hepatic support therapies patrick brophy md cs mott children’s hospital pediatric nephrology,...

Hepatic Support Hepatic Support TherapiesTherapiesPatrick Brophy MDPatrick Brophy MD

CS Mott Children’s HospitalCS Mott Children’s HospitalPediatric Nephrology, Pediatric Nephrology,

Transplantation and DialysisTransplantation and Dialysis

From GinaFrom Gina

OutlineOutline

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

Hepatic FailureHepatic Failure

Definition: Loss of functional liver cell Definition: Loss of functional liver cell mass below a critical level results in mass below a critical level results in liver failure (acute or complicating a liver failure (acute or complicating a chronic liver disease)chronic liver disease)

Results in: hepatic encephalopathy & Results in: hepatic encephalopathy & Coma, Jaundice, cholestasis, ascites, Coma, Jaundice, cholestasis, ascites, bleeding, renal failure, deathbleeding, renal failure, death

Hepatic FailureHepatic Failure

Production of Endogenous Toxins & Production of Endogenous Toxins & Drug metabolic FailureDrug metabolic Failure

Bile Acids, Bilirubin, Prostacyclins, NO, Toxic Bile Acids, Bilirubin, Prostacyclins, NO, Toxic fatty acids, Thiols, Indol-phenol metabolitesfatty acids, Thiols, Indol-phenol metabolites

These toxins cause further These toxins cause further necrosis/apoptosis and a vicious cyclenecrosis/apoptosis and a vicious cycle

Detrimental to renal, brain and bone Detrimental to renal, brain and bone marrow function; results in poor marrow function; results in poor vascular tonevascular tone

IndicationsIndications

Bridge to liver transplantationBridge to liver transplantation

Bridge to allow sufficient time for Bridge to allow sufficient time for hepatic regenerationhepatic regeneration

Improve clinical stability of patientImprove clinical stability of patient

What & Why are they?What & Why are they?

Two main approaches to liver Two main approaches to liver supportsupport

– Non-biologicalNon-biological Filtration of potentially harmful moleculesFiltration of potentially harmful molecules

– Hybrid Biological artificial support Hybrid Biological artificial support (hepatic cells in a synthetic framework)(hepatic cells in a synthetic framework)

Non-Biological Filtration Non-Biological Filtration TechniquesTechniques

Hemofiltration:Hemofiltration:– First attempt (hemodialysis) 1956 Kiley First attempt (hemodialysis) 1956 Kiley

et al (Proc. Soc. Exp. Biol. Medical 1956)et al (Proc. Soc. Exp. Biol. Medical 1956)– Noted Hemodialysis improved clinical Noted Hemodialysis improved clinical

(4/5-patients) neurological function, (4/5-patients) neurological function, didn’t change outcome thoughdidn’t change outcome though


– Hemofiltration:Hemofiltration:– CRRT support can buy time, help prevent CRRT support can buy time, help prevent

further deterioration/complication and allowfurther deterioration/complication and allow

Potential recovery of functional critical cell massPotential recovery of functional critical cell mass

Management of precipitating events that lead to Management of precipitating events that lead to decompensated diseasedecompensated disease

Bridge to liver transplantation Bridge to liver transplantation

CVVHD for NH4 Bridge to CVVHD for NH4 Bridge to Hepatic TransplantationHepatic Transplantation

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1 2 4 6 8 10 12 14 16

NH

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Time(days)

Successful Liver Transplantation


Hemofiltration:Hemofiltration: CRRT may not improve overall outcome of CRRT may not improve overall outcome of

liver failure- provide stability and prolongs liver failure- provide stability and prolongs life in the setting of hepatic failurelife in the setting of hepatic failure

Primary applications include use in control Primary applications include use in control of elevated ICP in fulminant hepatic failure of elevated ICP in fulminant hepatic failure (Davenport Lancet 1991:2:1604)(Davenport Lancet 1991:2:1604)

Management of Cerebral Edema through Management of Cerebral Edema through middle molecule removal- reversal of middle molecule removal- reversal of Coma Coma (Matsubara et.al. Crit Care Med1990:8:1331)(Matsubara et.al. Crit Care Med1990:8:1331)

Hepatic Failure-Role of Hepatic Failure-Role of CRRTCRRT

Others:Others:– Fluid BalanceFluid Balance– Nutritional supportNutritional support– Uremic ClearanceUremic Clearance


Hemoperfusion: Hemoperfusion: – Historically Charcoal gave rise to current Historically Charcoal gave rise to current

cartridge chambers in use todaycartridge chambers in use today– PolyAcryloNitrile-Initially noted to PolyAcryloNitrile-Initially noted to

remove substances up to 15000Da remove substances up to 15000Da (initial study) found clinical but not (initial study) found clinical but not statistical survival improvementstatistical survival improvement Issues:Issues:

– Non-specific removal of growth factorsNon-specific removal of growth factors– Reactivity with the membranesReactivity with the membranes


Hemoperfusion:Hemoperfusion:– Development of Resin Exchange Columns:Development of Resin Exchange Columns:

Amberlite- removal of cytokines, bilirubin, bile Amberlite- removal of cytokines, bilirubin, bile acidsacids

Polymixin-endotoxin removalPolymixin-endotoxin removal Hydrophilic Membranes- for removal NH4, Hydrophilic Membranes- for removal NH4,

phenols and fatty acidsphenols and fatty acids

Downside- also effective at removing Downside- also effective at removing leucocytes and plateletsleucocytes and platelets


Plasma Exchange:Plasma Exchange:– Allows removal of hepatic toxins with Allows removal of hepatic toxins with

replacement with equivalent volume of replacement with equivalent volume of Fresh Frozen PlasmaFresh Frozen Plasma

– Improved clinical response but no Improved clinical response but no significant increase in survival ratessignificant increase in survival rates

– In general- get limited toxin removal In general- get limited toxin removal and high FFP replacement volumes are and high FFP replacement volumes are required over time- costlyrequired over time- costly


Molecular Adsorbents Recycling Molecular Adsorbents Recycling System (MARS)System (MARS)– Commercially available-premise based Commercially available-premise based

on filtering out albumin bound toxinson filtering out albumin bound toxins– Uses albumin-enriched dialysate Uses albumin-enriched dialysate

combined with a charcoal filter and an combined with a charcoal filter and an ion exchange resinion exchange resin

– Utilizes existing Renal Dialysis Utilizes existing Renal Dialysis Machinery along with the MARS deviceMachinery along with the MARS device


Albumin dialysis pumps the blood out Albumin dialysis pumps the blood out of the body and into a plastic tube of the body and into a plastic tube filled with hollow fibers made of a filled with hollow fibers made of a membrane that has been coated with membrane that has been coated with albumin. albumin.

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


The toxins on the albumin in the The toxins on the albumin in the patient's blood are attracted to the patient's blood are attracted to the albumin on the membrane, which is albumin on the membrane, which is "stickier" because it has more room "stickier" because it has more room for molecules to attach. for molecules to attach.

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


Meanwhile, smaller toxin molecules Meanwhile, smaller toxin molecules that don't stick to albumin flow that don't stick to albumin flow through the membrane's tiny pores through the membrane's tiny pores into the less-concentrated dialysis into the less-concentrated dialysis solution. solution.

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

CARTOONS!CARTOONS!

Hybrid Biological artificial Hybrid Biological artificial supportsupport

Rooted in Cross Circulation Studies- using Rooted in Cross Circulation Studies- using Dogs and Human subjects & Porcine, Dogs and Human subjects & Porcine, Baboon extracorporeal liver perfusionBaboon extracorporeal liver perfusion

Conceptually: liver function-including Conceptually: liver function-including synthesis and homeostasis are replaced by synthesis and homeostasis are replaced by hepatocytes in an exogenous environmenthepatocytes in an exogenous environment– Peritoneal placement of hepatocytesPeritoneal placement of hepatocytes– Extracorporeal perfusion (cells in synthetic Extracorporeal perfusion (cells in synthetic

frame)frame)


Implantation: (using coated Implantation: (using coated microcarrier beads)microcarrier beads)– Within liver resulted in cell aggregation and Within liver resulted in cell aggregation and

portal hypertensionportal hypertension– Within peritoneum/spleen (animal models)Within peritoneum/spleen (animal models)– Benefits: relatively simple to doBenefits: relatively simple to do– Problems: delayed onset of function (less Problems: delayed onset of function (less

useful in Acute Hepatic Failure), Lose useful in Acute Hepatic Failure), Lose function over time-need re-implantation function over time-need re-implantation (animal studies), require (animal studies), require immunosuppresionimmunosuppresion


Implantation: (using coated Implantation: (using coated microcarrier beads)microcarrier beads)– Problems: Human pilot (Bilir et al. Liver Problems: Human pilot (Bilir et al. Liver

Transplantation 2000,6,32-40)Transplantation 2000,6,32-40)– 8 patients transplanted- no survivors, 8 patients transplanted- no survivors,

3/8 showed some neuro improvement3/8 showed some neuro improvement


Extracorporeal Bioartificial Liver Extracorporeal Bioartificial Liver Support Devices:Support Devices:– Extracorporeal systems that combine Extracorporeal systems that combine

hepatocytes in a plastic cartridge and hepatocytes in a plastic cartridge and semi-permeable membranesemi-permeable membrane

– Problems: 1) maintaining cell viability Problems: 1) maintaining cell viability and and numbers numbers

2) Membrane type and 2) Membrane type and structurestructure

3) cell mass and type of 3) cell mass and type of hepatocyte hepatocyte


Extracorporeal Bioartificial Liver Extracorporeal Bioartificial Liver Support Devices:Support Devices:– Types:Types:

HepatAssist 2000HepatAssist 2000 ELAD (extracorporeal liver assist device)ELAD (extracorporeal liver assist device) BLSS (bioartificial liver support system)BLSS (bioartificial liver support system) MELS (Modular extracorporeal liver system)MELS (Modular extracorporeal liver system) LiverX2000 systemLiverX2000 system AMC-BAL (academic medical centre) AMC-BAL (academic medical centre)

ChamuleauChamuleau


All of these therapies combine All of these therapies combine replacement hepatocytes (human, replacement hepatocytes (human, porcine, immortalized, inducible) porcine, immortalized, inducible) within a structured meshwork fiberwithin a structured meshwork fiber

Each has a different cell mass and Each has a different cell mass and nourishment system for the cellsnourishment system for the cells

Several provide charcoal columns for Several provide charcoal columns for toxin removal, and/or albumin toxin removal, and/or albumin dialysate along with the ability to add dialysate along with the ability to add in a dialysis unitin a dialysis unit


Most are in Phase I/II clinical trialsMost are in Phase I/II clinical trials Initial studies have been mixed with Initial studies have been mixed with

respect to outcomes (end points respect to outcomes (end points differ between studies)differ between studies)

Data just starting to emerge on these Data just starting to emerge on these devicesdevices


Issues:Issues:– Still don’t understand the complexity of Still don’t understand the complexity of

the liver and the causes of hepatic the liver and the causes of hepatic encephalopathy/comaencephalopathy/coma

– May be removing both good (growth May be removing both good (growth factors-for liver regeneration) and bad factors-for liver regeneration) and bad substancessubstances

– Possibility of introducing viruses with live Possibility of introducing viruses with live cell usecell use

– Need to standardize end points in these Need to standardize end points in these studiesstudies

Future HorizonsFuture Horizons

Huge potential Impact on critical care & Huge potential Impact on critical care & Transplantation!Transplantation!

50 years of research into the therapies- 50 years of research into the therapies- no major breakthroughs- but small, no major breakthroughs- but small, consistent stepsconsistent steps

Likely with emerging membrane Likely with emerging membrane technology and translational research technology and translational research with stem cells and cloning- will with stem cells and cloning- will continue to make small steps with continue to make small steps with eventual success in Liver Replacement eventual success in Liver Replacement TherapyTherapy

ThanksThanks

Theresa MottesTheresa Mottes Timothy KudelkaTimothy Kudelka Robin NievaardRobin Nievaard Betsy AdamsBetsy Adams Tammy KellyTammy Kelly

hepatic support therapies patrick brophy md cs mott children’s hospital pediatric nephrology,...

Documents

hepatic failure definition

liver failure acute

renal failure

liver transplantation

hepatic regeneration

hepatic encephalopathy

death slide

chronic liver disease