the history of liver tranplantation

 

15 years ago, shortly after I retired, I evaluated the history of Liver Transplant.  I’m sure the indications for transplant have changed in recent years.  

 

Never in the field of human conflict was so much owed by so many to so few.

  Winston Churchill (speaking of the RAF pilots during the London Blitz.)

 

I went to the UCSF liver transplant meeting that weekend.  Held at a fancy resort in the Napa Valley it was an event where local Gastroenterologists and Hepatologists gathered to eat free food, spend the night, hear about recent developments, earn education “hours”, and mingle with the faculty.  The lecturers thanked the nurses and staff and there were words of appreciation for the 11 pharmaceutical companies who were footing much of the bill.  We were invited to visit the tables in the hall where clean cut, well dressed, 30 something reps passed out literature, pencils, and books.  The presenters repeatedly praised the program and patted one another on the back as we applauded.  Not that they didn’t deserved the recognition and acclaim.  They did.  But their proclamations of admiration were a palpable reminder of how large, complex and competitive the transplant business has become.  Transplant services have traditionally been profit centers for major universities, and a lot of hospitals are trying to get into the act.

While listening to the presentations I thought of a few of my patients who had received transplants and of some who hadn’t.  I remembered a large woman who didn’t know there was anything wrong with her liver before she was admitted to the hospital with the hepato-renal syndrome.  Her kidneys had stopped working as a result of cryptic cirrhosis. 

She worked in a warehouse, drove a fork and lifted heavy boxes.  She was fat but her weight hadn’t slowed her down.  The liver cells of most “large” people are filled with fat, and since sixty percent of American adults are overweight and a fourth are “obese”, she seemed pretty normal before she got sick. 

Some fatty livers develop steatohepatitis, (inflammation) and cirrhosis, (scaring.)  A few of these people develop a hard-to-explain condition where the blood flow to the kidney becomes inadequate and the renal organs stop working.  When this happens dialysis isn’t very effective, but a liver transplant is curative. 

I phoned the transplant physician on call and told her my patient was dying and needed a liver.  It was Friday afternoon, and the physician said “No.”  The patient was not a candidate for a transplant.  She weighed too much.

We don’t offer a transplant to everyone dying of liver disease.  Recovering from the surgery is usually difficult.  People can spend weeks in intensive care.  Some die.  The drugs that suppress the immune system and keep us from rejecting the alien organ can be hard on the kidney; and there aren’t enough organs to go around. So a series of “rules” and barriers have been erected.  They were carefully thought out and debated, and they tended to change over time. 

An upper weight limit was one of those obstacles.  In very obese people If surgery goes well and after recovering an obese recipient doesn’t lose the weight, the new liver tends to get fatty, inflamed and cirrhotic.  That’s a huge problem because it’s really hard for very heavy people to lose a lot of weight and keep it off. 

My lady was swollen.  Some of her excess weight was fluid.  Without the extra liquid in her abdomen and legs her weight was well within the acceptable limits.  She was otherwise healthy, and she had a good chance of surviving the transplant and living a relatively normal life. I tried hard to persuade the person at the University, but like an umpire who makes a bad call she stuck to her guns.

I had to tell the lady whose kidney function was deteriorating that the doctor at the university had turned us down.  We weren’t transferring her after all. 

Her family cried.  I felt like crying.  A sister offered to donate a liver but the patient refused.  I hung my head and went home for the weekend.

She was still there on Monday.  A great hospital based doc had tweaked her medications and her kidney function had stabilized.  She stayed in the hospital and each day we checked the creatinine, the measure of how well the kidney was working.  It was level for a few days then it started getting worse. 

I called the medical center and again talked to the doc on call.  Liver transplant hepatologists at the local university are on duty for a week at a time, and a new person was in charge.  Hearing my story he became philosophical.  By the year 2020, he said, the chief cause of liver transplant will be complications of steatohepatitis.  That was his field of research and he figured he should get a taste of his own medicine.  He told me to send her over.                         

We did.  She was transplanted, did great post op, and went home within a week. You lose some and win some.  That’s the business.    

The H.S. football player with an obsession.

The American most responsible for taking the small, cautious, crucial steps that moved liver transplantation from a notion to a possibility to a reality was the son of a small town newspaper owner.  He worked for his dad as a kid, and was a proof reader for a Chicago paper in med school.  When a heart attack forced him to take a break, he used the time to write a “tell all” book.   His name was Thomas Starzl. 

Like Hewlett and Packard or Steve Jobs, Starzl did some of his early work (in this case on dogs) in a garage.  Surgical residents in those days spent part of their time in the “dog lab” perfecting techniques and pioneering new approaches.  As part of his research he developed a surgical method of removing the dogs liver without killing the animal.  Once his skills were perfected he assumed it wouldn’t be that difficult to sew the liver back in.  He was wrong.  The surgery was difficult and bloody and all the dogs died within 2 days. 

An NIH fellowship gave him the money and time to continue his work.  A liver, he discovered, would remain viable outside the body for 2 hours if a cool solution was forced into its blood vessels.  He also learned surgery would fail if he didn’t shunt blood around the liver.  Venous blood from the intestine is normally filtered by the liver before it enters the general circulation.  Without a surgical bypass blood from the gut that normally went to the liver “had no where to go, and the organs of the lower part of the body became stuffed with blood” with disastrous consequences.  Having solved these technical problems Starzl was able to keep dogs alive for a week, at which point their immune system was activated, and the transplanted livers were rejected.  

During the next few years researchers transplanting kidneys struggled with the rejection problem.  In 1962 they learned they could tone down the immune response and prevent many a body from destroying a kidney with a combination of two currently available drugs, prednisone and immuran. 

The first patient

In 1963 Starzl transplanted a liver into a three year old who had a lethal condition called biliary atresia.  The boy bled uncontrollably and died.  Starzl wrote of staying in the operating room for a long time afterwards, sitting on a low stool, looking at the ground, and saying nothing.  During the subsequent three years he confined his work to dogs.  Then between 1967 and 1979 he swapped out the livers of 170 patients.  56 people lived less than a year and 25 lived for 13 to 22 years.  Azathioprine the immunosuppressant of the day wasn’t predictably successful. 

Roy Calne M.D.

In England Roy Calne first started dreaming about transplants when he was a young doctor treating a patient his own age who was dying of renal failure. 

Years later he heard that a doctor Murray in Boston had transplanted a kidney from one identical twin to the next.  After operating on pigs and perfecting his technique, Calne transplanted a terminally ill Brit in 1968.

A bag of magic soil and the immune system

In 1969 a Swiss microbiologist named Borel vacationed on a “desolate highland plateau” in Southern Norway.  While there he collected soil samples and made a discovery.  At the time there was a precedent for roaming the world and collecting dirt.  The original mold Fleming found in 1928 didn’t make much Penicillin.    But in 1942 someone tested the rot on a cantaloupe in Peoria Illinois and found an organism that made 200 times as much antibiotic as the original.  It, in turn, allowed penicillin to be produced in commercial quantities.

The fungal product in Borel’s soil did something to the “part of the immune system that starts the process of detecting and attacking invaders.”  It didn’t destroy lymphocytes but it held them back.  Borel thought he’d hit the big time, but in 1972 when he explained his findings to his employer, the Sandoz pharmaceutical company felt the drug had no financial future.  (The chemical he discovered is now called Cyclosporine.)

Four years later Borel presented his data at a meeting of the British Society of Immunology and Calne was intrigued.  After he heard Borel’s presentation, Calne asked for and received some Cyclosporine.  He tested it in rats and dogs and showed that, as advertised, it suppressed their immune systems.  Borel brought Calne to Switzerland, the Brit convinced the money men at Sandoz that the drug had promise, and the company started making the drug. 

It took time to learn how to use cyclosporine, to give the right dose, to take appropriate precautions, and to stay alert for problems.  At times the medication unleashed fungi and viruses that lived in people’s bodies but had not previously caused trouble.  Too little drug meant rejection of transplanted organs.  Too high a dose led to kidney damage.  An occasional cancer or lymphomas popped up in people who were taking the medication.  By 1979 Cyclosporine was available at four American Universities:  Harvard, the University of Minnesota, Houston, and Colorado. 

A second major, now widely used, anti rejection drug, Tacrolimus was the result of long tedious hours spent by chemists at a Japanese pharmaceutical house.  In 1982 Fujisawa workers started “testing a wide range of fermented broths from streptomyces bacteria” and found a chemical that suppressed lymphocytes.  The FDA cleared the anti rejection drug Tacrolimus in 1994.   The year before Tacrolimus (Prograf) went generic, Astrellas, the manufacturer sold 2.1 billion dollars worth of the medication, and predicted its annual sales would fall to 676 million dollars once Novartis marketed a generic competitior.  In 2000 there were several generic forms of cyclosporin, and the U.S. market for the drug was about 480 million dollars.  (Cellcept the byproduct of a fungus found on rotting apples, was marketed in 1998 and was pricy before it went generic; and there are other others.)

Pittsburg becomes the transplant center of the world

Once anti rejection drugs were available transplanted livers survived for many years and Starzl’s group in Denver led the way.  In 1981 Starzl moved to the University of Pittsburg and brought liver transplantation east.  3 of the first four people he transplanted died but 19 of the next 22 survived.  People who were dying of liver disease came to Pittsburg and were admitted to beds on the medical service where most spent their last days. “54 residents and interns in the Department of medicine signed a resolution denouncing liver transplantation as unrealistic and potentially unethical.” In response Starzl admitted his cirrhotics to the surgery service. (He couldn’t make the patients live longer but he could get the internists off his back.)  Starzl and others turned the Pittsburg transplant program into the largest in the world. 

In 1983 when the FDA approved cyclosporine for use in transplant patients, surgeons operating in the “centers” had successes and failures.  The procedure was far from standard or easy. 

At the time some skilled doctors in the community apparently thought: if he can do it, I can too.  In the 1980s a California surgeon attempted a liver transplant and the patient bled to death.  In the process the operating physician transfused the person so aggressively that (hearsay) the blood supply of Southern California was threatened. 

When new skills and techniques are introduced, physicians who have been in practice for years are at risk of becoming obsolete.  A window opens, during which practitioners can attend a seminar, take a weekend course, watch a colleague do a few procedures, and then begin their personal learning curve.  Transplanting livers successfully, however, required much more than merely learning a few new tricks of the trade.   

           A SHERIFF RIDES INTO TOWN.

Enter Rudi Schmid.  He was tall, handsome, charismatic, and likeable.  An Olympic skier and physician, “Rudi” was the son of Swiss doctors; and he had rats or at least access to very special “Gunn” rats.  The animals were jaundiced; they couldn’t excrete their bilirubin normally because they lacked an enzyme.  By studying these animals researchers learned a lot about the yellow waste livers made from dead red cells.     

In the early 60s Dr. Schmid came to the University of California in San Francisco where he took over the GI department.  In 1983 he became dean of the medical school and in June of that year he chaired the NIH Consensus Development Conference on Liver Transplant.  It was time to bring order to the process. 

Those at the 1983 meeting decided that any institution that starts a liver transplant program must make a major commitment to its support.   

In addition to having access to a wide array of subspecialists the committee recommended the hospital needs kidney dialysis capability, respiratory therapy support, and an extensive blood bank.  Participating universities would need to make a large financial commitment to the process and transplants would be costly.

Surgeons must be trained specifically for liver grafting and must assemble and train a team to function whenever a donor organ is available.  People die at odd hours. If their parts are to be used in others, teams from various transplant groups have to show up post haste.  They must “harvest” the donor organs, keep them alive, and transport them quickly. Once transplant centers know a liver is on the way they have to call in two potential recipients, the person of that blood type who is at the top of their list and a back up, just in case.  People with active infections cannot be transplanted until the infection is gone.  After the new organ is planted the recipients are given drugs that turn off their immune system.  When they are in a compromised state a minor infection can become lethal. 

Rudi Schmid, returned to the University of California in San Francisco and set up a transplant service.  In 1988 he chose his chief surgeon, Nancy Asher. And she put together a program that now performs about 140 transplants a year.  93.3% of the patients they transplanted survive one year.  (That’s higher than the nationwide norm of 85.8%.)

85.8 percent of recipients are alive in 3 years (78% expected) and 700 people are on the waiting list.  The team includes 8 surgeons, 11 hepatologists, 5 coordinators,

and 8 nurses. 

Transplant programs were judged by the outcome of the patients; how many survived?  How many livers made it?  What about the complications? The approach, of course, created a paradox because donor livers went to the sickest people first, and the debilitated were more prone to complications.  Their survival was suboptimal. 

A Wall street Journal article (Nov 1, 2008) on the web talked about the Pittsburg program.  At its peak in the mid-1980s the “transplantation capital” performed about 600 liver transplants a year and charged close to half a million dollars for each of them.  The program generated $130 million of revenue in 2008.  The first month of life post liver transplant runs a little over half a million dollars. (transplant living.org)

A lot of the health care dollar is being spent to help a relatively small number of people.

Rationing by another name.

In the U.S. we’ve never had enough donor organs.  At the same time it’s hard to avoid supermarket tabloids that talked of celebrities who received fresh livers.  I’m talking about Evel Knievel and David Crosby of Crosby Stills and Nash.  The system appeared to be rigged.   

But after 1983 Liver Transplantation was a mainstream, sanctioned approach to end stage disease.  Everyone “officially” deserved a second chance, and the question in every sufferers mind must have been who’s on first? Why him and not me?

Philosophers ponder fairness.  Committees create rules.

In 1983 the consensus conference felt that participation in a donor procurement program and network is essential, and an interdisciplinary deliberative body should exist to determine on an equitable basis the suitability of candidates for transplantation.  (In other words we need rules please.)

Congress passed an authorizing law, and a private non profit corporation was established.  A system evolved for getting people to donate organs and to move them from the donor to recipient.  A queue was established so we could do our best to be “fair”, whatever that means.  There were helicopters and training; records were kept.  When the allocating organization moved from one Virginia office to another in 2003 there were 50 employees and UNOS (the United Network for Organ Sharing) was “linked” to 257 transplant hospitals and 59 procurement centers.

They established an A list and a B list.

People in the first group had previously been healthy but were now on the brink of death as a result of acute fulminant liver disease.  They had first dibs on the next liver that arrived by helicopter if it matched their blood type. (Causes of sudden severe liver failure include acetaminophen (Tylenol) over dose, poisonous mushrooms and idiosyncratic reaction to prescription drugs.)

People on the B list had a chronic liver diseases that was getting worse and it was gonna kill them.  Their organs were usually cirrhotic which means a honey comb of scar tissue surrounded islands of normal or inflamed liver cells.

Many people link the words cirrhosis with alcohol, and alcohol does cause liver disease and cirrhosis.  But it’s, by far, not the only condition.   Cirrhosis can be the end result of chronic viral hepatitis, of steatohepatitis (inflammation in people with obesity mediated fatty liver) and a slew of other conditions. 

In the 1980s we had a committee that decided what liver problems were best handled with a transplant.  A separate organization (UNOS) prioritized the distribution of donor organs.

Early on we didn’t transplant people with HIV.  People with hepatitis B were excluded because the new livers did poorly.  That’s all changed and it will keep changing.

  People being considered for transplant undergo an evaluation process that is detailed and expensive.  Using a group of criteria developed at the Mayo clinic (MELD) doctors predict who, in the absence of a transplant, will die soonest.  When possible these people are transplanted first.

Changing indications for transplantation

The last 20 years has seen a change in the population that we transplant. 

Years ago people whose livers had been destroyed by hepatitis B were not transplanted because the disease always recurred in the new liver; the patient’s life was hell for a few years; then he or she died.  We now have effective anti virals.  The hepatitis B problem has been solved, and hepatitis B transplants are among the most successful. 

People with alcoholic liver disease can now receive a new liver if they have stopped drinking and they are attending a program run by physicians or by alcoholics anonymous.  (That too may change.)  There’s a high incidence in recidivism in people who can’t prove they have been substance free for 6 months. 

HIV has become a chronic disease.  The drugs we use are now that good.  As a result, people with HIV can take drugs that suppress their immune system, and they can be transplanted.  Unfortunately people with HIV and advanced liver disease often have Hepatitis C.  And that poses problems.

People with liver disease are at risk for primary cancer of the liver, Hepatoma.  World wide it’s a huge problem.  More than 600,000 people die of this cancer each year, half in China.  The U.S. performs the more liver transplants than any other country, but China is number 2.  

Primary cancer of the liver is becoming more of a problem in this country.  If we catch it at an early stage and the person is not cirrhotic, surgeons can remove the tumor.  If the liver is scarred or the person has several masses we can cure some by giving them a new liver.  Problem is people with chronic Hepatitis B often get cancer when their liver function doesn’t qualify them for a liver, when their MELD score is low, when they are far from eligible for a transplant.  The UNOS people have reconfigured their formula and have a complicated system that gives people with early cancer extra points, though not enough to go to the front of the line.   

Ascites

There are individuals who have fluid filled abdomens that weigh them down and make them look pregnant.  Their cirrhosis (scarring) makes it difficult for venous blood from the intestines to flow through and be detoxified by the liver.  The red fluid by-passes the organ and goes to the brain causing confusion and drowsiness.  It backs up in the lower body causing legs to swell and the abdomen to fill with fluid.  When needles and syringes are used to drain the liquid it soon reaccumulates and makes life difficult.  Both harms could be cured with a transplant, but the person’s MELD score is often low and they are not a candidate for a random liver.  The allocation system needs constant tweaking. 

Coping with Donor shortages

I met a Norwegian transplant surgeon at the Silverado event 2 years ago.  He was on sabbatical, watching how people in California handled transplants, and he was bothered by the long wait times.  In Norway, he said; if someone has a bad liver we just transplant them. 

Are there enough livers? 

Sure.  People with end stage disease are contacted and they donate. 

I don’t know if he’s right, and if he is, Norway may be unique.  It has a small homogenous population and is North Sea oil rich.  What happens there may not work here.  (In Germany the organs of someone who is brain dead can only be used if his family opts-in, and 12 percent give their consent.  In Austria, which uses an opt-out approach, nearly all those eligible (99 percent) become donors.)  (NY Times Sept 26, 2009)

Between 1997 and 1999 a group of doctors and nurses reviewed the medical records of 18,000 people who were dying in ICU’s and were potential organ donors.  54% of the families asked to donate said yes and 42% of those who died became donors.  (N Eng J Med Aug 14, 2003.)

Currently 6000 livers are transplanted annually in the U.S.  The numbers would grow if more livers were available. 18,000 Americans nation wide are on waiting lists, and 10% will die before they are called.   

 A number of the people who died after they were “listed” had turned down organs whose quality was deemed inferior (and more likely to fail.)  These livers came from old donors or from the bodies of people who had died of a heart attack and whose liver had been deprived of blood for up to 14 minutes. 

About 10% of livers transplanted in our country come from living donors.  The son of a friend donated 60% of his liver to a relative.  The donor was 30 and healthy going in, and he was convinced that he would do well and that he matched for “a reason.”  He was told repeatedly that there was a one in 200 chance that he would have a complication and die.  It didn’t dissuade him any more than the risk of dying in Iraq or Afghanistan is a deterrent to young men and women bound and determined to join the marines.  After surgery the young donor was weak and limited for a month or more, then the 40% of liver that remained became 50% and 60%; he continues to improve. 

The liver is the largest organ in the body.  Typically it has a large right lobe and a smaller left lobe.  When an adult gives part of his liver to a child they remove the left lobe.  It’s a simpler operation, the donor recovers faster, and there is less risk of death. 

But the left lobe isn’t enough for an adult (unless they agree to have blood shunted around their liver and risk liver “confusion”.)  They need more.  The right lobe must be split, and that requires special training and creates extra risk.  If the amount of liver transplanted is insufficient, people can develop something called the small-for-size syndrome.  It happens during the first post transplant week.  The graft is unable to regenerate, there are mechanical problems with blood flow, and the person receiving the transplant dies. 

The ethics of liver donation are complex.  (N. Engl J Med Aug 4 2005)  People feel varying amounts of pressure when a loved one needs a liver and they are healthy enough to donate.  How do we deal with “radical altruism”, like the man who donated a kidney then explored the idea of giving away his other organs “in a dramatic suicide?”

Some people, apparently, advertise and sometimes pay for liver donors.  Quite a few used to go to China and receive the liver of a condemned prisoner.  Last year two UCSF transplant doctors debated the ethics of caring for these people when they return from such an endeavor.  The discussion was interesting but not really that pertinent.  The Chinese banned organ tourists on May 1, 2007, not for ethical reasons, but because there were over a million Chinese on transplant waiting lists.  I guess there weren’t enough prisoners to go around.  (NY Times Feb 17, 2009.)

We get a few extra livers by lowering our standards, using livers that are less likely to make it.  Some livers are thrown away because they are too fatty, because the person who died is too old.  At the time we did not use livers that were infected with hepatitis C.

A chapter in the book: The Troubled Health Dollar by Steven Fredman