Oxidative stress has been implicated in pathophysiology of various liver diseases. However, the role of oxidative stress has not been investigated in ALF in humans. The level of systemic oxidative stress was significantly higher among ALF patients as indicated by higher TBARS and SOD levels. The source of markers of oxidative stress is the ongoing hepatocyte injury and cell death. The lipid peroxidation products are liberated in the circulation as the membrane lipids are oxidized during cell lysis. These products are also a source of cytotoxicity and are suggested to invoke the inflammatory response in the body [24
]. Hence, an increased TBARS level may reflect the large-scale destruction of hepatocytes that may further aggravate the inflammation and cell death. The high SOD level may be a result of the overexpression of SOD mRNA, which is a normal physiologic response against the acute stress [26
]. Thus, the increased SOD levels may be a result of body’s adaptive response against the prevalent oxidative stress during ALF, which needs to be studied further by measuring expression of SOD
gene in patients with ALF.
Acetaminophen toxicity, which is the most common etiology of ALF in the West, has oxidative stress as a key pathogenic factor for liver cell injury and antioxidant therapy as treatment. Acetaminophen toxicity leading to liver failure is mediated by hepatic glutathione depletion and mitochondrial oxidant stress [30
]. No data are available on the intrahepatic or systemic oxidative stress among postnecrotic ALF. Among patients with nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease, both increased oxidative stress [31
] and an immune response to lipid peroxidation products have been shown to aggravate liver injury [32
Further support for the physiologic significance of the high oxidative stress is reflected by the depleted systemic antioxidant reserves. We found a significant negative correlation between the TBARS and the FRAP levels. Therefore, the levels of antioxidant reserves may be reduced by the increased utilization for quenching of the oxidant stress. Poor oral intake during the prodromal and hepatitis phase preceding the liver failure may also contribute to the depleted antioxidant reserves in these patients. Interestingly, among the survivors, the TBARS level decreased through the first week. This would reflect decreasing oxidative stress as the liver recovers. However, the oxidative stress at the end of first week still continued to be significantly higher than control levels. Also the antioxidant levels remained significantly lower even after 1 week among recovering patients, which indicates that there was a hyperdeficit of antioxidants during the acute phase of the disease.
We did not find a higher level of oxidative stress among the nonsurvivors. Also, we did not find any relation of oxidative stress with the complications of ALF. This is because oxidative stress may be a reflection of hepatocyte injury rather than having a causal role. The limitations of the present study include the small number of patients. A type-2 error might have underpowered the study to detect the clinical correlations of the level of oxidative stress. Another shortcoming was that normal levels for the assays among pregnant women were not known. Because a large number (11/20) of the females were pregnant, this might have influenced the comparisons. Finally, local milieu in the remaining hepatocytes might be different from the circulatory compartment. Perlemuter et al. [33
] have recently reported that erythrocyte and plasma antioxidant defenses did not reflect intrahepatic peroxidation in patients with NAFLD. This discrepancy between the systemic and intrahepatic oxidative stress and the antioxidant defenses in the setting of ALF cannot be discounted. Future studies should compare the level of oxidative stress between ALF and severe hepatitis without liver failure.
In conclusion, this study suggested that there is a high level of systemic oxidative stress when the patient presents with ALF along with a deficit in antioxidant defenses. The correlation of oxidative stress with disease severity and clinical outcomes and the influence of antioxidants as a therapeutic modality in ALF need to be studied further.