Download Types of Liver Transplantation

Organ Transplantation讲义
History of Organ Transplantation
1901 – Discovery of ABO blood types, allowing
safer transfusion (Landsteiner)
1902 – Technique of vascular anastomosis (Carrel)
1952 – Discovery of MHC genes in human (Dausset)
1953 – Clarifying the role of the immune system in
rejection (Billingham, Brent, Medawar)
1954 – First kidney transplantation (Murray)
1963 – First human liver transplantion (Starzl)
1963 – First lung transplantation (Hardy)
1967 – First heart transplantation (Barnard)
1967 – First one year survivor post transplant (use
of azathioprine and steroids)
1980 – Introduction of cyclosporine (Calne)
1987 – University of Winsconsin solution for organ
preservation (Belzer, Jamieson)
1989 – Introduction of tacrolimus
1992 – Baboon liver transplanted into human
patient (Starzl)
Concept of Transplantation
An organ transplant is a surgical operation where a failing or damaged
organ in the human body is removed and replaced with a new one.
A graft is similar to a transplant. It is the process of removing tissue from
one part of a person’s body (or another person’s body) and surgically
reimplanting it to replace or compensate for damaged tissue.
The term “organ transplant” typically refers to transplants of the solid
organs: heart, lungs, kidneys, liver, pancreas and intestines. Animal and
artificial organs may also serve as transplantable organs.
Graft – To transplant or surgically insert a living body part into an existing
organ or body part to compensate for damage or a defect.
Types of Grafts / Transplants
Autograft – from one part of the body to
another
Isograft – between two genetically identical
individuals
Allograft – between two genetically dissimilar
individuals of the same species
Xenograft – between two species
Transplantation Immunology
Transplantation Antigens
Antigenically similar tissues are called histocompatible.
Major Histocompatibility Complex (MHC) encodes the antigens for transplantation.
Set of histocompatibility antigens is called Haplotype.
Progeny of parents with different haplotypes inherit one haplotype from each parent.
MHC inheritance in an outbred population like humans is complex, therefore donor and
recipient in a transplantation reaction have to be matched.
Human Lymphocyte Antigen (HLA)
Class I HLA (HLA-A, HLA-B, and HLA-C)
Found on virtually all cell surfaces
Binding foreign protein antigens
Recognized by cytotoxic CD8+ T cells
Class II HLA (HLA-DR, HLA-DP, and HLA-DQ)
Found only on antigen-presenting cells such as B
macrophages, and dendritic cells
Activating CD4+ T cells
lymphocytes,
INITIATION OF THE IMMUNE RESPONSE
Recognition of Antigen
Direct Recognition of Antigen by Immunoglobulin
Recognition of Antigen by the T-Cell Receptor in the Context of the MHC
Antigen Processing
Endogenous pathway: CD8+ T cells recognize the class I MHC by way of the T-cell receptor complex.
Exogenous pathway: CD4+ T cells recognize the foreign peptide bound to class II MHC
Alloreactivity
Direct recognition: recognition of foreign or self-peptides loaded onto
allo-MHC
Indirect recognition: response to foreign MHC peptides loaded onto self-MHC
Homing and Trafficking
In the first step, leukocytes come in contact with the vascular endothelium and adhere to the surface.
In the second step, the leukocyte is activated to express other receptors and secretes cytokines.
In the third step, the leukocyte stops on the endothelial surface, and the adhesive interaction between the
cells increases.
The final step is transendothelial cell migration.
Cellular Effectors
B cells secrete specific antibody that binds to the allograft cell surface and can kill cells by
complement-mediated lysis.
Activated APCs can then cause local tissue destruction through direct cell lysis and phagocytosis or
indirectly through release of cytotoxic cytokines.
CD4+ T cells can also generate local tissue destruction through inflammatory processes similar to
delayed-type hypersensitivity.
Cytotoxic CD8+ T lymphocytes kill target cells through direct cell contact.
HLA typing
Serologic Typing (Lymphocytotoxicity or Microcytotoxicity)
Mixed Lymphocyte Reaction (MLR)
Graft Rejection
Characteristics of Graft rejection
Graft acceptance involves vascularization and healing of transplanted tissue, usually
takes  15 days.
1st set rejection: vascularization causes infiltration of graft with lymphocytes, monocytes
and neutrophils that cause inflammation and necrosis leading to complete rejection of
graft;  14 days.
2nd set rejection: second transplantation on primed recipient leads to a quicker cellular
infiltration and rejection;  6 days. Evidence of immunological memory.
Transplantation of a fresh, unrelated graft onto the primed recipient leads to rejection by
1st set rejection kinetics. Evidence of immunological specificity.
Role of T cells in allograft rejection
T cells and not serum antibody can transfer immunity to a graft from a
primed recipient to an unprimed recipient, graft rejection occurs with 2nd set
kinetics.
CD4+ Th cells and CD8+ TC cells are involved in graft rejection.
Course of Graft Rejection
Sensitization phase
Effector phase
Sensitization Phase
T lymphocytes recognize donor MHC molecules (on grafted tissue) and associated
peptide ligands in the cleft of MHC molecule, as foreign.
Allogeneic MHC I molecules (on grafted tissue) present peptides from proteins
synthesized within the cell.
Allogeneic MHC II molecules (on grafted tissue) present peptides from proteins
endocytosed by donor antigen presenting cells, usually dendritic cells.
Host APCs migrate into the graft, endocytose foreign alloantigens and present them as
processed peptides with self MHC molecules.
Vigorous proliferation of CD4+ Th cells that recognize MHC class II alloantigens
directly or alloantigenic peptides presented by self MHC.
Effector Phase
Significant influx of T cells and macrophages into graft
Major mechanism: delayed type hypersensitivity and TCTL mediated killing.
Cytokines (IL-2) secreted by Th cells activate TDTh and TCTL cells.
TDTh cells secrete γ-IFN and TNF- for to attract and hold phagocytic macrophages
and neutrophils into the graft causing inflammation and cell killing.
TCTL cells recognize foreign MHC I alloantigens and carry out direct killing of graft
cells.
Cytokines secreted by Th cells activate B cells to secrete graft specific antibodies that
facilitate complement-mediated lysis and FC receptor mediated phagocytic killing.
Clinical Manifestation of Graft Rejection
Hyperacute rejection
Occurs within 24 hours of transplantation.
Mediated by pre-existing antibodies specific for graft antigens.
Massive recruitment of neutrophils occurs followed by rapid
inflammation.
Acute rejection
Occurs  10 days after transplantation.
Massive infiltration by macrophages and lymphocytes.
Chronic rejection
Occurs months or years after transplantation.
Includes both humoral and cell mediated responses.
Immunosuppression
Immunosuppressants
Antimetablites
Azathioprine
Mycophenolate mofetil
Antibodies
Monoclonal
Anti-CD3
Interleukin-2 receptor antagonist
Polyclonal
Anti-lymphacyte immunoglobulin
Anti-thymocyte immunoglobulin
Cytokine inhibitors
Corticosteroids
Calcineurin
inhibitors
Cyclosporin
Tacrolimus
Cell Cycle Inhibitor
Sirolimus
Machanism and Sites of Immunosuppressants in Function
Immunosuppressive Protocol
Prevention of acute rejection
Steroids + CsA or FK506
Steroids + CsA or FK506 + MMF
Treatment of acute rejection
Large dose of Steroids
Augment of FK506
Conversion from CsA to FK506
ATG or ALG
Induction Therapy
Daclizumab or Basiliximab
Organ Procurement
Sources of Organs
Cadaveric organ donation: organs removing from recently deceased people. A person is
considered dead once either the heart stops beating or brain function ceases (called brain
death).
Living organ donation: organs removing from living persons.
Alternative organ sources:
Animal organs
Artificial organs
Stem cells
Aborted fetuses
Distribution of cadaveric organs
Organ type, blood type and organ size
Distance from the donor organ to the patient
Level of medical urgency (not considered for lung transplant candidates)
Time on the waiting list
Steps in Organ Procurement
Incision
Exploration and inspection
Individual organ mobilization
In situ perfusion
Removal of organs
Closure of the incision
Organ Preservation
Principles of Organ Preservation
Hypothermia
Prevention of cellular swelling
Avoidance of biochemical injury
Preservation Solusion
Euro-Collins solution:
Providing a hyperosmolar environment with intracellular
electrolyte composition that is intended to reduce cellular
swelling.
University of Wisconsin solution:
Providing high-energy phosphate precursors, hydrogen ion
buffering capacity, and antioxidant properties.
Cold Ischemia Reperfusion Injury
Liver Transplantation
Indications for Liver Transplantation
General Guidelines
Any patient with chronic or acute liver disease who is
unable to sustain normal quality of life, or patients
with serious complications related to the underlying
liver pathology should be considered for
transplantation.
Selection of Patients for Liver Transplantation
Accepted indications for liver transplantation
Advanced chronic liver disease
Acute liver failure
Hepatocellular carcinoma
Miscellaneous liver diseases
No alternative form of therapy
No absolute contraindication to liver transplantation
Willingness and ability to accept liver transplantation and comply with follow-up care
Ability to provide for the costs of liver transplantation and posttransplant care
Liver Disease of Adult Transplant Recipients
Primary liver disease
Chronic hepatitis C
Alcoholic liver disease
Alcoholic liver disease and hepatitis C
Chronic hepatitis B
Cryptogenic cirrhosis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Autoimmune hepatitis
Acute liver failure
Hepatic malignancy
Metabolic diseases
Other
Unknown
Non–Disease-Specific Minimal
Listing Criteria
Immediate need for liver transplantation
Estimated 1-yr survival  90%
Child–Turcotte–Pugh score  7 (Child class B or C)
Portal hypertensive bleeding, or a single episode of spontaneous bacterial
peritonitis, irrespective of Child–Turcotte–Pugh score
Contraindications to Liver Transplantation
Compensated cirrhosis without complications (Child–Turcotte–Pugh score,
5 - 6)
Extrahepatic malignancy
Active untreated sepsis
Advanced cardiopulmonary disease
Active alcoholism or substance abuse
Anatomic abnormality precluding liver transplantation
LIVER DONOR CRITERIA
 50 years
No hepatobiliary diseases
No liver trauma, ischemia, or infection
No systemic disease with liver repercussion: severe hypertension, diabetes mellitus type I,
vasculitis, collagen disease
No transmittable systemic infection
No neoplasia (except CNS)
No severe abdominal trauma (to consider)
Hemodynamic and respiratory stability:
SBP 100 mm Hg
CVP 5 cm H2O
Acceptable PaO2 and haemoglobin
50 ml/hr diuresis and normal creatinine
Dopamine 10 g/kg/min
Low-dose pitressin
LIVER DONOR CONTRAINDICATION
Absolute
Severe macrosteatosis†
Very long cold (24–30 hr?) and warm ischemia
Sepsis
HIV-1/2, HCV,* HBV†
HTLV-I/II, Creutzfeldt-Jakob and related processes
Malignancy‡
Relative§
A
B
C
Age
Steatosis (mild or moderate)
ICU stay
Altered liver function tests
Hypernatraemia
Hypotension pressors
Cold and warm ischemia
Sex
Immunological matching
ABO compatibility required
HLA matching - not routinely necessary
(although is probably preferable)
Types of Liver Transplantation
Classic orthotopic liver transplantation
Piggyback orthotopic liver transplantation
Split-liver transplantation
Living donor liver transplantation
Auxiliary liver transplantation
Domino liver transplantation
Operative Procedures of Orthotopic Liver
Transplantation
Donor Liver Harvesting
Often occurs in conjunction with harvesting of other organs –
Heart/lungs/kidneys/pancreas
Brain dead cadaveric donor
Assess the suitability of the liver–
visual assessment by surgeon significant prognostic factor
regarding the function of the liver
Donor Hepatectomy
Exposure – midline incision
Divide falciform and triangular ligaments
Delineate the vascular supply – Ligate gastroduodenal artery, disssect
hepatic artery back to coeliac
Bile duct divided low down
Portal vein dissected, clamped and divided.
Infra and suprahepatic IVC divided (hepatic veins removed)
Aorta and portal vein cannulated
Flush with cold preservation solution
Recipient Hepatectomy
Abdominal Mecerdes ’ incision
Mobilisation of liver - division of coronary and falciform ligaments
Mobilise the porta hepatis
Divide hepatic artery
Common Bile duct divided on the right side of the porta
Dissect around the portal vein, transected
Infrahepatic and supra-hepatic portions of IVC dissected out and clamped
Previously veno-venous bypass was used (not generally now)
Liver removed
Implantation procedure
Suprahepatic IVC anastamosis
Infrahepatic IVC anastamosis
Portal vein anastamosis
Hepatic artery anastamosis – careful to match the donor hepatic
artery to recipient dominant supply
Biliary anastamosis (+/- T-Tube)
Post operative Complication
Primary Non-function of graft (often ischemic in nature) – often
requires re-transplantation
Hyperacute rejection (rare) immediate
Acute cellular rejection (T cell mediated)
Chronic rejection (years) – sclerosis of bile ducts
Infection
Disease Recurrence
Hepatitis C
Hepatitis B (immune globulin prophylaxis and antiviral)
New treatments aimed at reducing recurrent viral infection (interferon and
antivirals)
10-15% of recurrent Hepatitis C go on to liver failure
Primary Sclerosing cholangitis, Primary biliary cirrhosis, Autoimmune
hepatitis.
Recurrent HCC
Split-liver transplantation
Other Organ Transplantation
Renal transplantation
Cardiac transplantation
Lung transplantation
Heart-lung transplantation
Pancreas transplantation
Pancreas-renal transplantation
Intestine transplantation
Abdominal multivisceral transplantation
Islet transplantation
Xenotransplantation