It has been frequently said that organ transplantation is tantamount to metamorphosis. In Gavin Francis's Shapeshifters, he used different examples to illustrate the concept of change in the human body. Transplantation is the resection of the old, welcoming the arrival of the new as a replacement organ takes the place of a disease-ridden counterpart having descended at the final steps of the ladder of its life. The first kidney transplant was carried out in 1954. The first liver transplant was executed in 1967. [1]
The rise of COVID-19 has shocked the world and most notably, the world of medicine. It maintained a firm grip on the local healthcare system and there has been a major disruption on the execution of major operations. Academic medicine and health policy are immediately driven to the direction of COVID-19 research, striving to gain a clearer picture of the beast COVID-19 initially portrays itself to be. This particularly affects liver transplant - in the UK and USA (see reference list, where multiple references point towards the issue), the numbers of liver transplants performed during the peak of the first wave (first lockdown in the UK started in March 2020) and living donors contacted (or potential ones) slumped drastically as compared to the same time-period in 2019. Recovery was made after the end of the first wave (estimated to be late June-early July). During the peak, there was an 86 per cent reduction in organ donor offering, with the number of liver transplantations having fallen by 84 per cent in the UK. [7] This is different from the German experience, where liver transplant has remained robust. [4] This can be attributed to the differing incidence rates of COVID-19 and healthcare policies between the aforementioned countries.
Patients having received liver transplantation are deemed to be more vulnerable to infectious complications due to the mandatory requirement of receiving immunosuppressive therapy. This is to reduce the likelihood of graft rejection and acute cellular injury. Contracting the disease is thought to lead to higher mortality. The logic continues to go that due to the inherently high risk of contracting COVID-19 in healthcare settings, especially in high-incidence areas such as the UK and USA, patients with more stable chronic liver disease or those who are responding well to bridging therapy (prior to COVID-19, there is already a system called the 'waiting list' since, sadly, the UK still doesn't have enough livers for everyone. Bridging therapy is given to patients with severe liver disease who can wait but cannot afford to wait too long for an available liver without experiencing a rapid increase in risk of disease progression) are discouraged from receiving liver transplantation. COVID-19, as a new beast, may also increase the rates of non-infectious complications after liver transplantation. Liver transplant, as a high-risk procedure, can lead to acute complications such as heavy bleeding, biliary strictures (especially common in patients having received livers from donors who died from circulatory disorders, such as heart failure), hepatic artery and portal venous thrombosis. [8] Donors are also less likely to donate. There are two sources of liver donation - living and deceased donors. For living donors, patient fear is observed. This means that patients or normal subjects are usually in fear of attending even routine hospital appointments. They refuse to go to healthcare settings due to the perceived high risk of contracting COVID-19. This is understandable but at the same time, this reduces the number of living donors that we can contact. This also reduces, to a certain extent, the number of recipients who are eligible for transplant, but nonetheless decline such opportunities. In terms of deceased donors, due to the higher incidence of COVID-19 in the locality (my locality is London, but this statement applies to the UK in general), patients are likely to die of COVID-19. Reports have suggested that COVID-19 can lead to liver injury [10], more often seen in patients having suffered from more severe disease (common definition: use of mechanical ventilation, hospitalisation, and ICU admission). Here, we are concerned about the transmission of COVID-19 through the deceased donor graft to the recipient. We're also worried about the reduced graft efficacy due to prior COVID-19 exposure and its associated liver injury. Receiving a sub-par graft with COVID-19 presence is worse than not receiving anything at all. Due to this, policies have been in place since March that all donors and recipients are screened for COVID-19 infection before the entire transplant kicks off. This is to ensure both parties are 'clean' and the process can contribute to clinical outcomes as optimal as possible.
All diagrams presented below are extracted from BMJ [11].
Diagram illustrating the surgical segments of the liver, also known as the Couinaud Segments. Segment I is actually harder to see since it is located over the posteriorly located caudate lobe, just above the porta hepatis (the entry point of the proper hepatic artery, hepatic bile ducts and portal vein) and the quadrate lobe.
Diagram illustrating orthotopic Liver Transplant and its associated procedures - the word 'orthotopic' refers to putting the new organ in the same place as the old one. There are two ways to do the anastomosis of the suprahepatic and infrahepatic vena cavas, which are respectively the end-to-end technique and the piggyback technique. A technique called veno-venous bypass is also utilised to avoid systemic hypotension since the major veins to the liver are clamped during the surgery. Venous return to the heart is expected to drop without intervention. Veno-venous bypass is performed by diverting venous blood from the distal part of the body (note inferior mesenteric and femoral veins) to the more proximal part of the body (note axillary and internal jugular veins). [8]
Diagram illustrating the split liver technique which is used in paediatric surgery. It is a mammoth task to find the exactly right liver for children since the paediatric mortality rate is lower than adults. The growth rate of children is also much more rapid than adults that the liver size is easily out of range if there is a significant age difference between the donor and recipient. This technique entails the dissection of the liver into two parts, where the child will receive a part of it, say the left lateral segment. Note that the liver is histologically more uniform than some organs, such as the brain and heart. It can grow back to its normal size after transplantation.
More importantly, there is the issue of logistics. A Correspondence recently published on Lancet Gastroenterology and Hepatology [2] stressed on the importance of prioritising patients with acute and severe conditions during this unprecedented health crisis. There are only seven liver transplant units across the UK, including Royal Free Hospital and King's College Hospital in London. The responsibility of paediatric procedures rest on merely three centres. [3] At the time of the pandemic, it has to be noted that many COVID-19 patients are of an older demographic and require more nursing and intensive care support. They require more resources. Liver transplant patients also demand the same level of attention, care and resources. This leads to inevitable competition and hospitals would unlikely be able to cope should organ transplant activity be maintained at as high levels as yester-year. The word resources is used aptly in this context, since it goes from supplemental oxygen and face masks (transplant patients need face masks to reduce the risk of aerosol transmission of diseases) all the way to oral nutrition (food) and blood products. This has led to the implementation of all sorts of policies surrounding liver transplantation. In the UK, apart from screening for COVID-19 (in donors and recipients), all procedures were stopped briefly in late March to early April. This was reported by the Birmingham Liver Unit. [6] Only super-urgent cases were still carried out (such as drug-induced or autoimmune-flare acute liver failure, in which transplantation is immediately required). The age thresholds for deceased donor transplantation were also substantially decreased, so as to reduce the size of the available organ pool. This was expected to reduce the number of operations executed during the height of COVID-19 (first lockdown) so as to concentrate resources on helping high-risk patients who contracted COVID-19 instead.
This figure shows the Milan and UCSF criteria for liver transplant in patients with hepatocellular carcinoma (a key indication for transplantation). This figure is extracted from: https://i.pinimg.com/originals/9f/ec/da/9fecda04b75d5f53888afe657e0bd865.jpg.
CT Scan showing Hepatocellular Carcinoma (contrast-enhanced). The hypodense lesion is located over the right lobe of the liver and the exact surgical segment can be confirmed by scrolling through the stack of images. However, judging by the placement of the liver and adjacent structures shown in this scan, my guess would be Segment 7 (for the classier amongst you, VII). Moreover, it is hypodense and thus we can deduce that this is the portal venous phase. Hepatocellular carcinomas get hyper-attenuated during the arterial phase, at odds with the rest of the liver, which receives the majority of blood supply through the portal vein. This scan is extracted from: https://www.researchgate.net/publication/230763754/figure/fig6/AS:667829623861264@1536234398494/CT-scan-of-hepatocellular-carcinoma-in-right-lobe-of-the-liver.png.
Liver transplantation, from a long time ago, shifted from a needs-based approach to a transplant benefit approach. The crux is the calculation of the maximum benefit to both recipient and donor accrued by the effectuation of such a transplantation. Urgency is not a necessary factor of consideration, since it is believed a better match leads to better clinical outcomes, including lower complication rates (therefore less medication, less follow-up and lower chance of ultimate graft injury and the need for re-transplantation). However, since we don't have a choice in the era of COVID-19, a hybrid approach is adopted. The urgency of need is included as a key factor of consideration. More urgent cases, such as decompensated cirrhosis, are done before less urgent ones, even though some of the less urgent cases might result in greater benefit by having received the organ. The high-urgency recipient category is defined as recipients 'anticipated to be at high risk of dying or progressing outside transplant criteria within the following 3 months'. This category includes patients with UKELD Score higher than 60 (a UK or Brexit version of MELD, which determines the queue position of a patient in the waiting list for liver transplantation; the factors underlying the score are serum creatinine, serum sodium, serum bilirubin and INR [international normalised ratio of prothrombin time]), patients subjectively identified to have a condition worse than the UKELD Score (indeed, it is intrinsically flawed, as judged by the authors of [12]) and patients with hepatocellular carcinoma close to the limits of transplantation.
Current research rests on several areas, all with great potential of development. Number 1 - is the logical belief that liver transplant patients with COVID-19 suffer from inferior clinical outcomes amenable to challenge? Number 2 - is COVID-19 an absolute contraindication for donor transplantation? Of course, many excellent research questions are also asked and resolved in the domain of health policy and guidance. However, I'm not exactly a public health expert. Nor am I (well, just being frank here) overly interested in this field. Therefore, in this article, I only focus on key questions Numbers 1 and 2. Moreover, since I've already summarised the findings of three major studies investigating the correlation between clinical outcomes and COVID-19 infection in patients having received liver transplant, and appraised whether the studies have adequately answered the two questions posed, in the paper I submitted, I want to take this opportunity to instead explain the rationale behind the variables I chose to answer the questions.**
Clinical Picture showing the Mercedes-Benz Scar, characteristic of liver transplant (extracted from: https://7468669c0013a7dae459-4d0fcf8d315d40f305ee2ebb6c32f79c.ssl.cf1.rackcdn.com/6876275_1456895882.6089_updates.jpg.
We cannot simply defy the notion that liver transplantation and COVID-19 are not mutually exclusive by asserting blindly that they are two separate matters. The way to resolve the conundrum is to ask what parameters should be adopted for determining whether such patients are subjected to worse clinical outcomes than not having received it in the first place, against the backdrop of COVID-19 infection. In my article submitted to Cambridge Medicine Journal, I proposed four elements: (a) mortality rates, (b) experiencing more severe form of disease (COVID-19), (c) COVID-19-associated reduction in graft efficacy (liver injury) and the need for re-transplantation, and (d) immunosuppression regimens.
These four elements are crucial in different ways. Naturally, we want to extend one's life and improve survival rates at various time-points by doing liver transplants. This is a core aim. If COVID-19 infection leads to higher risk of mortality, this aim is subverted. Since there is higher chance of nosocomial contraction of COVID-19 (nosocomial=in healthcare settings), the aim of achieving better survival outcomes may be better served by undertaking medical therapy. For instance, in cases of hepatocellular carcinoma, other forms of treatment are available to patients with early-stage disease. Transplantation is only one of them. The others include surgical resection and radiofrequency ablation. These two modalities also require hospital appointments. However, I think the point lies in immunosuppression. Out of the three options, only liver transplant requires the administration of drugs which dampen the immune system.
Experiencing more severe form of COVID-19 is relevant in two ways - (1) it is directly related to mortality, and (2) it leads to worse quality of life outcomes. Quality of Life is a rather fluid concept but, assessing it medically, we can split it into short-term and long-term outcomes. Due to the use of mechanical ventilation and longer hospital stays, short-term quality of life can be impaired in this subset of the population. Long-term outcomes are impaired if irreversible organ damage, such as meningo-encephalitis and post-event seizures, is induced by COVID-19.
Moving on to the third factor, this is also related to health policy concerns. When we are doing a transplant procedure, we need to be cognisant of the issue of scarcity. We may enwrap us in lies that we live in a compassionate, kind world where everyone strives their best to help others. However, this is not the case judging by organ donation figures. 5136 patients in total are waiting for an organ, with only 2185 having received a transplant since April 2020. This applies to all organs, not just livers. [13] We expect an organ to be used at maximum capacity and health when transplanted. We do our best to make sure that the donated organ works best for the recipient and no complications occur. Graft injury strays away from this aim. If it is too serious, it may even necessitate a re-transplantation procedure. It's like giving certain people a second chance when others in the queue have not even got their first. Unfairness aside, this can be construed as a waste of organs. Therefore, if COVID-19 leads to advanced liver injury, then transplantation is not recommended. It's better to have the organ shipped to patients living in places where COVID-19 is better controlled (such as New Zealand and Australia).
Last but not least, immunosuppression is a vital part of organ transplantation. Immunosuppression is divided into two key phases: initiation (for the first few months, usually 3 months) and maintenance. We are trying to use stronger drugs in the former to stabilise the condition, followed up by slightly weaker ones since we are also cognisant of the side effects of immunosuppressants such as hepatotoxicity (which is counter-intuitive) and renal toxicity (manifesting in ways such as acute kidney injury). Not all immunosuppressants, as you can gather, work the same. The major tensions rest on the tug-of-war between the orthodox view that immunosuppression leads to easier COVID-19 invasion and this directly contributes to higher mortality rates, and the novel view that some immunosuppressants are better than others. Moreover, some immunosuppressants are capable of reducing the replication of SARS-CoV-2 in the human body. It also has to be mentioned that severe COVID-19 features a hyperinflammatory state (basically meaning that the immune system gets into overdrive trying to get rid of the virus), which is better absent than present. It can lead to multi-organ failure as immune cells just keep attacking stuff that they ought not to touch. Cyclosporin A and Tacrolimus, both of which are calcineurin inhibitors, are found to reduce viral replication and hyperinflammation associated with late-stage COVID-19 infection. They inhibit calcineurin, which is a molecule in the signalling pathway conducive to the synthesis of IL-2. IL-2 is a key interleukin for immune cross-talks. For mycophenolate mofetil, worse outcomes are observed as compared to calcineurin inhibitors. It preferentially acts on lymphocytes due to its antagonism towards purine DNA base synthesis - something lymphocytes like more than other types of immune cells. [14, 15]. Clinical outcomes may vary because of many factors, but a key one is the difference in mechanisms of action.
An additional research question may be the differences in mortality rates and prevalence of COVID-19 in patients with varying indications for liver transplantation. There are multiple types of chronic liver disease necessitating liver transplant, including Hepatitis C infection and Non-alcoholic fatty liver disease (NAFLD). This contributes to the relative heterogeneity in comorbidity profiles of patients receiving liver transplants. Even greater heterogeneity can be observed between normal subjects and these patients. NAFLD is an increasingly common disease in more advanced economies. In Europe, its prevalence stands between 20 and 30 per cent. In the US, it reaches as high as 46 pre cent. [16] This is related to the rise of diabetes mellitus, hyperlipidaemia, and hypertension in these regions. Hepatitis C patients have a different comorbidity pattern. Since Hepatitis C is transmitted through blood, we are thinking about other blood-borne infections such as HIV and CMV (cytomegalovirus) co-infections. A study found that HIV co-infection was present in 4 per cent in patients with Hepatitis C. Cirrhosis was present in 26 per cent. Significant comorbidities included diabetes, renal failure, cancer, asthma, chronic obstructive pulmonary disease, substance use disorder, mood and anxiety disorders and liver failure. [17] The variations in comorbidity patterns may contribute to variations in individual (or cross-sectional) patient response to COVID-19. Plucking an example out of the blue, since diabetes mellitus leads to weakened immunity and is found more in patients having received a liver transplant in virtue of NAFLD, as compared to those having done so due to paracetamol overdose-induced acute liver failure, NAFLD-indicated patients may suffer from worse COVID-19 outcomes than paracetamol overdose-indicated patients. Clarifying differences in mortality and prevalence of severe COVID-19 amongst liver transplant patients of different indications can contribute to better risk stratification and health policy-making. For example, patients with NAFLD may be, upon being discovered to experience higher prevalence of severe COVID-19 than other indications, given long-term medical therapy unless more stringent (= higher threshold) requirements are met.
Figure showing the percentages of indications for liver transplantation in the UK in 2002. It is published on the BMJ [18].
In answering Number 2, we need to consider about the long-term implications of donors. Current health policies operate on an all-or-nothing pattern. If the donor has COVID-19, then he or she is automatically barred from donating an organ. This applies regardless of status (living vs deceased). However, COVID-19 is not something that is likely to disappear within a short period of time. It is likely to cause a persistent, significant impact on organ supply if people are automatically turned away even if they show signs of clinical resolution of COVID-19. Is COVID-19 infection, even when clinically resolved, a no by default? Taking this question farther, what if the patient has died from COVID-19 infection or is currently recovering from it? Is the viral seeding in the liver significant enough to justify reducing the number of available livers in the pool? Also, it is recommended that we look into the interval between the point of clinical resolution and acceptability of the liver for transplantation. These are big questions. Answering them can potentially save many more lives than we already do. Research in this area remains scarce - this is why the potential is vast.
Although this article mainly discusses about liver transplantation, the questions asked here are likely to stimulate discussion regarding transplantation in general. COVID-19 has taken many lives and given us many challenges. Life is what we make of it. We can picture ourselves living in the age of an apocalypse - a reimagining of the film 2012. At the same time, we can sober up and embrace this wonderful opportunity to do more impactful and engaging research. And save more lives.
*The cover picture is extracted from: https://apps.carleton.edu/reason_package/reason_4.0/www/images_local/324838.jpg?1188924649.
**It is a more detailed piece discussing future research directions of liver transplantation in the era of COVID-19, as well as current evidence examining whether COVID-19 contributes to sub-par clinical outcomes in patients having received liver transplantation. It has been submitted to Cambridge Medicine Journal (it's actually the first non-neurology article I've ever submitted to a medical journal).
References and Further Reading:
[1] The history of organ donation and transplantation. UNOS. https://unos.org/transplant/history/#:~:text=In%201954%2C%20the%20kidney%20was,were%20begun%20in%20the%201980s. Published 2020. Accessed December 26, 2020.
[2] Lembach H, Hann A, McKay SC, et al. Resuming liver transplantation amid the COVID-19 pandemic. Lancet Gastroenterol Hepatol. 2020;5(8):725-726. doi:10.1016/S2468-1253(20)30187-4.
[3] Liver transplant - Assessment. NHS. https://www.nhs.uk/conditions/liver-transplant/who-can-have-it/. Published 2020. Accessed December 24, 2020.
[4] Qu Z, Oedingen C, Bartling T, Schrem H, Krauth C. Organ procurement and transplantation in Germany during the COVID-19 pandemic. The Lancet. 2020;396(10260):1395. doi:10.1016/s0140-6736(20)32213-3.
[5] Manara A, Mumford L, Callaghan C, Ravanan R, Gardiner D. Donation and transplantation activity in the UK during the COVID-19 lockdown. The Lancet. 2020;396(10249):465-466. doi:10.1016/s0140-6736(20)31692-5.
[6] Lembach H, Hann A, McKay SC, et al. Resuming liver transplantation amid the COVID-19 pandemic. Lancet Gastroenterol Hepatol. 2020;5(8):725-726. doi:10.1016/S2468-1253(20)30187-4.
[7] Thorburn D, Taylor R, Whitney J, et al. Resuming liver transplantation amid the COVID-19 pandemic. Lancet Gastroenterol Hepatol. 2021;6(1):12-13. doi:10.1016/S2468-1253(20)30360-5.
[8] Farid S. Liver transplantation. Surgery (Oxford). 2020;38(7):389-397. doi:10.1016/j.mpsur.2020.04.011.
[9] Merola J, Schilsky M, Mulligan D. The Impact of COVID‐19 on Organ Donation, Procurement, and Liver Transplantation in the United States. Hepatol Commun. 2020. doi:10.1002/hep4.1620.
[10] Zhang C, Shi L, Wang F. Liver injury in COVID-19: management and challenges. The Lancet Gastroenterology & Hepatology. 2020;5(5):428-430. doi:10.1016/s2468-1253(20)30057-1.
[11] Vilca-Melendez H, Heaton ND. Paediatric liver transplantation: the surgical view. Postgraduate Medical Journal 2004;80:571-576.
[12] Stravitz R, Lee W. Acute liver failure. The Lancet. 2019;394(10201):869-881. doi:10.1016/s0140-6736(19)31894-x.
[13] Statistics about organ donation. NHS Organ Donation. https://www.organdonation.nhs.uk/helping-you-to-decide/about-organ-donation/statistics-about-organ-donation/. Published 2020. Accessed December 26, 2020.
[14] Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant. 1996;10(1 Pt 2):77-84.
[15] Willicombe M, Thomas D, McAdoo S. COVID-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm?. Journal of the American Society of Nephrology. 2020;31(6):1145-1146. doi:10.1681/asn.2020030348.
[16] Pais R, Barritt AS 4th, Calmus Y, et al. NAFLD and liver transplantation: Current burden and expected challenges. J Hepatol. 2016;65(6):1245-1257. doi:10.1016/j.jhep.2016.07.033.
[17] Cooper C, Galanakis C, Donelle J et al. HCV-infected individuals have higher prevalence of comorbidity and multimorbidity: a retrospective cohort study. BMC Infect Dis. 2019;19(1). doi:10.1186/s12879-019-4315-6.
[18] Gee I, Alexander G. Liver transplantation for hepatitis C virus related liver disease. Postgraduate Medical Journal 2005;81:765-771.
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