Liver support systems

Hepatic insufficiency implies the inability of the liver to carry out its metabolic, excretory and detoxifying functions owing to a decrease in the number of functional hepatocytes or because their normal activity is altered.Hepatic insufficiency can be acute or chronic. Acute liver failure (ALF) is produced without a previous liver disease whereas the chronic liver failure is the consequence of a liver disease evolution over a long period of time, independently of its etiology and degree.The incidence of acute liver failure is estimated to be of 1-6 cases per million of person. ALF can be subclassified into hyperacute, acute and subacute based on when hepatic encephalopathy occurs following the onset of jaundice (O`Grady et al., 1993), and this classification can sometimes help to identify the etiology, potential complications and patient prognosis (Table 1).In hyperacute and acute liver failure the clinical picture develops rapidly with progressive encephalopathy and multiorgan dysfunction such as hyperdynamic circulation, coagulopathy, acute renal and respiratory insufficiency, severe metabolic alterations and cerebral edema that can lead to brain death. In these cases the mortality without liver transplantation (LTx) ranges between 40-80%. LTx is the only effective treatment for these patients although it requires a precise indication and timing to achieve good results. Nevertheless, due to the scarcity of organs to carry out liver transplantations, it is estimated that one third of patients with ALF die while waiting to be transplanted.On the other hand, a patient with a chronic hepatic disease can suffer an acute decompensation of liver function following a precipitating event such as variceal bleeding, sepsis and excessive alcohol intake among others that can lead to a condition referred to as acute-on-chronic liver failure (ACLF).Both types of hepatic insufficiency, ALF and ACLF, can potentially be reversible and liver functionality can return to a level similar to that prior to the insult or precipitating event.LTx is the only treatment that has shown an improvement in the prognosis and survival with most severe cases of ALF. Nevertheless, cost and donor scarcity have prompted researchers to look for new supportive treatments that can act as “bridge” to the transplant procedure. By stabilizing the patient’s clinical state, or by creating the right conditions that could allow the recovery of native liver functions, both detoxification and synthesis can improve, after an episode of ALF or ACLF.Basically, three different types of supportive therapies have been developed: bio-artificial, artificial and hybrid liver support systems (Table 2).Bio-artificial liver support systems are experimental extracorporeal devices that use living cell lines to provide detoxification and synthesis support to the failing liver. Bio-artificial liver (BAL) Hepatassist 2000 uses porcine hepatocytes11 whereas ELAD system employs hepatocytes derived from human hepatoblastoma C3A cell lines.9, Both techniques can produce, in fulminat hepatic failure (FHF), an improvement of hepatic encephalopathy grade and biochemical parameters. Nevertheless, they are therapies with high complexity that require a complex logistic approach for implementation; a very high cost and possible inducement of important side effects such as immunological issues (porcine endogenous retrovirus transmission), infectious complications and tumor transmigration have been documented. Other biological hepatic systems are Bioartificial Liver Support (BLSS)12 and Radial Flow Bioreactor (RFB).15 Detoxification capacity of these systems is poor and therefore they must be used combined with other systems to mitigate this deficiency. Today its use is limited to centers with high experience in their application.Artificial liver support systems are aimed to temporally replace native liver detoxification functions and they use albumin as scavenger molecule to clear the toxins involved in the physiopathology of the failing liver. Most of the toxins that accumulate in the plasma of patients with liver insufficiency are protein bound, and therefore conventional renal dialysis techniques, such as hemofiltration, hemodialysis or hemodiafiltration are not able to adequately eliminate them.Between the different albumin dialysis modalities, single pass albumin dialysis (SPAD) has shown some positive results at a very high cost; it has been proposed that lowering the concentration of albumin in the dialysate does not seem to affect the detoxification capability of the procedure. Nevertheless, the most widely used systems today are based on hemodialysis and adsorption. These systems use conventional dialysis methods with an albumin containing dialysate that is latter regenerate by means of adsorption columns, filled with activated charcoal and ion exchange resins. At present, there are two artificial extracorporeal liver support systems: the Molecular Adsorbents Recirculating System (MARS)10 from Gambro and Fractionated Plasma Separation and Adsorption (FPSA), commercialised as Prometheus (PROM) from Fresenius Medical Care.13 Of the two therapies, MARS is the most frequently studied, and clinically used system to date.