Liver replacement



Liver replacement therapy

• Acute or fulminant hepatic failure, usually induced by chemical or viral hepatitis, is highly lethal, with a death rate of more than 75%.

• It results in life-threatening complications such as:

o Portal hypertension.

o Coagulopathy.

o Cerebral oedema.

o Metabolic disturbances.

o Variceal bleeding.

o Ascites.

o Hepatic encephalopathy.

• While the patient is waiting for possible liver transplantation, current treatment consists of intensive clinical support:

o Fluid and hemodynamic support.

o Correction of electrolyte and acid–base abnormalities.

o Respiratory assistance.

o Treatment of cerebral edema.

The indications of liver replacement therapy

1. AHF

a. Bridge to transplantation.

b. Recovery of normal liver function.

c. Stabilize a critically ill patient for transfer to a transplant center.

2. Chronic liver disease awaiting transplantation

a. Reversal of hepatic encephalopathy.

b. Stabilization of other forms of clinical deterioration.

c. Improve quality of life (eg, mild encephalopathy, severe pruritus).

3. Posthepatic surgery.

a. Regeneration of the liver after surgery.

b. When surgery results in hepatic insufficiency.

c. Posttransplantation

i. Primary nonfunction of the graft.

ii. A small-for-size graft from a living donor or from a split liver.

EARLY LIVER-SUPPORT THERAPIES (detoxifying liver-support therapies)

• In the past, it was thought that encephalopathy and cerebral edema were caused mainly by dialyzable toxins such as:

|Ammonia |False neurotransmitters |Aromatic amino acids |

|Phenols |Other substances with a molecular weight of less than 5,000 |

• Not enough by itself to improve the survival of patients with ALF.

• Early liver-support systems focused on blood detoxification.

1. A kidney dialysis machine

o Used to remove blood ammonia( no clinical improvement.

o Most of these toxins are protein-bound and traditional hemodialysis used cellulose membranes not filtering large molecules.

2. Hemodialysis with polyacrylonitrile membranes

o Allowed passage of molecules up to a molecular weight of 15 kDa.

o Temporary improvement in mental status and duration of survival.

3. Hemofiltration

o Limited application ( thrombocytopenia( bleeding in patients with an already compromised clotting system.

4. Exchange transfusion (plasma exchange or plasmapheresis)

o Significant improvements in neurologic status and biochemical profiles.

o Control hemorrhagic diathesis achieved through the addition of coagulation factors.

o A better overall survival rate.

5. Hemoperfusion or plasma perfusion

o The blood or plasma of a patient with ALF is perfused through a column containing:

▪ Activated charcoal. two problems resolved in system

• Platelet losses ( give prostacyclin to protect platelets.

• Hypotensive reactions( coating the columns.

▪ Encouraging survival rates among patients with ALF.

▪ Still in use because it is supposed to protect the adjacent liver support therapy from toxic substances.

▪ Anion exchange resins ( no significant improvement( early saturation of the resins and nonselective binding of the cations removed.

Modification of early liver support therapies

Sepet blood filtration device

• Facilitates removal of the plasma fraction that contains hepato- and neurotoxins, as well as mediators of inflammation and inhibitors of hepatic regeneration with molecular weights lower than 100 kDa.

• Sepet is for use with any commercially available kidney dialysis system.

MARS (molecular adsorbent recycling system) Albumin dialysis

• Uses an albumin gradient to increase removal of protein-bound molecules.

• The patient is connected to a conventional hemodialysis machine that pushes blood through an extracorporeal circuit into a MARS Flux dialyzer.

• It dialyzes the patient’s blood against a recirculating saline and human albumin solution rather than bicarbonate-based dialysate.

• Once the toxins are transported across the MARS Flux membrane and attached to the albumin in the dialysate, the albumin dialysate is passed through two different columns.

• These columns are designed to extract the toxins bound to albumin.

• The final step is dialysis of the solution against standard bicarbonate dialysate.

Prometheus (Dialysis with adsorber treatment)

• Combines a typical dialysis procedure with an adsorber treatment.

• The machine pumps blood through a filter that retains blood cells and large protein molecules.

• The blood plasma, along with albumin and smaller protein molecules, is then fed through two adsorbers that separate and bind toxins from the albumin.

• Following adsorption, the blood plasma and the detoxified albumin are joined with the cells retained by the filter and undergo dialysis to remove the remaining water-soluble toxins.

• The filtered blood is then reintroduced into the patient.

HemoCleanse-DT (Liver dialysis)

• It is indicated for:

o Acute hepatic encephalopathy due to decompensated cirrhosis or fulminant hepatic failure.

o Serious drug overdose, such as acetaminophen, tricyclics.

• This system is a blood-cleaning device for liver dialysis and other detoxifying therapies that transfers blood filtrate or plasma obtained from a dialyzer or plasma filter to a sorbent reactor that selectively removes unwanted substances.

• The reactor creates a sorbent flow pattern that optimizes clearance of unbound and bound toxins.

• Cleansed filtrate is returned to the dialyzer or plasma is returned directly to the patient.

BIOARTIFICIAL LIVER (BAL, hybrid liver)

▪ This technique has evolved due to:

o Limited success of detoxifying liver-support therapies.

o Improved techniques for culturing isolated hepatocytes that express high levels of differentiated liver function.

▪ These systems consist of biologic components in a synthetic framework:

o Freshly isolated pig hepatocytes.

o Human hepatoblastoma cell lines.

o Blastocyst-derived, pluripotential embryonic stem cell lines.

▪ Isolated hepatocytes have been used in two ways:

o Implantable hepatocyte systems.

o Extracorporeal hepatocyte bioreactors.

▪ Blood or plasma of the patient with ALF comes in contact with the cultured hepatocytes through an ex vivo perfusion system.

▪ The system is based on two main

o Culturing hepatocytes while maintaining their liver-specific function.

o Expanding the cell cultures to obtain sufficient quantities of hepatocytes.

BALs systems

• HepatAssist 2000 system.

• Extracorporeal Liver-Assist Device (ELAD Artificial Liver).

The HepatAssist 2000 System

• It is a system for the extracorporeal treatment of patients in end-stage liver failure.

• The patient's plasma is perfused through a hollow-fiber bioreactor containing primary porcine hepatocytes.

• The goal of the system is to assist the patient while the liver regenerates or a suitable liver is found for transplantation.

• The advantages of this device are:

o It uses plasma, which allows higher flow rates.

o It uses convective currents, allowing for greater transfer of molecules.

o Procurement of pigs and porcine cells is relatively easy.

o Safety has been demonstrated in phase I trials.

o Decreased intracranial pressure has been demonstrated in phase I trials.

• Potential disadvantages of the HepatAssist include:

o Pig cells make pig proteins, which may be immunogenic in humans.

o Difficulties are associated with the use of plasma separation.

o Use for citrate can lead to hypocalcemia and carries a risk of bleeding.

o The use of plasma separation limits its use to 6 hours a day.

o Antigen transfer evidenced by an increase in xenogeneic antibodies.

o Transfer of xenogeneic viruses, particularly the porcine endogenous retrovirus (PERV).

The ELAD Artificial Liver (phase I/II)

• It is a "metabolically active" hollow-fiber dialyzer analogous to cartridges used in kidney dialysis.

• The dialyzer's extracapillary space is inoculated with cloned immortalized human liver cells ( cells attach to the external membrane of the hollow-fiber capillaries and begin to grow and replicate.

• Connected to continuous hemodialysis machines that remove blood from the patient and circulate it through the disposable artificial liver and then return it to the patient.

• Designed to detoxify the blood, metabolize essential amino acids, and produce proteins and clotting factors. The ELAD Artificial Liver is

C3ASLI (Hepatix ELAD) (phase II trial)

• Another biologically active BAL device.

• Use a transformed human cell line, the C3A tumor cell line.

• C3A cell line is a highly differentiated, stable, and viral-free human cell line that performs a range of metabolic functions comparable to those of the normal liver.

• It has been shown to maintain viability and function for 4 to 8 months when seeded in a hollow fiber cartridge at high seeding density.

• This device uses whole blood, which requires lower flow rates than devices that use plasma.

• It requires heparin, but it can be used continuously.

• Advantages:

o Uses a larger cell mass.

o Uses whole blood.

o Continuous treatment.

o Uses human cells.

• Disadvantage:

o Potential for tumor transfer due to breakdown of the membrane and the infusion of the transformed human cells into the patient (1 in 1 trillion).

• Biochemical improvement good survival.

HepaLife's PICM-19 cells

• HepaLife's PICM-19 cells able to mimic the human liver's response in several important ways.

o Do not develop tumors or become cancerous.

o Uniquely differentiate into hepatocytes and bile duct epithelium.

o Express inducible P450 and GGT; important indicators of liver and bile duct functions, respectively.

o Are able to remain in continuous culture while retaining hepatic function.

o Can grow at high cell density.

o Successfully remove toxic ammonia and produce urea.

o Respond to acetaminophen exposure, similar to the human liver.

o Survive human plasma exposure.

EXTRACORPOREAL WHOLE LIVER PERFUSION

• The whole liver is used in an extracorporeal perfusion system.

• Ex vivo pig liver perfusions have been performed to treat patients with liver failure.

• The pig liver has been used in most cases because it is readily available.

Technique

1. Immediately before perfusion, hepatectomy is performed on pigs.

2. Cystic duct is ligated.

3. Common bile duct is cannulated to collect the bile produced during perfusion.

4. Hepatic artery and the portal vein are cannulated for inflow of human blood.

5. The isolated liver is placed in a sterile perfusion chamber and connected to the patient’s circulatory system within no more than 30 minutes.

6. Assess bile flow ( proved to be the single most reliable index of hepatic function.

7. Blood is drawn from the femoral artery and returned to the patient through the saphenous vein, or a direct arteriovenous shunt in the upper arm is used.

8. The addition of a heater-oxygenator unit to the perfusion system ensures a blood supply with a temperature of 37° to 39°C and 100% oxygen saturation.

9. A pump is used in the perfusion circuit to return the blood from the reservoir containing post-ex vivo liver blood to the patient.

10. Length of extracorporeal pig liver perfusion varied from 1.5 to 9 hours; one to four perfusions were performed per patient.

11. Regional or systemic heparin was administered.

Clinical Outcome

• Those with ALF may exhibit a better outcome compared with those with chronic liver disease.

• Neurologic improvement to at least coma hepaticum grade III to II.

• Improvement of survival.

• Most complications are due to preexisting cardiopulmonary disease.

• Uncontrolled bleeding secondary to thrombocytopenia.

IMMUNOLOGIC IMPLICATIONS

• Cell-mediated reaction is seen at an early stage, as indicated by activation of neutrophil granulocytes and natural killer cells after suppression of complement (less significant because therapy is intended to last only several days).

• Humoral response: xenoreactive pNAbs, which consist of IgG, IgA, and mainly IgM, form 2% to 4% of the total immunoglobulins directed against the GAL-alpha membrane epitope, the most important target antigen of the human humoral defense against porcine organs.

Hepatocyte transplantation

• Indications

o As gene therapy for a variety of inherited liver disorders.

o As a treatment for liver failure due to any cause.

• Concept

• Significant hepatocyte mass can develop and is associated with the appearance of bile cannuliculae, sinusoidal structures, and endothelial and stellate cells, producing morphologic similarity to the liver.

• Technique

• Individual hepatocytes are isolated by collagenase digestion of the liver and are usually transplanted fresh.

• Techniques for storage by cryopreservation are becoming increasingly successful.

• Sites for hepatocyte engraftment

• Liver( by portal vein infusion( transplanted hepatocytes integrate into the liver cords, leaving the hepatic architecture intact.

• This receive the benefits of:

o Exposure to portal nutrients.

o Contact with other hepatocytes and nonparenchymal cells.

o Proximity to paracrine factors.

o Ability to secrete bile into the native biliary system.

• The expanded extracellular matrix associated with liver cirrhosis increases the endothelial barrier to engraftment in the liver.

• However, transplanted hepatocytes can migrate into cirrhotic nodules and integrate into liver plates following intraportal infusion.

• Spleen ( by injection into the splenic pulp from which cells translocate to the liver through the splenic vein.

• Peritoneal cavity.

• Value

• Transplanted hepatocytes

o Express enzymes associated with normal liver function.

o Resistant to the underlying disease.

o Could potentially repopulate a severely diseased cirrhotic liver.

• Limitations

o Portal-systemic shunts will result in translocation of hepatocytes to the pulmonary circulation (rapidly cleared + pulmonary emboli.

o The presence of portal hypertension increases the risk of portal vein thrombosis.

Auxiliary liver transplantation

• Only part of the liver is replaced and the rest of the native liver is not removed.

• In as many as two thirds of the patients treated in this fashion, the native liver ultimately recovers function.

Xenotransplantation

• The use of pig livers to be implanted in humans is under way.

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