Hepatorenal syndrome

Q What is the current status of liver support devices in the United States?

A Rhonda K. Martin, RN, MS, MLT(ASCP), CCRN, CNS/ANP-C, replies:

Liver disease now ranks as the eleventh leading cause of death in the United States, (1) partly because of the peak in incidence of end-stage liver disease due to hepatitis C. Using a computer cohort simulation, Wong et al (2) predict 193000 US deaths between 2010 and 2019 from complications of hepatitis C. An obvious need remains to support liver disease patients with devices that can serve as a bridge to liver transplantation or ideally to regeneration and recovery of native organ function.

The development and availability of liver support devices, however, have lagged behind those of other artificial organ support devices, such as renal dialysis equipment, ventilators, membrane oxygenators, and ventricular support devices. This delay is related to the complexity of liver functions and the difficulty in developing technology to mimic these functions. The ideal liver support device must be able to regulate fluid, electrolyte, glucose, and acid-base balance, as well as provide clearance of circulating ammonia, false neurotransmitters (eg, [gamma]-aminobutyric acid), cytokines, and other hepatic toxins (particularly those that are protein-bound, such as bilirubin). The device must also synthesize critical molecules such as albumin, globulins, and clotting factors, and it must orchestrate all these functions to preserve homeostasis and allow hepatic regeneration. The therapy also should cause no complications. (3)

Depending on whether cellular components are used, liver support devices can be classified as nonbiological or biological. With the exception of the Liver Dialysis Unit (Hemotherapies, San Diego, Calif), all devices use a dual-lumen venous access catheter. A synopsis of such devices with their current status is listed in the Table.

Nonbiological Liver Support Devices

Nonbiological support devices use noncellular technologies to mimic certain aspects of liver function. Two devices have been used for this purpose in the United States. The Hemotherapies Liver Dialysis Unit was the first unit approved by the Food and Drug Administration for treatment of drug overdose. It is a single-needle, push-pull plasma filtration device that achieves filtration with a charcoalresin adsorbent in the dialysate. This method targets small-and middle-weight molecular toxins, including certain drugs (including acetaminophen), ammonia, and [gamma]-aminobutyric acid and some large-molecular-weight or protein-bound substances. (3) The Liver Dialysis Unit is no longer on the market. Hemocleanse, Inc, is developing the next generation of this device, the HemoCleanse--DT (DeToxifier). (4)

The Molecular Adsorbent Recirculations System (Teraklin, Rostock, Germany) is a module that attaches to a conventional hemodialysis machine. The patient's blood is circulated through a special hollow-fiber filter with a membrane that promotes uncoupling of proteinbound toxins. The uncoupled, free molecules pass out of the blood compartment, through the filter membrane, and attach to albumin in the dialysate compartment. The dialysate albumin is then regenerated or "cleaned" of toxins by continuously passing over charcoal and anion exchange resin columns, which trap the toxic molecules.

Standard hemodialysis can also be done simultaneously on the module to provide fluid removal and acid-base and electrolyte regulation. With these combined methods, the Molecular Adsorbent Recirculations System removes small-, middle-, and some large-molecular-weight molecules, along with protein-bound toxins, drugs, bilirubin, and bile salts. (5) Phase I and II trials have demonstrated improvement in patients with acute liver failure, primary graft nonfunction after liver transplantation, cholestasis, and hepatorenal syndrome. (6)

Conventional dialytic therapies are also used in part for liver support. These modalities are particularly useful in patients experiencing renal dysfunction, which is often seen with liver disease. Continuous renal replacement therapies are routinely used for fluid, glucose, electrolyte, and acid-base regulation, and for removal of small-to middle-molecular-weight molecules, including some cytokines. Plasmapheresis and therapeutic plasma exchange involve the removal of toxins by removing and replacing plasma. Previous studies showed no advantage to using this technique. (3) More recent case reports describe successful use of therapeutic plasma exchange with continuous renal replacement therapies to bridge patients to transplantation. (7) None of these nonbiological methods provide synthesis of critical substances.

Biological Liver Support Devices

These devices employ isolated liver cells in bioreactors to mimic liver function. Other detoxifying components, such as charcoal and resin columns, are sometimes added to the system. These devices have the advantage of providing some synthetic function and toxin clearance that is comparable to native liver function. Several types are being developed worldwide; 3 types are in active development in the United States with clinical trials in process (Table).

The HepatAssist 2000 (Arbios Systems, Inc, Los Angeles, Calif) uses cryogenically preserved porcine (pig) hepatocytes in the hollow fiber bioreactor. A randomized, controlled phase 2 study did not show an improvement in the primary end point of 30-day survival in the overall study population. Survival was improved, however, in the fulminant/subfulminant liver failure subgroup. (9) The Bioartificial Liver Support System (Excorp Medical Inc, Oakdale, Minn) also uses porcine hepatocytes in its bioreactor. The Extracorporeal Liver Assist Device (Vital Therapies, San Diego, Calif) has cultured liver tumor cells of the C3A line in hollow-fiber cartridges.

Problems in Developing Liver Support Devices

What is the best surface or medium on which to place the hepatocytes? Normal human hepatocytes in vitro will not function; they require proximity to endothelial cells, growth factors, and other substrates to survive and work. (8) Biological liver support devices must provide an adequate mass of hepatocytes to support an adult patient and keep these cells viable and functioning in vitro.

Controlled trials of devices are needed but are difficult to design and fund. Ongoing funding for research and development is required to bring a liver support device to market, but infusion of funds often parallels the stock market and general economy. Safety remains a concern, particularly transmission of disease from the bioreactor hepatocytes. The profession must actively focus on specific areas of development of liver support devices and must research and sequence these activities logically to best use time and resources. The Acute Liver Failure Group, formed in 2003 by 24 US centers and funded by the National Institutes of Health, will examine the role and development of liver support devices as part of its overall goal (T. Hassanein, MD, oral communication, May 2004).

The Future

As clinical trials are completed, it is anticipated that both nonbiological and biological liver support devices will have a place in treating liver failure, with the less expensive nonbiological devices used for less sick patients, and the more costly and complicated biological devices reserved for more critically ill patients with less liver function. (10) Besides liver support devices, other modalities in development include implantable "constructed" livers of hepatocytes grown on an artificial matrix, hepatocyte transplantation, and transgenic xenografts harvested from genetically altered animals to resemble human livers. (9)

References

1. Centers for Disease Control and Prevention. National Vital Statistics Report. 2003;9:11.

2. Wong J, Mcquillan G, McHutchinson J, Paynad T. Estimated future hepatitis C mortality, morbidity, and costs in the U.S. Am J Pub Health. 2000;90:1562-1569.

3. Huges R, Williams R. Use of bioartificial and artificial liver support devices. Semin Liver Dis. 1996;16:435-444.

4. Hemoclense Web site. Available at: www.hemocleanse.com. Accessed June 1, 2004.

5. Mitzner S, Stange J, Klammt S, Peszynski P, Schmidt R. Albumin dialysis using the molecular adsorbent recirculating system. Curr Opin Nephrol Hypertens. 2001;10:777-783.

6. Stange J, Hassanein T, Mehta, Mitzer S, Bartlett R. The Molecular Adsorbent Recycling System as a liver support system based on albumin dialysis: a summary of preclinical investigations, prospective, randomized, controlled clinical trial and clinical experience from 19 centers. Artif Organ. 2002;26:103-110.

7. Biancofiore G, Bindi l, Urbani L, et al. Combined twice-daily plasma exchange and continuous veno-venous hemodiafiltration for bridging severe acute liver failure. Transplant Proc. 2003;35:3011-3014.

8. Allen J, Hassanein T, Bhatia S. Advances in bioartificial liver devices. Hepatology. 2001;34:447-455.

9. Demetriou A, Brown R, Busuttil R, et al. Prospective, randomized controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg. 2004;239:667-670.

10. Stuart S. Liver assist devices: proof of life. Start-Up. March 2002:19-28.

Author

Rhonda K. Martin is nurse practitioner/clinical nurse specialist for hepatology and liver transplantation at the University of California, San Diego Medical Center, San Diego, Calif.

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