Liver Transplants in Birmingham

Ros Dodd, freelance writer University of Birmingham

It is hard to imagine that as recently as 33 years ago, attempts to launch a pioneering liver transplant programme in Birmingham were met with hostility from the medical establishment: The groundbreaking practice was viewed as an ego trip on the part of the surgeons; the patients wouldn’t survive, would they? But they did survive, and today Birmingham has the largest liver transplant unit in Europe, having performed more than 4,000 operations since 1982, now at the rate of four a week.

In 2013, the unit achieved its best one-year survival rate to date – 94 per cent – despite patients being sicker and donor

livers older and therefore less healthy than they were three decades ago. ‘The survival rates can’t go up by huge amounts anymore,’ explains Darius Mirza, Professor of Hepatobiliary and Transplant Surgery. ‘And, anyway, we don’t want to get to the stage where we have 100 per cent survival; if you do it means you’re not pushing the envelope as much as you should be: you’ve got to keep challenging and pushing the boundaries. You’re trying to grow the practice as well as improve the

outcome for patients.’

Also within the last 30 years, hepatitis C virus (HCV) has not only been identified, but a cure all but found – and, again, Birmingham has been at the vanguard. In the last two years, a major breakthrough has been made in preventing transplanted livers being re-infected with HCV – which can irreparably damage the new organ – by researchers at the Centre for Liver Research (CLR) and National Institute for Health Research (NIHR) Birmingham Liver Biomedical

Research Unit (BRU), along with colleagues at the Queen Elizabeth Hospital.

In addition to its transplant programme, Birmingham’s Liver and Hepato-Pancreato-Biliary (HPB) Unit is a national

Centre of Excellence for the treatment of all types of biliary, pancreatic and liver diseases, such as liver, gall bladder and

pancreatic cancers, cirrhosis and pancreatitis. So how did Birmingham become one of the biggest and most successful liver units in the world?

As is often the case, a number of factors came together at the right place and at the right time. But the key was undoubtedly the transplant programme. ‘It was this that unlocked the full spectrum of liver disease treatment,’ says Prof Mirza. ‘Transplants formed the backbone on to which everything else could be added, and without which the glue that binds it all together would be los

David Mutimer, Professor of Clinical Hepatology, agrees. ‘The transplant programme took Birmingham from being just

another specialty hospital to being something special. It gave it a mystique and put it at the cutting-edge. The characters that had to be involved to launch it and make a success of it had, by definition, to be good clinically and academically And they were.’

Geography was another factor. ‘Here was a centre in a largely urban area with a vast hinterland and little in the way of competing units within an 80-mile radius,’ says Prof Mirza. ‘The movement from secondary to tertiary hospitals was

already in place, and there was a children’s hospital three miles away. So we were providing something different and

to a large population.’ The scope to develop in different areas – adult, paediatric, specialist pancreatic and specialist cancer care – also played a significant role, as did the ability to work in multi-disciplinary teams.

The icing on the cake was the move from a converted 1930s building to a state-of-the-art 21st century centre, ‘which was recognition that if you are providing complex, high-spec work, it can only be delivered in an environment that’s modern and progressive.’

It all began in 1980, with the arrival at the QE of Paul McMaster, a consultant surgeon specialising in kidney transplantation but one of the few people in the world at the time who had trained in liver transplantation, and physician Elwyn Elias, who had an interest in hepatology having worked with Prof Dame Sheila Sherlock at the Royal Free Hospital. Liver transplantation had been done in US since the mid- 1960s, but in Europe there was only Cambridge and Hanover

in Germany that carried out the groundbreaking, complex and highly-risky surgery. Survival rates were very poor – fewer

than one in three patients living a year

But Professor McMaster – who now works for Médecins Sans Frontières – was determined to set up a liver transplantation

programme, despite coming up against strong resistance from the medical fraternity. ‘He drove it through against a lot of resistance – it was considered egotistical, experimental treatment that used up valuable resources, and all the patients were dying anyway,’ recalls David Adams, Professor of Hepatology and Dean of Medicine for the College of Medical and Dental Sciences, who is also Director of the CLR and NIHR BRU. ‘Paul wasn’t properly funded, so had to do the transplants out of the general budget to prove they could be done before he looked for proper funding.’

To save money, Prof McMaster would use his own car – an old police Jaguar – to drive to donor hospitals all over the country, where he removed the livers in an eight-hour operation, drove back to Birmingham and transplanted them the same day, involving a further 12 hours of surgery. The first transplant was carried out on January 19, 1982. Although the patient died soon afterwards, survival rates quickly picked up: the next three recipients lived for between 20 and 28 years.

Yvonne Munro, who received her new organ in 1985, went on to become the first liver recipient in Europe to have a baby.

Within ten years, the unit had become the most active centre in Europe, with 162 transplants in that year alone.

The relationship between Profs McMaster and Elias was pivotal to the early success of the programme, which by

1986 had been recognised as a national centre and was receiving specific funding as a supra-regional centre. The

foundations the two men built were reinforced by the recruitment of extra key staff, including hepatic pathologist Stefan Hubscher. "Stefan is now the world’s foremost liver pathologist, but he was a lecturer at the time,’ explains Prof Adams. ‘He,

McMaster and Elias started to develop a clinical programme, which made valuable contributions, such as defining what is

meant by rejection of liver transplant. They set up a protocol that many people all over the world have followed and which attracted doctors-in-training to come to Birmingham.’

Prof McMaster also had the vision to see that not only was a clinical unit necessary, but so too was a research unit.

‘So we set up what became the liver research laboratories in the Robert Aitken Building in the mid-1980s, which is whenI came on board as a research fellow,’ recalls Prof Adams, whose own expertise includes alcoholic liver disease and

autoimmune liver disease and immune regulation. ‘Alastair Strain, Professor of Biochemistry, who is a liver cell biologist,

joined us to improve the basic science within the unit, and James Neuberger, now an honorary Professor in Hepatology, was recruited from King’s College Hospital, London.’

Again, the coming together of different experts – physicians, surgeons, basic scientists and pathologists – along with access to unique clinical material via the transplant programme was the driver for the success of the research group.

‘Early on we set up a process to allow us to study patients’ old diseased livers after they were removed during the transplant operation,’ says Prof Adams. ‘Previously, the livers were destroyed, but we set up ways of isolating all the different cellular components from human livers and looked at how they might behave in a laboratory. So that put us at the forefront of in-vitro cell culture of liver physiology and pathology.’ As the research side continued to grow and flourish, so the need for modern, purpose-built facilities became more acute.

In 2004, the unit moved into the Institute for Biomedical Research, which provided ‘really outstanding’ lab facilities and paved the way for work to start on hepatitis viruses. Prof Jane McKeating, a virologist, was recruited from the Rockefeller Institute in New York to set up a scientific research programme into viral hepatitis, to work alongside the clinical programme led by David Mutimer.

‘The next big thing was in 2008, when we were awarded Liver Biomedical Research Unit status, funded by the National

Institute for Health Research,’ says Prof Adams. ‘This was a unique opportunity to translate what we were doing in the lab

into clinical trials and new treatment for liver diseases.’ It provided the infrastructure for translational research and

early-phase clinical trials; for example, taking the results of lab research on immunity and inflammation mechanisms of liver disease, including cancer, liver regeneration and repair and translating it directly into new treatments for patients.

One new treatment currently being trialled was developed as the result of research into dendritic cells, a type of white

blood cell that stimulates the immune system. ‘We took those cells from patients with liver cancer, stimulated them

with a liver tumour and then grew them for a week in the lab and put them back into the patient in order to stimulate their

immune system. We are getting responses from patients who haven’t otherwise responded to treatment

Philip Newsome, Professor of Experimental Hepatology and Clinical Director of the Birmingham University Stem Cell Centre, who was recruited from Edinburgh seven years ago, has been working on the largest randomised culture trial of

stem cells in liver cirrhosis ever carried out. Australian-born Prof Mutimer arrived in Birmingham in 1989 – the year HCV was discovered. Thanks in large part to the work he and Prof McKeating have done, the recurrence of hepatitis B and C viruses after transplantation can be managed successfully, and many patients can be cured of infection.

What is more, their research has led to the development of a new drug that blocks HCV from entering the liver – thus

reducing the re-infection of transplanted liver, which can irreparably damage the new organ.

Patients who receive a new liver because their own was damaged by HCV will experience recurrent infection after the

transplant, and the infection can be even more virulent than before. This means the new liver can cease to function after

just a few years. Until recently, doctors were unable to prevent HCV from entering the new liver. But in November 2013, the results were announced of a Birmingham clinical trial to evaluatean HCV entry inhibitor drug, ITX5061, given before, during

and after the transplant. These showed that the treatment dramatically slowed the progress of the virus re-infecting

the liver.

Treatment for hepatitis B (HBV) has also been developed at Birmingham. Says Prof Mutimer: ‘We did the original studies with new types of drugs. New strategies were developed in the 1990s and we can now completely prevent HBV coming

back and doing any damage to the transplanted liver.’

Over the past three decades, there has been a dramatic rise in liver disease – with non-alcoholic fatty liver disease

caused by obesity and diabetes and alcoholic liver disease by excessive drinking – which makes the continued success

of Birmingham’s liver centre vital for the future health of the population.

‘When I arrived, Elwyn and James were doing two outpatient clinics each a week and a shared one at the General Hospital,’ remembers Prof Mutimer. ‘There were a small number of clinics a week shared between the consultants. Today,

hundreds of patients are seen at the new outpatient clinic every week.’

This underlines how Birmingham has evolved to become one of the world’s foremost liver centres – and points to

it continuing to lead the way in learning more about and finding new cures for liver disease.

‘I think increasingly we will be doing more translational work – new diagnostic and treatment work, and more stratified medicine,’ says Prof Adams. ‘The future also lies in large national and international collaborations.

Currently, advances in HCV are really exciting: through the development of drugs that Birmingham has helped to

trial, it looks like we are going to be able to cure 80 per cent of our patients. For a virus that was only discovered in 1989,

to be curing it 25 years later is incredible. And Birmingham has played a major role in that.’

He adds: ‘All that Birmingham has achieved over the past 30 or so years has been very much down to team work.

Everyone is working together and pulling in the same direction – and that’s made it work.’

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