1 / 32

Hepatic Support Therapies

Hepatic Support Therapies. Patrick Brophy MD CS Mott Children’s Hospital Pediatric Nephrology, Transplantation and Dialysis. From Gina. Outline. Hepatic Failure-definition(s) Indications-when do we use them? What are hepatic support therapies Future. Hepatic Failure.

brent
Download Presentation

Hepatic Support Therapies

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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.

  20. CARTOONS!

  21. 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)

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

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

More Related