One of the great joys of caring for children is the prospect of seeing someone achieve goals in their life that would otherwise not have been possible even a few short years ago. This is seen on a daily basis in pediatric hepatology, mostly in liver transplant recipients. Whereas during the very early years, transplantation was viewed as experimental and even sometimes as a last-ditch attempt, nowadays it has wonderfully evolved to be a routine component of top-level care around the world. Along with this high surgical bar has come evidence of quite good long-term outcomes. In pediatrics, where the vast majority of liver diseases do not recur, we now predict a greater than 80% likelihood of a normal life 20 years (and beyond) after transplantation for the most common disease—biliary atresia. Because most pediatric transplants for biliary atresia are performed in the very young (less than 2 years of age), typically utilizing segments of livers from donors who may range in age from the teens to 50s, it now means that we have a growing cohort of transplant recipients whose donor livers work well, yet are substantially older than the rest of the recipient. Whether the donor liver's clock is reset to the recipient's, or continues on along its own predetermined path is unknown, and forms the focus of this commentary.
A segment from a 52-year-old donor liver placed in a 2-year-old girl will be a 90-year-old liver when she reaches 40 years of age. This may be an even bigger issue 30 years later, when the liver will be 120 years old when she reaches 70. This is not far-fetched, given the expectations of low-dose immunosuppression, and close continued care of these patients. As one thinks more broadly, this opens up a whole host of issues, mainly about all that time in between college and when she reaches her 70s. With work, childbearing, typical life stressors, and the usual age-related issues of cancer, atherosclerotic disease, and cognitive changes, one now has to engage an additional player: the discrepantly aging, possibly senescing liver. Perhaps this could be best thought of as caring for that well-adjusted, but aging, single parent in your own home. That aging parent may be working well now, but who knows what will happen in the next few years. And how best to care for that aging relative. I think the same for these older livers in young recipients.
On the other hand, think of the opportunities provided by this cohort to discover what happens to the liver in the far reaches of time—as it ages to 100 and beyond. Many questions come to mind: Does the transplanted liver's timeline revert to the recipient's clock? Or, hopefully, not vice versa? How does the liver's self-protective and regenerative pathways change over time? Does this older liver respond appropriately to signals from a younger body? What are the drivers of senescence? How does this liver integrate diet and metabolism, especially if the recipient gains a lot of weight?
One can think of a few analogies in life when planning for the role played by the older liver. These could be along the lines of “age-gap” marriages (previously called “May-December” marriages), deciding whether or not to refurbish an older home or beloved car, or even whatever it is that keeps Dick Clark looking so young. It expands our spectrum of care for the transplant recipient beyond dosages and screening, and back into a need to know biology. In some ways, it may involve a parallel plan of caring for the older liver with one series of concerns, while simultaneously thinking of the rest of the recipient with younger, and distinct, issues. Yet one more consideration for the multitasking hepatologist.
So, how to advise these long-term transplant recipients with older livers. Can they drink? Take certain medications? Take supplements? Change their diet? Have children? Worry about cancer? Worry about their weight? Or the big bear in the room: is there a new anxiety about the lifespan of their liver? These are all currently addressed to some degree with standard excellent care, but not with a focus on this internal organic time-shift discrepancy.
As the general population ages, and more cases of end-stage liver disease and hepatocellular carcinoma are recognized, donor shortages will likely worsen. And consequently in the near future, we will undoubtedly be using a larger percentage of older donors for pediatric recipients. As we expand our needs to find suitable donors, this may ultimately lead to using truly elderly livers in some children. Where this will bring those recipients' level of health for the coming decades is absolutely unknown.
These concerns may not come to fruition if it quickly becomes apparent that there is no self-driven senescent “clock” for livers. Perhaps as is true in many instances, the liver is smarter than the hepatologist and knows how best to respond. Let's hope so. Support for such a concept comes from serial hepatocyte cell transplantation experiments and parabiotic experiments in regeneration. But these data are from specific animal models studied for at most a few years. The long-term human study is now underway.
In sum, we are now the victims of our own success in pediatric liver transplantation and should be planning decades ahead for older patients and even older livers. It is an exciting time to prepare for the future—one where we pass the baton squarely and firmly into the palms of our adult hepatology colleagues. Run fast.