Hepatic apolipoprotein production in liver cirrhosis

Abstract

The liver represents the major site of apolipoprotein metabolism, and therefore determines concentrations of lipoprotein particles. So far there are no data about arterial and hepatic venous apolipoprotein concentrations in patients with documented liver cirrhosis. We have studied 20 patients (Child A=4, Child B=9, Child C=7) of different etiology (cholestatic liver disease= 7, non-cholestatic=13). All studied patients received hepatic venous catherization. Liver blood flow was assessed by ICG steady state infusion method. Arterial and hepatic venous blood samples were obtained and assayed for the concentrations of apolipoprotein (apo) A-I, apoB and apoE using a standardized, nephelome~c assay. The mean concentrations of apoA-I were 96 mg/dl in the artery and 93 mg/dl in the hepatic vein. The liver extraction rate was 16.7 rag/rain (range -51,9-97.0 mg/min). The mean concentrations of apnB were 75 mg/dl in the artery and 76 mg/dl in the hepatic vein. The mean synthesis rate was 8.9 mg/min (range -21.8-43.7). The mean concentrations of apoE Were 9.1 mg/dl in the artery and 10.4 mg/dl in the hepatic vein. ApoA-I and apoB concentrations are significantly higher in Child A patients compared to Child B and C (p=0.009 and p=0.03, respectively). However apoA-I concentration is not correlated with ICG clearance and ICG half-life time. These data confirm the data of the lipoprotein subfractions determined in cirrhotic patients. Interestingly, patients with cholestatic disease have decreased apoB levels as well as decreased production rates (p<0.05) in contrast to apoE, which is significantly increased (p<0.05). In summary, although apoA-I is a good predictor for liver synthesis, it does not correlate with liver function tests in our studied patients and the degree of portal hypertension. ApoE seems to be inverse correlated in cholestatic liver disease compared to apoA-I and apoB. Further studies are required to get more insights into the liver dependent apolipoprotein metabolism. Q ENDOGENOUS GLUCOCORTICOIDS INHIBIT LEUKOCYTE RECRUITMENT TO INFLAMMATORY SITES IN CHOLESTATIC RATS. K. Tiandra, M. Marie, P. Kubcs, M.G. Swain, GIRG, Calgary, Canada. Cholestatic patients have a high incidence of septic complications. Glucocorticoids inhibit leukocyte recruitment to inflammatory sites and we have recently documented elevated plasma glucocorticoid levels (corticosterone; C) in cholestatic rats (Gastroenterology 107:1469,1994). Therefore, we investigated the role of endogenous C in leukocyte recruitment during carrageenan-induced inflammation in cholestatic rats. Rats were bile duct (BDR) or sham (sham) reseeted and injected 5 days later with a 2% carragecnan solution into a preformed air pouch on their hacks. 5 hrs later rats were sacrificed, plasma C levels determined, and the inflammatory response quantitated by measuring exudate cell count (cell#/ml) and MPO activity (U/ml). BDR rats exhibited an impaired inflammatory response reflected by 52 % and 42 % decreases in exudatc cell count and MPO activity respectively compared to sham rats (all p<0.05). Exudate cell differentials by cytospot were similar in BDR and sham rats. Total C levels were similar in BDR and sham rats; however, free C levels (bioactive form) were 5-fold higher in BDR than sham rats (p<0.001). To investigate whether the elevated C levels in BDR rats were suppressing inflammation, we prctreated BDR and sham rats with RU486 (20mg/kg), a C receptor antagonist, before earrageenan injection. Treatment with RU486 significantly increased the inflammatory response in BDR (to sham levels) but not in sham rats; suggesting endogenous C was suppressing the inflammatory response in BDR rats. We have previously shown that BDR plasma is anti-adhesive to lcukocytcs in vitro (Gastroenterology 106; A992,1993). To investigate whether endogenous C in BDR plasma was inhibiting the inflammatory resEonsc by interfering with leukocyte adhesion, we examined PMA-stimulated 51C-labelled rat leukocyte adhesion to a rat biological substratum in vitro. Leukocyte adhesion was inhibited to a similar extent by plasma derived from either BDR or adrenalectomized BDR (devoid of C) rats. Furthermore, the addition of RU486 with BDR plasma did not alter leukocyte adhesion from that observed in the presence of BDR plasma alone. In conclusion, endogenous C contributes to an inhibition of the inflammatory response in BDR rats. This C effect is not due to an inhibition of leukocyte adhesion. Glucocorticoids may inhibit leukocyte recruitment to inflammatory sites in cholestasis by suppressing inflammatory mediator generation or by preventing the upregulation of endothelial adhesion molecules (eg.ICAM-1).