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

From Gina

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

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

Hepatic Failure Production of Endogenous Toxins & Drug metabolic 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 Detrimental to renal, brain and bone marrow function; results in poor vascular tone

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

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

Non-Biological Filtration Techniques Hemofiltration: 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

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

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

Non-Biological Filtration Techniques Hemofiltration: Hemofiltration: CRRT may not improve overall outcome of liver failure- provide stability and prolongs life in the setting of hepatic failure 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) 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) Management of Cerebral Edema through middle molecule removal- reversal of Coma (Matsubara et.al. Crit Care Med1990:8:1331)

Hepatic Failure-Role of CRRT Others: Others: –Fluid Balance –Nutritional support –Uremic Clearance

Non-Biological Filtration Techniques Hemoperfusion: 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

Non-Biological Filtration Techniques Hemoperfusion: 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

Non-Biological Filtration Techniques Plasma Exchange: 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

Non-Biological Filtration Techniques Molecular Adsorbents Recycling System (MARS) 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

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. 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. On one side of the fiber's membrane is the blood; on the other, a dialysis solution containing more albumin.

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. 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. Then, the albumin on the membrane passes the toxins along to the albumin in the solution as it flows by.

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. 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. The patient's own albumin, too large to fit through the membrane's pores, returns to the body with the blood.

CARTOONS!

Hybrid Biological artificial support Rooted in Cross Circulation Studies- using Dogs and Human subjects & Porcine, Baboon extracorporeal liver perfusion 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 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)

Hybrid Biological artificial support Implantation: (using coated microcarrier beads) 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

Hybrid Biological artificial support Implantation: (using coated microcarrier beads) 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

Hybrid Biological artificial support Extracorporeal Bioartificial Liver Support Devices: 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 2) Membrane type and structure 3) cell mass and type of hepatocyte 3) cell mass and type of hepatocyte

Hybrid Biological artificial support Extracorporeal Bioartificial Liver Support Devices: 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

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

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

Hybrid Biological artificial support Issues: 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

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

Thanks Theresa Mottes Theresa Mottes Timothy Kudelka Timothy Kudelka Robin Nievaard Robin Nievaard Betsy Adams Betsy Adams Tammy Kelly Tammy Kelly