Hepatic Support Therapies

1. Hepatic Support Therapies Patrick Brophy MD CS Mott Children’s Hospital Pediatric Nephrology, Transplantation and Dialysis

2. From Gina

3. Outline • Hepatic Failure-definition(s) • Indications-when do we use them? • What are hepatic support therapies • Future

4. Hepatic Failure • Definition: Loss of functional liver cell mass below a critical level results in liver failure (acute or complicating a chronic liver disease) • Results in: hepatic encephalopathy & Coma, Jaundice, cholestasis, ascites, bleeding, renal failure, death

5. Hepatic Failure • Production of Endogenous Toxins & Drug metabolic Failure • Bile Acids, Bilirubin, Prostacyclins, NO, Toxic fatty acids, Thiols, Indol-phenol metabolites • These toxins cause further necrosis/apoptosis and a vicious cycle • Detrimental to renal, brain and bone marrow function; results in poor vascular tone

6. Indications • Bridge to liver transplantation • Bridge to allow sufficient time for hepatic regeneration • Improve clinical stability of patient

7. What & Why are they? • Two main approaches to liver support • Non-biological • Filtration of potentially harmful molecules • Hybrid Biological artificial support (hepatic cells in a synthetic framework)

8. Non-Biological Filtration Techniques • Hemofiltration: • First attempt (hemodialysis) 1956 Kiley et al (Proc. Soc. Exp. Biol. Medical 1956) • Noted Hemodialysis improved clinical (4/5-patients) neurological function, didn’t change outcome though

9. Non-Biological Filtration Techniques • Hemofiltration: • CRRT support can buy time, help prevent further deterioration/complication and allow • Potential recovery of functional critical cell mass • Management of precipitating events that lead to decompensated disease • Bridge to liver transplantation

10. CVVHD for NH4 Bridge to Hepatic Transplantation Successful Liver Transplantation NH4 micromoles/L Time (days)

11. Non-Biological Filtration Techniques • Hemofiltration: • CRRT may not improve overall outcome of liver failure- provide stability and prolongs life in the setting of hepatic failure • Primary applications include use in control of elevated ICP in fulminant hepatic failure (Davenport Lancet 1991:2:1604) • Management of Cerebral Edema through middle molecule removal- reversal of Coma (Matsubara et.al. Crit Care Med1990:8:1331)

12. Hepatic Failure-Role of CRRT • Others: • Fluid Balance • Nutritional support • Uremic Clearance

13. Non-Biological Filtration Techniques • Hemoperfusion: • Historically Charcoal gave rise to current cartridge chambers in use today • PolyAcryloNitrile-Initially noted to remove substances up to 15000Da (initial study) found clinical but not statistical survival improvement • Issues: • Non-specific removal of growth factors • Reactivity with the membranes

14. Non-Biological Filtration Techniques • Hemoperfusion: • Development of Resin Exchange Columns: • Amberlite- removal of cytokines, bilirubin, bile acids • Polymixin-endotoxin removal • Hydrophilic Membranes- for removal NH4, phenols and fatty acids • Downside- also effective at removing leucocytes and platelets

15. Non-Biological Filtration Techniques • Plasma Exchange: • Allows removal of hepatic toxins with replacement with equivalent volume of Fresh Frozen Plasma • Improved clinical response but no significant increase in survival rates • In general- get limited toxin removal and high FFP replacement volumes are required over time- costly

16. Non-Biological Filtration Techniques • Molecular Adsorbents Recycling System (MARS) • Commercially available-premise based on filtering out albumin bound toxins • Uses albumin-enriched dialysate combined with a charcoal filter and an ion exchange resin • Utilizes existing Renal Dialysis Machinery along with the MARS device

17. Non-Biological Filtration Techniques • Albumin dialysis pumps the blood out of the body and into a plastic tube filled with hollow fibers made of a membrane that has been coated with albumin. • On one side of the fiber's membrane is the blood; on the other, a dialysis solution containing more albumin.

18. Non-Biological Filtration Techniques • The toxins on the albumin in the patient's blood are attracted to the albumin on the membrane, which is "stickier" because it has more room for molecules to attach. • Then, the albumin on the membrane passes the toxins along to the albumin in the solution as it flows by.

19. Non-Biological Filtration Techniques • Meanwhile, smaller toxin molecules that don't stick to albumin flow through the membrane's tiny pores into the less-concentrated dialysis solution. • The patient's own albumin, too large to fit through the membrane's pores, returns to the body with the blood.

22. CARTOONS!

23. Hybrid Biological artificial support • Rooted in Cross Circulation Studies- using Dogs and Human subjects & Porcine, Baboon extracorporeal liver perfusion • Conceptually: liver function-including synthesis and homeostasis are replaced by hepatocytes in an exogenous environment • Peritoneal placement of hepatocytes • Extracorporeal perfusion (cells in synthetic frame)

24. Hybrid Biological artificial support • Implantation: (using coated microcarrier beads) • Within liver resulted in cell aggregation and portal hypertension • Within peritoneum/spleen (animal models) • Benefits: relatively simple to do • Problems: delayed onset of function (less useful in Acute Hepatic Failure), Lose function over time-need re-implantation (animal studies), require immunosuppresion

25. Hybrid Biological artificial support • Implantation: (using coated microcarrier beads) • Problems: Human pilot (Bilir et al. Liver Transplantation 2000,6,32-40) • 8 patients transplanted- no survivors, 3/8 showed some neuro improvement

26. Hybrid Biological artificial support • Extracorporeal Bioartificial Liver Support Devices: • Extracorporeal systems that combine hepatocytes in a plastic cartridge and semi-permeable membrane • Problems: 1) maintaining cell viability and numbers 2) Membrane type and structure 3) cell mass and type of hepatocyte

27. Hybrid Biological artificial support • Extracorporeal Bioartificial Liver Support Devices: • Types: • HepatAssist 2000 • ELAD (extracorporeal liver assist device) • BLSS (bioartificial liver support system) • MELS (Modular extracorporeal liver system) • LiverX2000 system • AMC-BAL (academic medical centre) Chamuleau

28. Hybrid Biological artificial support • All of these therapies combine replacement hepatocytes (human, porcine, immortalized, inducible) within a structured meshwork fiber • Each has a different cell mass and nourishment system for the cells • Several provide charcoal columns for toxin removal, and/or albumin dialysate along with the ability to add in a dialysis unit

29. Hybrid Biological artificial support • Most are in Phase I/II clinical trials • Initial studies have been mixed with respect to outcomes (end points differ between studies) • Data just starting to emerge on these devices

30. Hybrid Biological artificial support • Issues: • Still don’t understand the complexity of the liver and the causes of hepatic encephalopathy/coma • May be removing both good (growth factors-for liver regeneration) and bad substances • Possibility of introducing viruses with live cell use • Need to standardize end points in these studies

31. Future Horizons Huge potential Impact on critical care & Transplantation! 50 years of research into the therapies- no major breakthroughs- but small, consistent steps Likely with emerging membrane technology and translational research with stem cells and cloning- will continue to make small steps with eventual success in Liver Replacement Therapy

32. Thanks • Theresa Mottes • Timothy Kudelka • Robin Nievaard • Betsy Adams • Tammy Kelly