Transcript 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
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

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
Indications

Bridge to liver transplantation

Bridge to allow sufficient time for hepatic
regeneration

Improve clinical stability of patient
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)
Non-Biological Filtration
Techniques

Hemofiltration:
– First attempt (hemodialysis) 1956 Kiley et al
(Proc. Soc. Exp. Biol. Medical 1956)
– Noted Hemodialysis improved clinical (4/5patients) 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
800
700
micromoles/L
NH4
600
Successful Liver
Transplantation
500
400
300
200
100
0
1
2
4
6
8
Time
(days)
10
12
14
16
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)
Hepatic Failure-Role of CRRT

Others:
– Fluid Balance
– Nutritional support
– Uremic Clearance
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
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
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
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
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.

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.

Non-Biological Filtration
Techniques
Meanwhile, smaller toxin molecules that
don't stick to albumin flow through the
membrane's tiny pores into the lessconcentrated dialysis solution.
 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

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)
– 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)
– 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 systems that combine
hepatocytes in a plastic cartridge and semipermeable membrane
– Problems: 1) maintaining cell viability and
numbers
2) Membrane type and structure
3) cell mass and type of
hepatocyte
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
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

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

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 factorsfor 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
 Timothy Kudelka
 Robin Nievaard
 Betsy Adams
 Tammy Kelly
