Liver Transplantation

Currently, orthotopic liver transplant, the transplant of a donor liver into the recipient’s body where the liver would normally rest (after removal of the recipient’s liver), is the most effective treatment for end stage liver disease and acute liver failure.  It has a relatively high rates of survival, from 94% of patients after a month, 85.4% of patients after a year, and 75.9% after 3 years.  These rates continue to grow, and without surgery, patients with liver failure would face imminent death within weeks.  Waiting times are increasing for those who need liver transplants; from 41 days in 1988 to 171 days in 1993.  This is largely due to the shortage of donors in the US.  In the year 2000 there were 17,607 people on the waiting list to receive a liver transplantation, while there were only 4954 actual transplantations.

The Waiting List

Patients fit numerous standards and go through series of tests in order to qualify for the waiting list to receive a liver transplantation.  Three categories of criteria are used to judge if patients’ need a liver transplant: 

Table 1: Indications for Transplantation

In opposition to these indications are absolute and relative contraindications, if patients have any of the absolute contraindication, they cannot qualify for a  liver transplantation.  If they qualify for a relative contraindication, there is serious reserve to place the patient on the waiting list, and often the patient is not prioritized as highly.

 Tables 2a and 2b: Contraindications for Transplant

Once patients are on the waiting list, they are ranked into different statuses that will determine in what order they receive their transplant:

1. Most urgent, will receive transplant first.  These are patients who are in the intensive care unit with fulminant liver failure, which is categorized as rapid acute liver failure, occurring within 8 weeks, and accompanied by encephalopathy.   Also included in this group are those patients who received a transplant in the previous 7 days that did not work, or those whose transplant from the previous 7 days was rejected.  These patients have a life expectancy of less than 7 days and are often on life support.
2. These are hospital inpatients whose life expectancy is not limited to 7 days, but who cannot leave the hospital without receiving a liver transplant.
3. These are the majority of transplant recipients in the US. They are receiving outpatient care for liver failure.

In addition to these factors, the waiting list is based on geographical distribution.  Matches are first looked for within a local area, before moving on to regions, of which there are 11 nationwide, and finally the nation at large is examined.  Factors such as timing in the course of the disease, as well as blood type, body size, cardiovascular and pulmonary health and alcohol and drug status are also tested and considered pre-transplantation.

The Transplantation Surgery

Donor organs can be taken either from cadaveric donors or live donors.  In the case of live donors, part of the liver is excised, usually the left lobe, and is expected to regenerate within the recipient.  A major landmark in the laws surrounding organ donation occurred in 1976 when the concept of brain death was accepted, versus the previous concept which required the heart to stop beating.  The brain death concept reduced the amount of time that the donor organ was not being perfused by blood or by perfusion solution.  Thus the amount of time that the cells are not being provided with oxygen is greatly reduced, which increased hepatocyte viability and thus increased post-operative success of the transplants. 

The removal procedures for the donor organs vary between live and cadaveric donors.

 For cadaveric donors:

·        The liver is removed and stored in a perfusate at 4°C, where it can remain up to 48 hours.

·        In 48 hours:   

§         A recipient is selected

§         The recipient is run through tests to assure that they can go through surgery.

§         The liver is transported to the site of the recipient.

§         The recipient undergoes surgery to remove their existing liver. 

·        In some cases of cadaveric donation, the liver is split and distributed between two donors. 

For live donors the recipient is prepped for surgery while part of the donor’s liver is removed in a neighboring operating room. The organ is stored in perfusate while the recipient undergoes surgery to remove their liver, at which point the donor organ is wheeled in and implanted.

The transplantation surgery takes approximately 6 hours, during which the recipient’s liver is removed, the major hepatic blood vessels are joined of the graft are joined to the host, as is the common bile duct.  Immunosuppressants are administered during the surgery, and at the end, a biopsy of the implanted liver is taken to check for signs of rejection.  The patient will remain in the intensive care unit for 1-3 days, and then will remain in the hospital for another 10-21 days.  During this time, biopsies will keep being taken as well as looking at clinical features such as bile production, coagulation, consciousness, and acid-base balance of the blood. 

Immunosuppression

Immunosuppression starts during surgery and continues throughout the patient’s life.  Before its initial use in 1960 when azathriopine was first used, organ transplantation was not feasible due to rapid rejection and destruction of the graft by the host’s immune system.  There are now multiple immunosuppressants out on the market, most of which are used in some combination.

Table 3: Immunosupressive Drugs

Most immunosuppressants are given in high dosage and combination for the first several weeks post-op.  After the initial risk of acute rejection passes, the dosage is scaled down, as immunosuppressants have many side effects.  Immunosuppressants are often relatively nephrotoxic, as well as causing hypertension and a loss in bone density.  All immunosuppressants leave the patient more susceptible to infections, as well as less able to fight them off.  In addition, many immunosuppressants act against rapidly dividing cells, like chemotherapeutic agents, and so often have the same side effects of hair loss and intense nausea. 

Complications

While transplantation greatly extends the life of those with acute liver failure, it is in itself a huge risk:

Complications from Surgery

·        Reduced clotting factors, more chance that patients can hemorrhage from surgery

·        Immunosuppressants increase risk for infection

·        Vessels do not properly join together, causing bleeding

·        Thrombosis in hepatic arteries

·        Leakage or stenosis of bile ducts.

Primary Non-Function

This is the phenomena that occurs in which the liver is inserted into the recipient, and does not work.  It is usually due to ischemia, improper perfusion, or lack of recipient blood flow through graft.  Clinical signs of primary non-function include jaundice, problems with blood clotting, and lack of bile flow.  Primary non-function is one of the conditions that result in being in the top ranking for receiving a transplant. 

Rejection

• Accelerated rejection, hyperacute rejection is not common in liver transplants, probably due to the blood flow in the liver.  Instead, the pre-formed antibody reaction is manifested between 3 and 20 days, causing necrosis of transplanted liver.
• Acute cellular rejection is the most common type of rejection, is mediated by T cells and occurs between 14 and 21 days.  For liver transplants, there are 3 defining features associated with acute cellular rejection:
  • Portal tract inflammation
  • Lymphocytes attacking the bile ducts and venules
  • Endothelial swelling with macrophage attachment
• Chronic rejection occurs months to years after the initial transplant.  Ideally, one would hope that with a transplant, a state of microchimerism is reached, in which there are donor cells circulating in the bloodstream of the recipient, this is associated with acceptance of the grafted organ.  In chronic rejection, the bile ducts disappear and there is inflammation of the arteries.  Chronic rejection is irreversible and progressive.

Click here for a transcript of an interview from a liver transplant recipient

References:

http://www.unos.org/

http://liver.bsd.uchicago.edu/html/overview.html

http://cpmcnet.columbia.edu/dept/gi/transplant.html

http://www.centerspan.org/pubs/liver/roberts1.htm

Schiff, Eugene R. ed. Schiff’s Diseases of the Liver. 8^th ed. Vol 2. Lipincott-Raven; Philadelphia, 1999

Wight, Derek G.D. ed.  Liver, Biliary Track and Exocrine Pancreas. Vol. 11. Churchill Livingstone; Edinburgh, 1994

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