Artificial and bioartificial liver support:A review of perfusion treatment for hepatic failure patients

Liver transplantation and blood purification therapy,including plasmapheresis,hemodiafiltration,and bioartificial liver support,are the available treatments for patients with severe hepatic failure.Bioartificial liver support,in which living liver tissue is used to support hepatic function,has been anticipated as an effective treatment for hepatic failure.The two mainstream systems developed for bioartificial liver support are extracorporeal whole liver perfusion(ECLP)and bioreactor systems.Comparing various types of bioartificial liver in view of function,safety,and operability,we concluded that the best efficacy can be provided by the ECLP system.Moreover,in our subsequent experiments comparing ECLP and apheresis therapy,ECLP offers more ammonia metabolism than HD and HF.In addition,ECLP can compensate amino acid imbalance and can secret bile.A controversial point with ECLP is the procedure is labor intensive,resulting in high costs.However,ECLP has the potential to reduce elevated serum ammonia levels of hepatic coma patients in a short duration.When these problems are solved,bioartificial liver support,especially ECLP,can be adopted as an option in ordinary clinical therapy to treat patients with hepatic failure.

Establishment and evaluation of the system of extracorporeal liver perfusion in pigs

BACKGROUND; In recent years, extracorporeal liver per- fusion (ECLP) has been regarded as a treatment of acute liver failure ( ALF ); but the system of ECLP has many problems. The purpose of this experiment was to detect the factors affecting the system of ECLP and to establish a sta- ble and effective system of ECLP. METHODS; Livers were harvested from health pigs, ac- cording to the different styles of perfusion and oxygena- tion, which were randomly divided into 3 groups. The liv- ers in group A (n =4) were subjected to single portal vein perfusion, oxygenating perfusion blood; the livers in group B (n =4) to dual ( portal vein and hepatic artery) vessel perfusion, oxygenating blood, together; and the livers in group C ( n = 4) to dual (portal vein and hepatic artery) vessel perfusion, but oxygenating blood, separately. The perfusion time, the data of bile production, and hemody- namic parameters of extracorporeal livers in each group were tested. The histological examination of liver tissues from each group was performed at the end of perfusion. RESULTS: The perfusion time of the liver in group A is significantly shorter than in groups B and C (P<0.05). At 1 , 3 , 6 hours after perfusion, the data of bile production and hemodynamic parameters of livers in group A were sta- tistically different from those of livers in groups B and C (P<0.05). At 1, 3, 6 hours after perfusion, the data of group B were not statistically different from those of livers in group C (P>0.05). But at 12 hours after perfusion, the data of group B were statistically different from those of liv- ers in group C (P<0.01). CONCLUSION: The system of ECLP, which is performed by dual ( portal vein and hepatic artery) vessel perfusionand oxygenating blood separately, is more stable and effec- tive to keep the function of extracorporeal liver.

Preservation of non-heart-beating donor livers in extracorporeal liver perfusion and histidine-trytophan-ketoglutarate solution

AIM: To compare the preservation of non-heart- beating donor (NHBD) livers in cold histidine-trytophan- ketoglutarate (HTK) solution and extracorporeal liver perfusion (ECLP). METHODS: Livers harvested from health pigs were stored for 10 h in cold HTK solution (group A, n = 4) or perfused with oxygenated autologous blood at body temperature (group B, n = 4). Both groups were then tested on the circuit for 4 h. Bile production, hemodynamic parameters, hepatocyte markers and reperfusion injury of extracorporeal livers were tested in each group. Liver tissues from each group were examined at the end of reperfusion. RESULTS: At 1, 2, 3 and 4 h after reperfusion, bile production, hemodynamic parameters, hepatocyte markers and reperfusion injury of livers in group A were statistically different from those in group B (P < 0.05 or P < 0.01). CONCLUSION: ECLP is better than HTK solution to preserve NHBD livers. ECLP can assess the graft viabilitybefore liver transplantation.

Implementing an innovated liver ex-situ machine perfusion technology:The 2018 Joint International Congress of ILTS,ELITA and LICAGE

The 2018 Joint International Congress of ILTS,ELITA and LICAGE were held in Lisbon,Portugal on May 23–26,2018.The exciting and innovative program brought together 1144 experts in liver transplantation(LT)such as surgeons,physicians or basic scientists from 61 countries.The presentations included 110 invited speakers,181 oral presentations,and 545 posters.This editorial highlights some of the most innovative and impactful presentations in

Machine perfusion of the liver:Putting the puzzle pieces together

The realm of extended criteria liver transplantation created the'adjacent possible'for dynamic organ preservation.Machine perfusion of the liver greatly expanded donor organ preservation possibilities,reaching before unattainable goals,including the mitigation of ischemia-reperfusion injury,viability assessment,and organ reconditioning prior to transplantation.However,current scientific evidence lacks uniformity between studies,perfusion protocols,and acceptance criteria.Construction of collaborative research networks for sharing knowledge should,therefore,enable the development of high-level evidence and guidelines for machine perfusion utilization,including donor acceptance criteria.Finally,this approach shall guarantee conditions for further progress to occur.

Contrast-enhanced ultrasound evaluation of hepatic microvascular changes in liver diseases

AIM： To assess if software assisted-contrast-enhanced ultrasonography （CEUS） provides reproducible perfu- sion parameters of hepatic parenchyma in patients af- fected by chronic liver disease. METHODS： Forty patients with chronic viral liver dis- ease, with （n = 20） or without （n = 20） cirrhosis, and 10 healthy subjects underwent CEUS and video re- cordings of each examination were then analysed with Esaote＇s Qontrast software. CEUS dedicated software Qontrast was used to determine peak （the maximum signal intensity）, time to peak （TTP）, region of blood value （RBV） proportional to the area under the time- intensity curve, mean transit time （MTT） measured in seconds and region of blood flow （RBF）. RESULTS： Qontrast-assisted CEUS parameters dis- played high inter-observer reproducibility （κ： coefficients of 0.87 for MTT and 0.90 TTP）. When the region of in-terest included a main hepatic vein, Qontrast-calculated TTP was significantly shorter in cirrhotic patients （vs non-cirrhotics and healthy subjects） （71.0 ± 11.3 s vs 82.4±15.6 s, 86.3±20.3 s, P 〈 0.05）. MTIs in the patients with liver cirrhosis were significantly shorter than those of controls （111.9±22.0 s vs 139.4±39.8 s, P 〈 0.05）, but there was no significant difference between the cirrhotic and non-cirrhotic groups （111.9± 22.0 s vs 110.3 ±14.6 s）. Peak enhancement in the patients with liver cirrhosis was also higher than that observed in controls （23.9± 5.9 vs 18.9±7.1, P = 0.05）. There were no significant intergroup differences in the RBVs and RBFs. CONCLUSION： Qontrast-assisted CEUS revealed re- producible differences in liver perfusion parameters during the development of hepatic fibrogenesis.

AngiotensinⅡor epinephrine hemodynamic and metabolic responses in the liver of L-NAME induced hypertension and spontaneous hypertensive rats

AIM To study hepatic vasoconstriction and glucose release induced by angiotensin(Ang)Ⅱ or Epi in rats with pharmacological hypertension and spontaneously hypertensive rat(SHR).METHODS Isolated liver perfusion was performed following portal vein and vena cava cannulation; AngⅡ or epinephrine(Epi) was injected in bolus and portal pressure monitored; glucose release was measured in perfusate aliquots. RESULTS The portal hypertensive response(PHR) and the glucose release induced by AngⅡ of L-NAME were similar to normal rats(WIS). On the other hand, the PHR inducedby Epi in L-NAME was higher whereas the glucose release was lower compared to WIS. Despite the similar glycogen content, glucose release induced by AngⅡ was lower in SHR compared to Wistar-Kyoto rats although both PHR and glucose release induced by Epi in were similar. CONCLUSION AngⅡ and Epi responses are altered in different ways in these hypertension models. Our results suggest that inhibition of NO production seems to be involved in the hepatic effects induced by Epi but not by AngⅡ; the diminished glucose release induced by AngⅡ in SHR is not related to glycogen content.

BRIEF HYPOXIA PRECEDING E.COLI BACTEREMIA DOWNREGULATES HEPATIC TNF-α PRODUCTION

Hepatic TNF production following gramnegative bacteremia or hypovolemic shock predisposes to acute lung injury. However, TNF expression may be modified by the manner in which the hepatic O2 supply is reduced and equally important, its timing relative to bacteremia. Brief secondary hypoxic stress of bufferperfused rat livers downregulates E. Coli (EC)induced TNF expression whereas lowflow ischemia preceding EC increases subsequent TNF production owing to reactive O2 species (ROS). Here we determined whether 30 min of constantflow hypoxia preceding 109 intraportal EC likewise increases antigenic and bioactive TNF protein concentrations during reoxygenation via production of ROS. Multiple groups (n=38) were studied over 180 minutes, circulation antigenic TNF decreased in H/R+EC vs. EC controls (1 939640 vs. 12 4072 476 g/L at t=180 min; P<001, along with TNF bioactivity). TNF protein were not restored to control levels in ALLO+H/R+EC. Thus, ECinduced hepatic TNF production and export is strongly O2dependent in intact liver regardless of the generation of ROS or the sequence of bacteremia and modest hypoxic stress.

Modified cold storage of rat livers with self-made HYD solution

Objective To investigate the cold preservation effect on rat livers of a modified storage method with self-made HYD solution.Methods The vascular bed of rat livers was expanded with an additional 20 to 40?ml self-made HYD solution/100?g liver. After resection of the liver, the extra HYD solution (expressed as % liver weight) was entrapped via portal infusion by tying off the supra- and infra-hepatic inferior vena cava. Forty rats were randomly divided into four groups including control group with conventional storage method, and 20%, 30% and 40% groups according to the amount of extra HYD solution. We compared the preservation effect of the modified storage method with that of the conventional storage method using an isolated perfused rat liver model.Results Bile production and all the indices of hepatic microcirculation including portal perfusion pressure, endothelin-1 in the effluent, trypan blue distribution time and histology were significantly superior in the modified method groups compared to those in the control group (P<0.05). The contents of dihydroxybenzoic acid (DHBA) in the modified method groups were significantly lower than those in the control group (P<0.05). Liver enzymes activities in the 30% group were markedly lower than those in the control group (P<0.05). The preservation effect on rat liver in the 30% group was the best among the modified method groups.Conclusion The modified cold storage method is effective and may have potential for clinical application in liver preservation.