2,8–10
]. These discrepancies can be attributed to differences in patients' selection criteria as well as in the severity of the underlying disease.
Liver histology in sepsis has been evaluated mainly in animal studies and in postmortem human liver tissue where a significant time period had elapsed between autopsy and time of death[4,9,11–13
]. In jaundiced septic patients, three histological patterns have been described in a limited number of studies[4,9,11
]: canalicular cholestasis, usually most severe in zone 3, ductular cholestasis with inflammation and non-bacterial cholangitis associated with the toxic shock syndrome[12
]. Intrahepatic cholestasis in septicemia could be attributed to many factors such as circulating endotoxin causing functional disorders in bile secretion, disturbances in bile canalicular contraction and ischemia[14–17
The lack of detailed histological data has led clinicians to evaluate sepsis-related liver damage from the serum biochemical markers while no studies have addressed the correlation between laboratory values and pathologic findings. In the current study, we have obtained liver tissue from our septic patients immediately after death leading to the most accurate identification of sepsis-related liver pathology. Our findings showed that sepsis is characterized by a “hepatitic” like liver injury in 60% of our patients and a “mixed”, cholestatic and hepatitic type in 40% of them. Cholangitis and/or cholangiolitis were observed in a few patients. Additionally, ductular cholestasis, a sepsis-specific hepatic lesion[11,12
], suggesting increased risk of mortality[16
] was identified only in two of our patients dying of sepsis, while canalicular cholestasis was present in one. Damage to bile duct epithelium has been previously observed in the liver of a female patient with E. coli
]; however, it was not detected in any of our patients. The contrast between our histological findings and that of previous morphological studies where canalicular or ductular cholestasis predominated in the liver of jaundiced patients who died of sepsis, maybe attributed to the small number of cases examined. The presence of mixed, cholestatic and hepatitic, features in the majority of our patients with hyperbilirubinemia may alternatively be the result of the direct effect of endotoxin or a drug-induced injury. Centrilobular hemorrhagic necrosis, which was common in our cases, is a frequent finding in livers from patients with peripheral circulatory failure[19
]. Among the above histopathological findings, the presence of portal inflammation, a common finding in chronic hepatitis, was associated with prolonged hospitalization that may reflect the effect of prolonged exposure to treatment medication.
Steatosis was evident in the liver of most of our septic patients. In previous studies, although steatosis was a common finding in the post-mortem liver of septic patients, its extent and type has not been examined in detail or commented on[4,9,11
]. The majority of our patients had moderate to severe fatty liver change comprising 40-80% of the liver parenchyma. It is known that sepsis and bacterial toxins may cause macrovesicular[20
] or microvesicular steatosis[21
] and hypoxia may play a role in these cases. Also, a wide variety of drugs and total parenteral nutrition may be responsible for the development of fatty liver change[20
Liver apoptosis can be ascribed to a wide variety of individually or simultaneously acting underlying mechanisms. Tissue hypoxia, inflammatory mediators, free radicals, bacterial toxins and drug toxicity are all implicated in the above mechanisms[3,20,22,23
]. The presence of apoptosis was much more common in patients with more severe liver histology, as defined by the intensity of portal and lobular inflammation as well as the presence of lobular necrosis and the ductular cholestatic lesions. Prognostic determinants cannot be inferred from the current study, since all our patients succumbed due to multiple organ failure. However, the absence of pre-existing liver disease, as well as the fact that all biopsies were optimally performed immediately after death, suggests that the subsequent pathologic evaluation demonstrates terminal sepsis-related histologic changes in the liver parenchyma.
Summarizing our results, the liver of end stage patients mainly shows histopathological features of hepatitis injury, with additionally cholestatic findings along with steatosis. Biopsies were performed almost immediately after each patients death giving the most precise evaluation of sepsis-induced liver injury. Further studies are needed to clarify the role of apoptosis and application of innovative drugs in sepsis-induced liver injury.