Albumin-bound substances - a new target in liver failure therapy

Human serum albumin (HSA) is the most abundant soluble protein of the body and the most prominent molecule in the plasma. Representing 60 % of the mass of the plasma proteins, HSA is responsible for 80 % of the colloid osmotic pressure of the plasma. It accounts for almost all of the macromolecular anions of the plasma and supplies most of the acid/base buffering action of the plasma proteins, the latter being especially important in extravascular fluids like ascites. It has protective functions such as sequestration of exogenous toxic compounds and is an carries antioxidant properties. Last not least HSA is a transport protein for such drugs and metabolites, that do not freely solve in water [1]. It represents the most important transporter for liver-bound hydrophobic metabolites in man, a function, that is facilitated by the unique three-dimensional structure of the molecule (Figure [1]). A list of the hydrophobic metabolites using HSA is given in Table [1].

Figure 1 Schematic drawing of the albumin including different binding sides (from Carter DC, Advances in Protein Chemistry 1994; 45).

Table 1 Hydrophobic metabolites using human serum albumin as a transporter in extracellular fluid and plasma with increased plasmaconcentrations in hepatic failure Aromatic amino acids Bile acids Bilirubin Copper (Wilson’s disease) Digoxin-like immune-reactive substances Endogenous benzodiazepines Indols Mercaptans Middle and short chain fatty acids Nitric oxide Phenols Prostacyclins Tryptophan

Recently, a number of reports were published that describe favorable therapeutic effects of HSA in different conditions related to chronic liver disease. These comprise of refractory ascites [2], spontaneous bacterial peritonitis [3], and HRS [4]. A number of hypotheses exist about the protective mechanism of the HSA, including the antioxidant and sequestration function [1].

The albumin dialysis MARS (Molecular Adsorbent Recirculating System) is an extracorporeal dialysis method for the combined removal of water-soluble and albumin-bound ligands [5]. MARS uses an albumin-enriched dialysate to facilitate the removal of albumin-bound toxins (ABT) (Figure [1]). It requires a standard dialysis machine or a CVVH monitor (in the trial an AK 10 HFM [Gambro AG, Munich, Germany]) and an extra device to run and monitor a closed loop albumin circuit (e. g. MARS Monitor, Teraklin AG, Rostock, Germany). The blood circuit uses a venovenous access (double lumen catheter) and is driven by the blood roller pump of the dialysis machine resp. CVVH monitor. The blood flow rate is 150-250 ml/min, depending on hemodynamic situation of the patient. Blood is passed through a not albumin permeable high flux dialysis membrane (P 5 S, Gambro, Hechingen, Germany). A closed loop dialysate circuit containing 10-15 % human serum albumin (HSA) is driven by a roller pump of the MARS Monitor with 150/min. The dialysate HSA is passed through the dialysate compartment of the blood dialyzer and subsequently regenerated by dialysis against a bicarbonate buffered dialysate (that is processed by the dialysis machine resp. CVVH monitor) followed by passage through a column with uncoated charcoal and a second column with an anion exchanger resin. Treatment is normally done intermittently for 6-8 h per day.

Figure 2 Schematic drawing of the Molecular Adsorbent Recirculating System (MARS).

MARS showed significant decrease of albumin-bound metabolites like bilirubin, bile acids or fatty acids in patients with an acute decompensation of their chronic liver failure [6]. This was associated with significant prolongation of survival, e. g. in patients with HRS type I [7]. As the control group in the latter study received hemodiafiltration for the kidney failure present in HRS, the beneficial effect in the MARS group must be attributed to the removal of albumin bound ligands from patients blood through the MARS procedure, as this is the only additional mechanism MARS adds to the conventional techniques of hemodialysis and -filtration.

In the light of these observations, it is postulated, that the accumulation of metabolites, that use albumin as a transporter protein, as it occurs during a detoxification insufficiency of the liver, contributes to the pathogenetical findings in the different forms of liver failure that are associated with such a detoxification insufficiency (intractable pruritus, hepatic encephalopathy, disturbed hemodynamics, and renal failure). Moreover, the effective removal of such metabolites from the circulating albumin, e. g. by an extracorporeal method like the albumin dialysis MARS, may lead to a redistribution of the tissue-bound metabolites from the cells to the albumin transporters, rendering these metabolites untoxic for the tissues.

References

• 1 All about Albumin. Peters T Jr Biochemistry, Genetics, and Medical Applications San Diego; Academic Press 1996: 234-240
• 2 Gentilini P, Casini-Raggi V, Di Fiore G. et al . Albumin improves the response to diuretics in patients with cirrhosis and ascites: Results of a randomized, controlled trial.  J Hepatol. 1999;  30 639-645
• 3 Sort P, Navasa M, Arroyo V. et al . Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.  N Engl J Med. 1999;  341 403-409
• 4 Uriz J, Gines P, Cardenas A. et al . Terlipressin plus albumin infusion: An effective and safe therapy of hepatorenal syndrome.  J Hepatol. 2000;  33 43-48
• 5 Stange J, Mitzner S, Ramlow W. et al . A new procedure for the removal of protein bound drugs and toxins.  ASAIO J. 1993;  39 M621-M625
• 6 Stange J, Mitzner S, Klammt S. et al . Liver Support by Extracorporeal Blood Purification - a Clinical Observation.  Liver Transpl. 2000;  6 603-613
• 7 Mitzner S, Stange J, Klammt S. et al . Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: Results of a prospective, controlled clinical trial.  Liver Transpl. 2000;  6 277-286

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