Liver disease is a rising public health threat, with a shortage of donated organs for those in need. Researchers have now proven that technical advances now allow for new eligibility criteria to enable once-discarded livers to be safely used.
Chronic liver disease incidence in the UK is rising annually, a result of increasing alcohol misuse and obesity, causing approximately 8500 deaths per year. For those with end-stage liver disease, a transplant is the only hope for survival, but demand for livers suitable for transplantation far outstrips supply. In 2016/17 up to 20% of people awaiting a transplant operation died or were removed from waiting lists due to ill health.
For a donated liver to be transplanted, it must pose minimal risk of complications. Many do not meet existing criteria and are discarded. But researchers are questioning whether common criteria are causing unduly high rejection rates.
Supply is already short of demand. Young donors were once a big contributor of healthy livers in the event they suffered brain death (for example, following accidents). “As a country we have become much safer and more risk-averse and as a result the number of deaths from trauma have declined”, explains Richard Laing, from Birmingham University’s Centre for Liver Research.
Consequently, a growing proportion of donated livers are instead coming from donors following circulatory death (DCD) - in which patients with no prospect of recovery are allowed to die naturally and their organs harvested or when a patient has suffered cardiac arrest that is unexpected and from the patient cannot or should not be resuscitated. These livers are of lower quality both because of donor characteristics such as comorbidities (they are usually of older age), having been deprived of blood supply which damages tissue and also because the frequency of steatosis (fatty liver) has increased.
So-called ‘marginal livers’ pose risks to recipients, such as allograft dysfunction (where a newly transplanted organ subsequently develops severe tissue damage), renal failure or primary organ nonfunction. Consequently, the majority of DCD livers are not transplanted.
The criteria for rejection, however, are not consistently made - and may be subjective. There are significant regional differences in decision-making, and in expertise regarding organ viability. This means people on waiting lists may not be receiving viable organs that could save or prolong their lives. Concerns about the increased demand for transplantation is driving a team of researchers to challenge viability criteria through a novel research programme which is delivering promising results.
Re-thinking organ viability
Birmingham has been at the forefront of liver transplantation medicine; it was the location of the UK’s first liver transplant and currently houses one of the largest liver transplant programmes in Europe. Now, researchers at the University of Birmingham and the Queen Elizabeth Hospitals Trust are pushing the frontiers of transplantation science by exploring ways to improve patient safety and efficiency in liver transplantation.
Normothermic machine perfusion of the liver (NMPL) is a method for maintaining near-physiological conditions in livers by supplying them with oxygen and nutrients at body temperature. This prevents detrimental effects of static cold storage such as ischaemic cell damage, and permits the study of liver function outside the human body. Research has demonstrated that NMPL is superior to static cold storage at preserving liver function. A groundbreaking operation in 2014 saw a team of surgeons at Birmingham’s Queen Elizabeth Hospital successfully transplanting a liver from a cardiac death donor that had been “revived” after transportation to the hospital by being perfused with oxygenated blood.
However, the use of this technology to study the physiological function of high-risk livers is now progressing rapidly. If ex vivo liver function can be objectively assessed, rates of transplantation could be increased without necessarily increasing the risk to recipients. Richard Laing explains that a surgeon’s assessment of suitability prior to transplantation must include a wide range of factors.
“It is not only the appearance of the organ itself, but the medical history of the donor, the cause and circumstances of death, what the recipient is like and whether they are going to require a very good quality liver or might be a bit more stable”. This can make the assessment process subjective, and Laing suggests that there is widespread regional variation in what is considered a viable organ.
Research is currently pursuing the development of quantitatively objective criteria regarding organ viability. The team successfully demonstrated that a significant proportion of high-risk livers previously rejected for transplant in the UK do in fact meet viability criteria. A subsequent pilot study at the University of Birmingham and Queen Elizabeth hospital found five out of six high-risk livers that were deemed to meet viability criteria were successfully transplanted into waiting recipients. Success was measured using the nationally-accepted standard of 90-day survival.
On the back of this pilot study, the Wellcome Trust funded the VITTAL (Viability Testing and Transplantation of Marginal Livers) clinical trial. The research team began recruiting patients on a waiting list for liver transplantation in October 2016. The study was designed to determine if a rejected liver is viable using normothermic machine liver perfusion, and to demonstrate successful transplantation of livers that had previously been declined but subsequently demonstrated to meet viability criteria.
The study team hoped to achieve 50% salvage levels and to demonstrate that their viability criteria were robust. In the study, livers considered unsuitable for transplant according to conventional criteria were placed under perfusion with oxygen and nutrients at body temperature for six hours. Following this, a range of indicators of liver function were measured. The primary indicator was the organ’s ability to clear lactate to an accepted level, a function of a normal liver.
Other criteria indicators included bile production, pH, glucose metabolism, histopathological and macroscopic appearance of the hepatic tissue (to identify cellular damage), and flow rates and pressures in the hepatic artery and hepatic portal circuits. Livers able to metabolise lactate were more likely to show positive characteristics in the other identified criteria.
The team identified a correlation between the new criteria and the proper application of previous methods of viability assessment. In other words, organs that appeared to have healthy tissue when examined under the microscope also demonstrated good levels of lactate clearance. This finding affirms that the new criteria were essentially refinements of existing assessment techniques. Of 31 perfused livers, 22 were deemed viable and were transplanted. This represented a salvage rate of 70%, significantly higher than the 50% the team initially hoped to attain.
This research marks important progress in transplantation medicine, indicating both the development of more objective viability criteria, and the novel application of NMLP to maintaining liver function until transplantation. Laing says: “we hope to reduce the discard rates and to do this through being able to give surgeons more confidence when making decisions about using a particular organ, by giving them more objective criteria to base their decisions on.”
The National Institute of Care Excellence in the UK recommended in January 2019 the use of machine perfusion under special arrangement while more data is gathered into it's efficiency and NHS England will decide whether to fund the technique.
The research team are also investigating the feasibility of combining hypothermic (HOPE) and normothermic perfusion (NMP) of livers as a way of minimising the risk of tissue damage, to further enhance the condition of marginal livers awaiting transplant. Both HOPE and NMP have benefits. HOPE reduces the risk of tissue damage by slowing down energy use, whilst NMP enables the assessment of how the liver will function under normal physiological conditions. The former reduces the risk of tissue damage and slowing down the use of energy. The team hope that combining the techniques may offer valuable ways to store and assess high-risk livers.
The team hope to see further refinement of the assessment techniques used to develop viability criteria, involving the use of novel biomarkers alongside the existing physiological and anatomical parameters, and are also leading the pharmacological treatment and reconditioning of steatotic donor livers to remove excessive fat and improve bile production, developing a perfusion solution which contains an artificial oxygen carrier rather than blood.
The VITTAL Study is a collaboration of experts from the University of Birmingham's Centre for Liver and Gastrointestinal Research, University Hospitals Birmingham NHS Foundation Trust and the National Institute for Health Research. Read more about the University's work in liver transplantation.
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