The use of the ELAD at Kings College Hospital

At King's College Hospital, the author and colleagues have evaluated the ELAD bioartificial liver system, based on a human liver cell line (C3A) which is considered to retain good hepatocyte function and which is contained in the extracapillary compartment of a hollow fibre dialyser [9]. Two cartridges (400 g cells?) in series were perfused continuously with blood from patients with ALF for up to 1 week. Twelve patients were treated with the ELAD and 12 were followed similarly as controls [10]. A series of clinical and biochemical tests was performed to assess the effects of this treatment on the patients. Changes in encephalopathy and haemodynamic variables were used as clinical biomarkers. The intracranial pressure was only measured in a small number of the cases. For metabolic function, arterial blood ammonia resulting from the failure of urea synthesis in the liver was measured using the Ammonia Checker II (Biomen Ltd.) and showed some decrease with ELAD treatment initially, but this was not statistically significant. Blood lactate, which is normally cleared by the liver, was measured using an analyser (YSI Ltd.) and increased slightly in both treatment and control groups. The galactose elimination capacity is a measure of dynamic liver function and is used as a prognostic marker in ALF [11]. Galactose is infused into the patient and the plasma clearance (GEC) determined by enzyme assay (Boehringer Mannheim). A small but significant increase in GEC was seen in the ELAD-treated group in the first 6 hours. The

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Figure 19.1 The arterial ketone body ratio (AKBR) on admission in acute liver failure patients entered into the ELAD study. Patients who underwent liver transplantation are included as nonsurvivors. Horizontal bars show median values.

arterial ketone body ratio of acetoacetate: ^-hydroxybutyrate (AKBR) developed by Ozawa et al. [12] is considered to reflect hepatic mitochondrial redox state -which is a measure of hepatic energy charge (ATP production). Normal values of AKBR are around 1, with values <0.4 denoting patients at risk and those of <0.25 indicating fatality. Initial AKBR values assayed using an enzymatic assay (Ketorex kit, Sanawa Co.) in the ELAD patients are shown in Figure 19.1 related to outcome, AKBR being significantly lower in those that died. The difficulty of measuring the function of the device in use was mentioned above, but the oxygen extraction/consumption across it can give a measure of overall cellular metabolic activity. With the ELAD, maximum oxygen extraction was observed after 48 hours of perfusion with a value of about 2.5 ml/min, which, if related to normal human liver values, approximates to a maximum of about 80-90 g of functioning cells. Good oxygenation is an essential component to ensure optimal cell function is maintained, but diffusion of oxygen across the polymer fibres of the bioreactor cartridge may be limiting. Another key measure of liver function is the metabolism of bile acids but measurement of total bile acids in the study showed little change over the first 24

hours in both ELAD-treated and control patients. There is no equivalent of the biliary system in a bioartificial liver device unless suitable adsorbents are incorporated into the circuit, so excretion is dependent on bile flow in the native liver. Similarly, determination of conjugation of bilirubin should be a useful metabolic parameter, which is also dependent on final biliary elimination, but no additional conjugation was observed with the ELAD. In this study, any assays of CYP-depen-dent drug-metabolizing activity were not performed, which might have been helpful. There are limited substrates for such tests, with the clearance of lignocaine (monoethylglycinexylidide [MEGX]) test often being used, but there were concerns about its possible cardiac effects with repeated use in patients with ALF. This type of function is an area for the development of future tests that can be used in vivo.

Protein synthetic function of the device was monitored mainly with blood clotting tests. Factor V is a recognized and widely used prognostic marker in ALF. No significant effects were observed with the ELAD compared with the controls, but there was a progressive increase in factor V in both treated and untreated patients reflecting the overall survival of around 60% in both groups. The balance of clotting factors to inhibitors is also important, with the tendency to disseminated intravascular coagulation in ALF. Measurements of antithrombin III showed a tendency to decrease in both patient groups, indicating a less rapid recovery in this inhibitory activity. For fibrinogen, a significant reduction was seen in the first 6 hours of treatment, probably reflecting the binding of fibrinogen to components of the perfusion circuit, but this did not persist subsequently. In terms of other markers of the effects of the extracorporeal circuit, plasma levels of the terminal complement component (C5b-9) were determined. There were small increases in the first 6 hours with the ELAD, indicating activation of complement, but these increases were not greatly outside the normal range.

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