State of the Union: Liver Care in 2021
Edited May 2021 to maintain the latest information in treatment and research.
An interview with Tomoaki Kato, MD, Chief of the Division of Abdominal Organ Transplantation and Surgical Director of Liver and Gastrointestinal Transplantation.
What’s new in the treatment of liver disease?
Well, the huge change is viral hepatitis treatment. Hepatitis C used to be a poor target for transplant, but now it's a totally different story; things have really transformed since new medications for hepatitis C have been discovered. It is no longer a threat, we have a cure.
I started doing liver transplants in 1995, and from then until just recently, it was the same terrible story—a patient with hepatitis C would have a liver transplant but end up with recurrence. And it goes so quickly, then the patient ends up dying of it. We would try to do a second transplant, but the results were universally poor with hepatitis C. Recurrence happened in pretty much everybody, and in some, it happened violently.
Wow. How has the medication changed things? Is this something you would take before and potentially after transplant?
It’s called a Direct Antiviral Agent (DAA), a very simple name. All we do is give it for six to 12 months and that’s it—it cures the hepatitis. And if they recur, now we use the medicine. It's now almost like a minor infection.
But the medicine is still quite expensive, so we have to do a lot of preparation for that. So far, everybody who has a hepatitis-C-positive liver ends up being treated, and we haven’t really heard of any case of recurring hepatitis C being untreatable. It's changed a lot of our patients’ lives. Hepatitis C may actually go away—at some point you may no longer need liver transplant for hepatitis C because of this medication.
Does that mean you are actually seeing fewer patients in need of liver transplant overall?
Well, no. We all thought “now that hepatitis C can be cured there's no longer such a need for transplant,” but that was not the case.
Very interestingly, right around the same time that hepatitis C got a cure, the population shifted much more towards obesity-related liver disease. It's called NAFLD, nonalcoholic fatty liver disease, a disease that causes excess fat to be stored in the liver. So, fatty liver disease has started to become the main indication for liver transplant, along with alcoholic liver disease.
The problem has been more of an issue in the past 20 years than the previous 20 years as the entire country has become more obese, and those people are getting older. Obesity in young individuals doesn’t necessarily damage their livers early on, but after some time they can have cirrhosis of the liver and can also develop cancer from that. It’s really the biggest change we’ve seen in the last few years aside from the cure of hepatitis C.
Has the rise in nonalcoholic fatty liver disease also created an increase in liver cancer?
You know, it’s possible, but we have not drawn a direct line. But there is an alarming upward trend of liver cancer in the United States. A lot of cancer-related deaths are going down, like breast cancer, lung cancer…all the major cancers in the U.S. show a decreasing trend for cancer-related mortality. The only one that keeps going up is liver cancer. Liver cancer-related mortality has not gone down at all. With that, incidence of liver cancer is going up, liver cancer that is not curable is going up.
What are some other causes of this rise in liver cancer?
That’s a good question. Some part is definitely the growing immigrant population from Asia; Chinese immigrants have a higher incidence of liver cancer, so that's a big factor. But I don't think that's the only thing that explains it. There must be some overall incidence increase in other populations because there hasn’t been that much of a shift within the Asian population over the last 10 years. You know, the growing Asian population alone doesn’t explain the rise in liver cancer-related mortality.
Hepatitis C was the main reason for liver cancer for a long time. Now that hepatitis C is going down so rapidly, how do you really explain the increased incidents? I’m curious to know, really. Maybe it is still a leftover problem because even if hepatitis C is cured those who suffered from it for a long time can still develop cancer.
Do you think this current upward trend of liver cancer will continue to rise?
Maybe over the next few years to 10 years the cancer incidence could start to go down, but it's not the case right now. We used to say liver cancer only happened in cirrhosis, hepatitis C, hepatitis B, but lately, we've been seeing non-cirrhotic, non-hepatitis liver cancers as well.
So, there may be some specific increasing trend there. The liver cancer increase is clear. If you look at the National Cancer Database, liver cancer is really the highest and it’s going up; in women is increasing by 3 percent per year. And liver cancers are really bad, they’re fatal, you know?
Could environmental factors have something to do with it? Or a combination of other new factors?
You know, I don’t want to speculate. You have to look for something that has changed in this population for a long time, an extended period. I don't really see anything, you know, majorly different.
Let’s talk about other treatments for fatty liver disease besides transplant. Is there anything new we should know about?
You know, treating liver disease, developing ways to deal with it, has been a struggle. There are some medications for fatty liver disease in clinical trials that have been ongoing, but it takes a long time to really prove the effect. Treating nonalcoholic fatty liver disease and the problems with it, there isn’t a ‘one treatment’ fix-all. It’s related to habit and psychology and chemistry. Fatty liver disease is based on obesity and obesity is not just treated with medicine.
So, this requires a wider scope of treatment strategy compared to hepatitis C, with just one-anti-viral-kills-everything type of idea.
How do you think we change our approach? Have you seen a shift in strategy yet?
Not yet as a society, but there are a lot of preventative medicine ideas starting to gain popularity in areas like cardiovascular disease prevention, hypertension prevention, and diabetes prevention. Exploring strategies to modify behavior or modify diet to change the outcome— fatty liver disease may fall into that category. The way to prevent fatty liver from happening should start right from the get-go: when you're a child.
You know, it doesn't become a real problem until after your 50s or 60s. But all those fatty livers may have been there since childhood, right? So, starting with teenage obesity is how to really prevent that—really fix the problem before it becomes liver disease with preventative medicine and preventative health, diet, and nutrition.
What about treatments for alcoholic liver disease? How does it differ?
Treating liver disease in an acute alcohol-related liver issue is changing. It used to be that those patients were rejected for liver transplant upfront, we didn’t really treat them. But recently we started opening the door.
There's a sort of landmark publication of a French study that showed that with acute alcohol liver problems, if you select the patient really well they could do really well—those ready to stop drinking alcohol, stop destroying their liver. But family support is really important, and the patient has to be willing to cope with the medical system too and rehab prevention. In that French study, if you do select those patients for liver transplant carefully, and include a relapse prevention program, they tended to do well.
So what does that look like exactly? Can you give an example?
Sure. Say a 40-year-old man who has a history of binge drinking suddenly became unconscious, and then came to the hospital with jaundice, fluid in the abdomen, was acutely ill, and never really stopped drinking alcohol—we used to not do transplant. They were denied and could die. But we started to change this for selected individuals, and we have started to do transplants.
It’s still a controversial area because there are a lot of people who need a liver. But those young individuals, if you select them really well, they do really well, and they go back to society as a healthy individual and live a productive life. You know, we really need better alcoholism prevention too, education and support.
Alcoholism is a real disease, and we believe everybody deserves a chance. But the larger crisis is that there are not enough livers for everybody. We need more organ donors, especially in New York. Everyone should be an organ donor.
Talking about the liver shortage is a good segue into living liver donation. Tell us about the Living Liver Donation Program.
Columbia is one of the biggest centers for living donor liver transplant in the country, both adults and children. It was started here, and this year marks the 30 year anniversary of the first-ever living donor transplant done in the United States. The patient is around 30 years old now [she was an infant at the time] and doing really well. So that really means something—the first one ever done in the country is still doing so well.
That’s amazing. How does living liver transplant work exactly?
Let’s start with kids because it’s a little bit different from adults. Living liver donation is when an adult gives a small piece of liver to transplant into a child. And it's not really a big deal for the donor. We do it laparoscopically [through small incisions] now, and their liver grows back to normal size in a couple of months. They don’t need medication afterward either.
Living liver donation is something that we want to really establish as a standard of care in children. You know, it is part of the standard of care, but not everybody chooses to go for a living donor. They try to wait for a deceased organ. The thing is there aren’t very many deceased organs available. A child has to die and become a donor, and that doesn’t happen often. We don't want to see that happen, ever. So, in those cases, we often end up taking a deceased adult liver and splitting it, which is okay, it works. But living donor in that sense works much better.
In adults, deceased liver availability is not as bad, so living liver transplant isn’t as common. It’s a bit harder to do living donation in adults because of size. Children only need a small piece of the liver, but adults need a much bigger piece. Sometimes donors would have to give over 50 percent of their liver, and there are concerns with that. Even then it still might not be enough. That’s why you have to select the case really well. As long as there is good case selection and it’s a good match, the outcome has been excellent.
How do you go about selecting? What makes a good match?
We make sure the size is enough for both the recipient and donor because we don't want the donor to lose too much liver. The liver regenerates after all, but at the beginning, if there is too much reduction of the liver, that can be dangerous. And the recipient size, in adults, matters too. If it's too small a piece, it won’t work. We use technology to helps us determine this.
So, in the 3 months after transplant that we’re waiting for full regeneration [in the donor], we monitor the growth closely. We’re getting better and better at doing this too. Our technology keeps getting smarter, and living donor transplant at Columbia is already such a success. Our mission is to do this as safely and effectively as possible.
Could living liver transplantation, the technology as you say, advance or refine even further?
Yes, certainly. We have a pre-clinical study that is getting close to a human clinical trial that is very exciting—liver transplant without the need for immunosuppression. It’s not quite there yet, but it’s getting close. We’ve developed the protocol and tested it in animals so far. It’s going well.
Let’s jump into another exciting realm of liver surgery—What is ex vivo surgery?
Ex Vivo means ‘out of the body’. So, in any ex vivo surgery, the organ is taken out of the body and then put in a cold preservation solution. And then, after the tumor is removed from the organ, we put the organ back in. Sometimes we do as many as 6 abdominal organs in one surgery.
The reason why it's necessary is that the tumor is on the blood vessel. So, if you just take the tumor out, the blood vessel will be cut and blood supply would be shut off. And the organ needs the blood supply. But, if you remove the tumor in a preservation solution, an organ can still survive while we are taking the tumor out.
And so far, we have done close to 50 cases since beginning the Ex Vivo program [in 2008] and we’ve found that the surgery itself is really working. The efficacy of the surgery is pretty much comparable to any other surgery. But, ex vivo is only done for the cases other surgery cannot really treat. Meaning that this surgery is an expansion of care, another sort of extreme tool, an addition to the toolbox for the surgeon, which I really think is important for the community and society to know.
Has the ex vivo surgery changed at all since you started? Has patient selection changed?
Well, I’ll tell you what we know—what really matters is tumor biology, and ex vivo works especially well in patients with low-grade tumors. People that couldn’t get another surgery because the area or location of the tumors were bad and they couldn't resect.
If the tumor biology is bad, the outcome is still bad. But, if the biology is good, outcome is good. So, we have refined and keep fine-tuning our technology, and it seems that technology works. We just have to find the right target tumors to prove that idea.
The second factor is the location of the tumor. In certain locations, even with ex vivo, it can be so challenging. Other locations make ex vivo easier, and it's an extensive surgery. So, you have to have a patient in good physical shape too.
What does that mean, exactly, when you say that you're refining the technology?
So, let's say, if the technology, the ex vivo resection, was the reason that a patient doesn't survive, then you don't get a good outcome, even for the low-grade malignancy disease. But, even if the technology works and you keep operating on tumors with really bad biology, and they all recurred and the patient died, it’s not good enough to convince people, right? So, we did 45+ cases, and we divided it into several different groups. And, the low-grade to benign cases did perfectly. So, that at least proves the concept that the technology itself works.
And then, even in malignant cases, very bad malignant cases, we have some long-term survivors. What that tells us, is that if ex vivo works for certain cases, it still works. You know, in a regular surgery, it’s the same thing. If you've got pancreas cancer surgery or bowel cancer surgery, long-term survival is really poor. But, a small portion always survives long-term and cure.
The same thing happened in ex vivo surgery. We can’t yet pin down long-term survival—you need to do like 1,000 cases for that. But the concept of the surgery works, and the technology works. That is most important because that's the basis that we can push this surgery to everybody. And then it makes a difference in many, many people’s lives. People who are otherwise inoperable.
Wow. That leads me to ask, what are you optimistic about in liver care? What excites you about the future of care, surgery, of transplant?
Well, interesting question. I think we are all in a fine-tuning stage of liver transplant technology. It's not that we anticipate any extreme changes in transplant itself, it’s [about] who gets a transplant. One thing that I do think we’ll see in the future is that the more organs become available, or fewer patients are in need of transplant (especially with the medicine for hep C), we can probably expand the use of liver transplant into oncology.
You know, we’re working on this now, but the future will likely see animal to human liver transplant, using liver of the pig. I think it’s still pretty far away, 10 years or so. But if you can make pig liver available to humans, you really solve the liver shortage.
Would that then open up the field of transplant oncology even more?
Oh yes, I think so, and we need more livers to do it. We need to solve the liver shortage.
Transplant oncology may be the next evolving field, meaning we may be able to establish the use of transplant for oncological surgery. Ex vivo, maybe, isn't a part of it, but using a transplant organ for cancer surgery. Use of transplant for liver cancer is already a very established field, but for the other cancers, like colorectal cancer metastasis or some other type of cancer, the use of liver transplant or use of organ transplant has not been well-established.
What would a liver transplant do for someone with, say, colorectal cancer?
Right. So once the primary colorectal cancer is removed and liver metastasis happens, some patients can live for a long, long time with just controlling metastasis. But at some point, you can no longer go on, because of the liver problem. So, we’re asking “what if we just changed the liver? In those cases, how did they do?” That is the big question.
There’s a European clinical trial happening in transplant oncology, and it seems to have very reasonable outcomes. Patients can still have a recurrence, but some patients do extremely well and transplant can cure the disease.
Jumping back to the present, there are pretty big racial disparities in access to liver transplant, even when clinical indications call for it. How are you working to address this systemic inequity?
This is a matter of health justice for liver transplant because there are known disparities in access to liver transplantation. And studies show that Black patients and Asian patients, other minorities, are less likely undergo liver transplant than white patients. And with HCC [Hepatocellular Carcinoma] for example, these are curative therapies. So we started the Black Liver Initiative to determine exactly what causes those disparities and how we will fix it. We also have the Asian Liver Initiative that started about 3 years ago as well.
Does one of the main factors in the racial disparity come down to a barrier to access that’s baked into systemic inequity, systemic racism?
Yes, it could certainly be. Even cultural barriers too. For instance, Asian people are much less likely to undergo liver transplant than a white person in the same exact condition for HCC, liver cancer. And think about the amount of information required, the many visits, surgical consults, medical information needed before having a transplant. The process isn’t built to function the same for everybody and cultural sensitivity in evaluation is lacking.
A very basic example is, what if English isn’t your first language? Translators are typically always available, but it's not like the language-capable people are doing the evaluations, they are transmitting it and maybe even causing misunderstandings.
If you go to Korea, there's a lot of liver transplants done in Korea. In China, as well. So Asian-Americans living in the United States shouldn't be any different. Right? The same should be for African-Americans.
I know that it's the beginning of this initiative, but have there been aspects of disparity, of systemic racism, that surprised you as a physician?
No, not really. I don't think it's surprised me because that type of disparity exists in many other therapies, in many other treatment options. And the focus is finally on it. In the same exact condition, patients are offered different treatments. It’s our side of things that needs to change.
What we want most, what’s most important, is that liver transplants serve everybody equally. That’s our responsibility.
Would you say that’s one of your biggest goals for the next year, even 5 to 10 years?
Oh yes, it’s our priority. Along with that, the increased indication for liver transplant to oncology. Aside from surgery, I think education is a big one too, even as a culture, reaching people and dealing with the growth of fatty liver in the U.S. We need education and resources to help change the way we eat and how we live.
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