Dietary copper triggers onset of fulminant hepatitis in the Long-Evans cinnamon rat model

AIM： To investigate the impact of dietary copper given at different time points on the onset of fulminant hepatitis. METHODS： The Long-Evans cinnamon （LEC） rat mod- el of Wilson＇s disease （WD） was used to study the im- pact of high dietary copper （hCu） on the induction of fulminant hepatitis at early or late time points of life. High Cu diet was started in rat pups or in adults （month 5） for three months. Animals that received reduced di- etary copper （rCu） throughout their lifetime served as a control. Hepatitis-associated serum markers （alanine aminotransferase, aspartate transaminase, bilirubin） were analyzed in animal groups receiving hCu or rCu. Liver copper content and liver histology were revealed at sacrifice. A set of 5 marker genes previously found to be affected in injured liver and which are related to angiogenesis （Vegfa）, fat metabolism （Srebf1）, ex- tracellular matrix （Timp1）, oxidative stress （Hmox1）, and the cell cycle （Cdknla） were analyzed by real-time polymerase chain reaction. RESULTS： Regardless of the time point when hCu was started, LEC rats （35/36） developed fulminant hepati- tis and died. Animals receiving rCu （36/36） remained healthy, did not develop hepatitis, and survived long term without symptoms of overt disease, although liver copper accumulated in adult animals （477 ± 75 μg/g）. With regard to start of hCu, onset of fulminant hepatitis was significantly （P 〈 0.001） earlier in adults （35±9 d） that showed pre-accumulation of liver copper as com- pared to the pup group （77±15 d）. Hepatitis-associ- ated serum markers, liver copper and liver histology, as well as gene expression, were affected in LEC rats re- ceiving hCu. However, except for early and rapid onset of hepatitis, biochemical and molecular markers were similar at the early and late time points of disease. CONCLUSION： Rapid onset of fulminant hepatitis in asymptomatic LEC rats with elevated liver copper sug- gests that there is a critical threshold of liver copper which is important to trigger the course of WD.

Hyperlactatemia in patients with non-acetaminophen-related acute liver failure

AIM： To characterize hyperlactatemia in patients with non-acetaminophen acute liver failure （ALF） in an attempt to clarify the mechanisms implicated and the role as a prognosis factor. METHODS： In the setting of liver transplantation, 63 consecutive patients with non-acetaminophen acute liver failure were studied in relation to tissue oxygenation, hemodynamic and metabolic parameters. Before and after transplantation, the number of infected patients and outcome were registered. RESULTS： Acute ALF showed higher levels of lactate than subacute ALF （5.4 ± 1 mmol/L versus 2.2 ± 0.6 mmol/L, P= 0.01）. Oxygenation parameters were within the normal range. Lactate levels showed good correlation with respiratory quotient （r=0.759, P〈 0.005）, mean glucose administration （r= 0.664, P= 0.01） and encephalopathy （r= 0.698, P= 0.02）, but not with splanchnic arteriovenous difference in PCO2, pH and the presence of infection （P=0.1）. Portal vein lactate was higher （P〈0.05） than arterial and mixed venous lactate, suggesting its production of hyperlactatemia in the intestine and spleen. The presence of infection was an independent predictor of survival. CONCLUSION： Hyperlactatemia is not a prognosis factor due to byproduct of the overall acceleration in glycolysis.