Marcel Zeegers

Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure

IntroductionPatients with acute-on-chronic liver failure show an aggravated hyperdynamic circulation. We evaluated, in a controlled manner, potential changes in systemic haemodynamics induced by the molecular adsorbent recirculating system (MARS) and the Prometheus system liver detoxification devices in a group of patients with acute-on-chronic liver failure.MethodsEighteen patients (51.2 ± 2.3 years old; Child–Pugh score, 12.5 ± 0.2; Maddrey score, 63.1 ± 5.0; hepatic venous pressure gradient, 17.6 ± 0.9 mmHg) with biopsy-proven alcoholic cirrhosis and superimposed alcoholic hepatitis were either treated with standard medical therapy (SMT) combined with MARS (n = 6) or Prometheus (n = 6) or were treated with SMT alone (n = 6) on three consecutive days (6 hours/session). Liver tests, systemic haemodynamics and vasoactive substances were determined before and after each session.ResultsGroups were comparable for baseline haemodynamics and levels of vasoactive substances. Both MARS and Prometheus decreased serum bilirubin levels (P < 0.005 versus SMT), the Prometheus device being more effective than MARS (P = 0.002). Only MARS showed significant improvement in the mean arterial pressure (Δchange, +9 ± 2.4 mmHg versus -0.3 ± 2.4 mmHg with Prometheus and -5.2 ± 2.1 mmHg with SMT, P < 0.05) and in the systemic vascular resistance index (Δchange, +131.5 ± 46.2 dyne.s/cm5/m2 versus -92.8 ± 85.2 dyne.s/cm5/m2with Prometheus and -30.7 ± 32.5 dyne.s/cm5/m2 with SMT; P < 0.05), while the cardiac index and central filling remained constant. This circulatory improvement in the MARS group was paralleled by a decrease in plasma renin activity (P < 0.05), aldosterone (P < 0.03), norepinephrine (P < 0.05), vasopressin (P = 0.005) and nitrate/nitrite levels (P < 0.02).ConclusionThe MARS device, and not the Prometheus device, significantly attenuates the hyperdynamic circulation in acute-on-chronic liver failure, presumably by a difference in removal rate of certain vasoactive substances. These findings suggest conspicuous conceptual differences among the albumin dialysis devices.

A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis

Reduced intrahepatic endothelial nitric oxide synthase (eNOS) activity contributes to the pathogenesis of portal hypertension (PHT) associated with cirrhosis. We evaluated whether asymmetric dimethylarginine (ADMA), a putative endogenous NOS inhibitor, may be involved in PHT associated with cirrhosis. Two rat models of cirrhosis (thioacetamide [TAA]‐induced and bile duct excision [BDE]‐induced, n = 10 each), one rat model of PHT without cirrhosis (partial portal vein–ligated [PPVL], n = 10), and sham‐operated control rats (n = 10) were studied. We assessed hepatic NOS activity, eNOS protein expression, plasma ADMA levels, and intrahepatic endothelial function. To evaluate intrahepatic endothelial function, concentration–effect curves of acetylcholine were determined in situ in perfused normal rat livers and livers of rats with TAA‐ or BDE‐induced cirrhosis (n = 10) that had been preincubated with either vehicle or ADMA; in addition, measurements of nitrite/nitrate (NOx) and ADMA were made in perfusates. Both models of cirrhosis exhibited decreased hepatic NOS activity. In rats with TAA‐induced cirrhosis, this decrease was associated with reduced hepatic eNOS protein levels and immunoreactivity. Rats with BDE‐induced cirrhosis had eNOS protein levels comparable to those in control rats but exhibited significantly higher plasma ADMA levels than those in all other groups. In normal perfused liver, ADMA induced impaired endothelium‐dependent vasorelaxation and reduced NOx perfusate levels, phenomena that were mimicked by NG‐nitro‐L‐arginine‐methyl ester. In contrast to perfused livers with cirrhosis induced by TAA, impaired endothelial cell‐mediated relaxation in perfused livers with cirrhosis induced by BDE was exacerbated by ADMA and was associated with a decreased rate of removal of ADMA (34.3% ± 6.0% vs. 70.9% ± 3.2%). In conclusion, in rats with TAA‐induced cirrhosis, decreased eNOS enzyme levels seem to be responsible for impaired NOS activity; in rats with biliary cirrhosis, an endogenous NOS inhibitor, ADMA, may mediate decreased NOS activity. (HEPATOLOGY 2005;42:1382–1390.)

A stable model of cirrhotic portal hypertension in the rat: thioacetamide revisited.

Background  Cirrhotic animal models are vital to investigate complications of chronic liver disease. We chronologically characterized the effect of thioacetamide, administrated orally and adapted weekly to weight changes, focusing on the optimal moment to obtain all typical features of portal hypertension and cirrhosis.

Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver

Background/Objective: Carbon monoxide (CO) produced by haem‐oxygenase isoforms (HO‐1 & HO‐2) is involved in the regulation of systemic vascular tone. We aimed to elucidate the vasoregulatory role of CO in the microcirculation in normal and thioacetamide cirrhotic rat livers.

Increased serum phospholipase A2 activity after non-heart-beating donor liver transplantation and association with ischemia-reperfusion injury.

BACKGROUND Secretory phospholipase A(2) (sPLA(2)) degrades cell membrane phospholipids and plays an important role in the synthesis of pro-inflammatory lipid mediators (arachidonic acid and cytokines) during inflammatory events such as ischemia-reperfusion injury after liver transplantation (LTx). A role for sPLA(2) in LTx from non-heart-beating donors (NHBD) has never been demonstrated. Furthermore data on the natural sPLA(2) inhibition capacity are scarce. MATERIALS AND METHODS Using our previously validated pig model of NHBD-LTx, we evaluated changes in sPLA(2) enzyme activity in serum early after reperfusion of livers exposed to warm ischemia. Porcine livers were exposed to incremental periods of warm ischemia, procured, and transplanted after 4 h of cold storage. In serum samples, collected prior to and after reperfusion, sPLA(2) enzyme activity, tumor necrosis factor-alpha, and interleukin-6 levels were determined. RESULTS After reperfusion, sPLA(2) activity increased and peaked significantly at 60 min in recipients with primary nonfunction (PNF). Tumor necrosis factor-alpha and interleukin-6 peaked later (at 180 min) in these PNF recipients. We observed a strong natural inhibition of sPLA(2) activity in serum at baseline; this inhibition was substantial reduced 1 h after reperfusion in both PNF and non-PNF recipients. In the non-PNF recipients, however, this natural PLA(2) inhibition was restored within 24 h after reperfusion. CONCLUSIONS This study suggests that an increased sPLA(2) activity and a reduced inhibition may play an important role in the pathogenesis of ischemia-reperfusion injury of NHBD liver grafts.