Graft-versus-Host Disease: Gastrointestinal Tract and Liver

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GVHD: Gastrointestinal Tract and Liver

Sunday, April 30, 2023

Presenter: Theo Heller MB, Bch, FAASLD, National Institute of Diabetes and Digestive and Kidney Diseases.

The presentation is 38 minutes followed by 21 minutes of Q &A.

Many thanks to Incyte Corporation and Sanofi, whose support helped make this workshop possible.

Summary:

Graft-versus-host disease (GVHD) is a condition that can occur after a stem cell using donor cells (an allogenic transplant). This presentation describes how GVHD can affect the mouth, esophagus, stomach, small intestine, large intestine and liver.

Highlights:

• Graft-versus-host disease (GVHD) can be a short-term, recurring or life-long problem after transplant, and is often not fully discussed with patients prior to transplant.
• GVHD of the GI tract and liver are common. Depending on the study, GI GVHD affects 13% to 74% of patients. Liver GVHD affects 6% to 44% of patients.
• It’s important for patients to get involved in their healthcare, be proactive, and educate and empower themselves with information from reliable sources about GVHD, particularly if their healthcare provider has little experience managing GVHD.

Key Points:

(12:04): The first 100 days after transplant are typically when acute GVHD may attack the liver, gut and skin, but it can also occur after the first 100 days.

(11:09): The microbiome has become an incredibly hot topic. The best thing you can do for your microbiome is to eat your greens.

(12:59): Symptoms of acute GVHD in the gut include nausea, vomiting, diarrhea, bleeding mucous, feeling full or feeling hungry.

(13:29): Symptoms of GVHD in the liver include nausea, vomiting, not feeling hungry, jaundice and light-colored stool.

(13:47): It’s important to rule out other possible causes of the symptoms of GI and liver GVHD before beginning treatment.

(17:14): Endoscopy is sometimes needed to determine whether symptoms are actually GVHD or another problem.

(22:56): Steroids, such as methylprednisolone, prednisone, and budesonide, are the initial treatment for GI and liver GVHD, and are effective for most people.

(25:24): Chronic GVHD typically occurs after 100 days, is more fibrotic and can affect many more organs than acute GVHD.

(29:14): Liver biopsies are sometimes needed to properly diagnose liver problems.  

(34:07): Currently, clinical trials are taking place to explore the effectiveness of fecal transplants and plant-based diets in promoting gut bacteria diversity.

Transcript of Presentation:

(In this presentation, the term bone marrow transplant includes bone marrow, stem cell and cord blood transplants.)

(00:00): [Lynne Spina]:  Welcome to the workshop, Graft-versus-Host Disease: Gastrointestinal Tract and Liver. My name is Lynn Spina, and I will be your moderator for this workshop.

(00:12): I'd like to thank Incyte Corporation and Sanofi, whose support helped make this workshop possible.

(00:19): Introduction of Speaker. It is my pleasure to introduce today's speaker, Dr. Theo Heller. Dr. Heller is section chief of the Translational Hepatology Section of the Liver Diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases. His work focuses on the connection between the innate immune system and liver-related damage and the repair in patients with graft-versus-host disease or GVHD, as well as those with a chronic granulomatous disease, sickle cell disease, Turner syndrome, hepatitis, and congenital hepatic fibrosis. Please join me in welcoming Dr. Heller.

(01:11): [Dr. Theo Heller]: Thank you for that lovely invitation. I'm very grateful to be here today, and I'm also excited. It's been very inspiring for me to learn about BMT InfoNet and the incredible work that BMT InfoNet does.

(01:26): First, my disclosure. I'm a gastroenterologist. I'm not a bone marrow transplanter. My primary interest is the intestine and the liver, and that's my obsession. My wife wishes I would think about other things, but that's where I live.

(01:43): I also assume most of the audience is post-transplant, not pre or during.

(01:54): As for financial disclosure, I have none. I'm your tax dollars, and I must thank all of you for paying your taxes. I'm a federal employee.

(02:05): Patients who have been through transplant and develop graft-versus-host disease can feel overwhelmed, as can their doctors. I'd like to start with the problem. I want to start with the fact that most people going through a process like a bone marrow transplant feel alone and overwhelmed. And this is true after the transplant as well, especially afterward. And often needs to be understood. And I can't tell you how often my patients have told me that they've seen doctors who've told them, "You're the first patient I've seen with…and you can fill in whatever you like." Or the doctors told them, "This was not meant to happen."

(02:40): And the time, the time it takes to go to all the doctors, the time it takes to deal with the illness, the time it takes to deal with the stress. The cost, the financial cost beyond insurance, and the emotional cost, not just on the patient but also on the family.

(02:57): Uncertainty about graft-versus-host disease, and how to treat it, can add to the trauma. An additional problem is that of uncertainty. And practicing in Washington DC, I have the fortune of seeing patients who work for all those parts of the government that we're not allowed to discuss. And one of the patients told me something really interesting. He told me that when we're taught about torture, not how to torture others, but if we're ever captured, and people try to torture us, they will try and make us question our core values. They will try to make us uncertain about the most important things. And I can't think of anything more fundamental than your life, your family, or a loved one's life and creating uncertainty about it. And when you ask the doctor questions, they give you percentages. I don't know what percentages mean for an individual. So, there's great uncertainty at a core level, making dealing with things like this very difficult.

0(03:59): I'll tell you a little secret from the physician's perspective. And I will deny I said this, and you're not allowed to tell anyone that I said this, but in some ways, the gut and the liver are pretty dumb. The gut only knows a few ways to respond. If I say something inappropriate to a good friend, the friend can respond with all sorts of witticisms. But the gut responds with diarrhea or bleeding or mucus, or pain. That's it. And it doesn't matter what infection or drug or GVHD caused it. And the liver is the same. The liver becomes jaundiced.

(04:40): We add to that Hickam's dictum. Hickam was a famous physician in Vienna who said patients could have as many diseases as they wanted. So, from a physician's perspective, the way the patients present is very similar, no matter what the cause, and they don't just have to have one disease. So, it's even worse than we thought. Is that what you're telling us? That's what all of you are thinking right now. Hold on, hold on. No, there are solutions.

(05:09): It’s important to get involved, be proactive, educate yourself and empower yourself with information from reliable sources about your GVHD care. Let's start with the non-clinical stuff, which is important. Get involved and be proactive; it's possible. And I can look you in the eye, not person-to-person, and you can't see me, but I'll stare at the screen, look you in the eye, and say, "It's not hopeless." You have to educate yourself. You have to empower yourself. The single most important thing you can do is to educate yourself. You should know more than the average physician does about your condition.

(05:40): And there's this incredible organization; I wonder if you're aware of it; it's called BMT InfoNet. I've just discovered it this year. It is unbelievable. The amount of work, so few people, produce is incredible. The number of resources, the amount of knowledge, the amount of institutional memory, and the national knowledge are just overwhelming. And if you haven't connected with them yet, or if you haven't heard of them yet, I strongly encourage you to.

(06:08): Next level would be below that, which would be Academic Centers. I'm part of the intramural program at the National Institutes of Health. We have a program, but not everyone can come to us. We have websites and ways of searching medical data, clinical trials. And embrace and beware of Dr. Google. When I say Dr. Google, I talk about Facebook, Instagram, and Snapchat. I'm talking about the whole package, everything on your phone or computer. Embrace because, through that, you can connect to BMT InfoNet, academic centers, NIH, and Clinical Trials. Real data, real resources. But you can also connect to the person who's selling snake oil. It'll only be half a million for you, but it's worth it because they will promise it works.

(06:55): Empower yourself from appropriate sources but be aware of people who make it sound too good to be true or are trying to take advantage of you because you're vulnerable. When hepatitis C had no treatments, about 60% of my patients would take complementary medicine. Now that we can cure 99%, no one takes complementary medicine. So, as hard as it is, I would stick to what's known I would stick to what's known, as hard as it is.

(07:25): Today’s talk focuses on how graft-versus-host disease (GVHD) affects the mouth, esophagus, stomach, small intestine, large intestine and liver. What's the geography? Today's geography for our talk starts at the mouth, going down the esophagus. You can see the esophagus in the chest; that's that pipe. And then below it is the stomach, the small intestine, and the large intestine all jumbled up. It looks like worms. And next to it, in the dark red, is the liver. You can see the liver over here, the stomach here, the large intestine forms an N, and packed in between it is the small intestine. And that's the territory we're going to cover today.

(07:59): The elephant in the room is GVHD. GVHD is when the new immune self does not recognize the old self. Sometimes we want that because grafts can destroy the tumor. But on the other hand, when you get graft-versus-host disease, that's suboptimal; that's not something we want. And GVHD, for me, is one of the biggest things, pre-transplant, that should be discussed completely and isn't because it needs to be better understood. Then, after the transplant, it becomes a major issue.

(08:41): GI and liver GVHD are common after transplant. How often does it occur? GI GVHD depends on the study. Thirteen to 50 to 74%. Liver GVHD six to 30 to 44%. There are lots of reasons I showed you the figures like that. The first is to show you it depends; as Bill Clinton said, "It depends on what the definition of 'is' is." It depends on what you mean by GVHD. There are different ways to define it. It depends on the conditioning regimen; it depends on the prophylaxis; it depends on how it was treated afterward. But the point of showing these figures is to make the point that it's not rare.

(09:16): GI GVHD occurs before and during the first one hundred days, and after. And that’s how the talk is going to break down.

(09:28): Before transplant, it’s important for the doctor to know about pre-existing medical conditions, like metabolic syndrome, iron overload and pre-existing viruses which may influence the GVHD prevention and treatment plan. Let's start with the before. There are preexisting conditions, and they're often overlooked because of the urgency. In my center, we've become more aggressive about looking at preexisting conditions. Today, metabolic syndrome is very common. Metabolic syndrome means obesity, diabetes, hypertension, and fatty liver disease. Iron overload is incredibly common. And while iron overload doesn't cause GVHD, it can cause liver damage. And iron overload is common because people have been transfused because of chemotherapy, conditioning, and preexisting viruses like hepatitis B.

(10:11): The gastrointestinal diseases that people can have been less significant than before. And it's essential to consider all of this, risk stratification and prophylaxis. And the most typical way to prophylaxis is by using calcineurin inhibitors, cyclosporin, or tacrolimus.

(10:26): Coming to transplant as healthy as possible is recommended. What can you do? Well, come in optimized. The fitter you are, the healthier you are, the better. A fantastic study got published recently, and when I first saw it, I laughed and said, how could they publish this? But then I reread it, and I thought it was essential. They did a study showing that healthier patients coming into surgery did better after surgery. And the same is true for bone marrow transplants. And if you know that you have a liver condition or if you know have a gastrointestinal condition, make sure you discuss that with your physicians.

(11:00): However, I shouldn't say that to you, because I need business. Instead, I should tell you to smoke and drink because you'll likely end up with me.

(11:09): The microbiome has become an incredibly hot topic. Everyone is talking about it. I'm going to come back to this at the end. But the best thing you can do for your microbiome is to eat your greens. It is to eat a plant-based diet. One of the most important aspects of the microbiome is diversity. And the greater variety of bacteria, viruses, and fungi you have in your colon, the better. And the best way to induce this is by eating your greens.

(11:39): Sometimes, we have no choice. Sometimes the transplant's urgent, and you can't say, I don't want my donor to be a woman with three children. And I don't want it to be a bone marrow biopsy source. I'd like it to be a cord blood source. So, we don't have that choice ahead of time. And after the fact, we for sure don't have the option. So that's why only two slides about this because this is often beyond our control.

(12:04): The first 100 days after transplant is when acute GVHD may attack the liver, gut and skin, but it can also occur after the first 100 days. What about during the first hundred days or so? This is a classic acute GVHD. It's mostly inflammatory and the company it keeps is the liver, gut, and skin. And that's interesting because this probably has to do with the microbiome.

(12:24): The new kid on the block, I'm not showing you anymore, but it overlaps. Because if you think about it, the T-cells responsible for inflammation don't suddenly say at a hundred days, "End of shift, guys, I'm checking out, fibrotic guys, you come in." No. Biology doesn't work that way. It doesn't know there's a clock of a hundred days. But in general, acute is seen in the first hundred days and chronic beyond that, but you can see chronic as soon as 50 days (about one and a half months), and you can see acute even a year out. So, the concept of overlap is important because it forces us to keep our minds open.

(12:59): Symptoms of acute GVHD in the gut include nausea, vomiting, diarrhea, bleeding mucous, feeling full or feeling hungry. What will I see or feel? This is a common question. And in the gut, remember I told you, which I told you never to tell anyone else and don't repeat, and I didn't say it—the gut, really, nausea, vomiting, diarrhea, bleeding, mucus. And patients tell you they don't feel hungry, or they feel full. Feeling full, we have a term for that. We call it early satiety. And not being hungry, we call it anorexia, not to be confused with the disease. Anorexia medically just means not wanting to eat.

(13:29): Symptoms of GVHD in the liver include nausea, vomiting, not feeling hungry, jaundice and light-colored stool. What about the liver? Nausea, vomiting, not hungry at all, feeling full. And then, people can develop jaundice, seen by yellow eyes, dark urine, and light stool. However, dark urine and light stool aren't necessary. And in real extremes, you can see swollen stomachs where the stomach accumulates fluid.

(13:47): It’s important to first rule out other possible causes of the symptoms for GI and liver GVHD before beginning treatment. One common mistake I often notice is that people assume every symptom is related to GVHD when it may not be. It's essential to consider other possibilities and ask what else it could be. In the gut, viruses, and bacteria are also potential causes to consider.

(14:09): The website LiverTox provides information on potential liver damage from each FDA-approved drug. Liver damage caused by drugs is a frequent issue within the first 100 days of acute treatment. For more information on this topic, visit the LiverTox website maintained by J. Hoofnagle. This website details every FDA-approved drug and its potential to cause liver damage. Awareness of liver damage is crucial, so remember to check it out If I had liver GVHD and my doctor prescribed an antibiotic, I would want to be sure that they checked it in LiverTox to avoid further liver damage.

(14:51) It's important to note that various viruses and diseases, such as sinusoidal obstructive syndrome, cholangitis lenta, and thrombotic microangiopathies, can affect the liver. While you don't need to know the exact meaning of these terms, you should ask your doctor to explain, in simple terms, and don't hesitate to ask for clarification if you're unsure about anything.

(15:23): What are the steps to determine if you have GI GVHD? You and your doctors should investigate and analyze the situation. The first step is to review the patient's medical history, especially regarding bowel movements. It's essential to determine whether they are small and frequent or large. A thorough physical examination, including abdominal palpation, is critical. Additionally, blood and stool tests are crucial for identifying infections. While not every patient requires endoscopy, it can be incredibly helpful and should be considered. Later, I'll provide some pictures to illustrate these points.

(15:58): What are the steps to determine if you have liver GVHD? What about the liver? Blood tests are the start and end of liver disease. Cholestatic means that it's more of an alkaline phosphatase or jaundice picture. And hepatic is more of hepatitis, like viral ALT/AST or SGPT/SGOT. So, you may use those terms. And both can be GVHD. And for both, we have to exclude other causes.

Cholestatic is the classic GVHD. Hepatitis can occur on withdrawal of immunosuppression or with donor lymphocyte infusion. But either way, for both, you have to ask “what else it could be?”

(16:37): An ultrasound will help determine if blood clots in the veins are going into or coming out of the liver. In imaging, we usually start with an ultrasound because one of the problems that can occur is blood clots in the veins going into the liver or coming from the liver. And rarely, we suggest a biopsy. At the end, I will give you an example of why biopsy can be so important. We only do a biopsy if we have to. So, if your doctor recommends a biopsy, they should have thought about everything else and done everything else they can to avoid it. But, if necessary, it can and should be done safely.

(17:14): Endoscopy can help determine whether the symptoms are actually GVHD and the proper treatment. Let's talk about endoscopy. So, these pictures are taken from a book chapter I wrote, and the pictures are from endoscopies I performed on patients I've seen. The first is a mild to moderate GVHD, a part of the colon called sigmoid. This is just above the rectum. The white dots and the redness around them are abnormal. It should look pink, like the inside of your cheek.

(17:43): And if you go, then, to a more severe case, this is the stomach, and this looks like a road rash. The lining is falling off, and there are little bits of bleeding. If you look in the top left hand, there's some blood. If you look at the bottom, there are some clots. And this, on the left is mild to moderate, and on the right is severe. The patient on the left had about 400 ml (about 13.53 oz) of stool a day, and the patient on the right had about 2000 ml, but they both had diarrhea.

(18:13): Two patients with unique cases: one had small examples of Epstein-Barr virus-induced post-transplant lymphoproliferative disorder, and the other had a tiny ulcer that turned out to be CMV. Both had a stool output of 1000 ml (about 33.81 oz) daily and looked similar to previous patients but required different treatments. Accurate diagnosis is crucial for proper treatment.

(19:07): Once the diagnosis of GVHD is made, there are several more steps required before starting treatment. Now what? So, you've done this thinking, investigating, and got a diagnosis; teamwork makes the dream work. And in most centers, during transplant, there's a team. There's the transplant team, infectious disease doctors, people like me, the gastroenterologist, nutrition, nursing, PT/OT. And this team works hard on diagnosing before treating, and treating early before problems become severe. And it's important to define severity because the number of organs involved, and the severity of each organ's involvement, determines the extent of treatment.

(19:50): So, before we talk about treatment, it's not as simple as starting treatment. You don't press the button when you get into your car and switch it on. We're not yet at the stage where you end up at your destination. You still have to drive; there are red lights along the way, stop signs, other bad drivers, and all sorts of things. So, there are lots of things to consider during treatment.

(20:14): It's essential for the physician to monitor the patient multiple times a day. How does the patient look and feel? I want to walk into the room and see your face. I want to know what you look like. What is the stool volume? What does blood work show? Have we prophylaxed for infections? Have we given you drugs that are going to prevent infections?

And are we screening for infections once you've started treatment for GVHD? Do you need a repeat endoscopy? Why are you not responding to treatment? Other causes. Symptomatic treatment. While we are waiting for treatment to work, there are other things we can do to make diarrhea get better? Or there are other things we can do to improve your appetite?

(21:01): Eating is essential for preventing and mitigating GVHD and promoting healing; nutrition and activity should be prioritized. Let's talk about nutrition and activity. Our mothers were right - eating is crucial for our well-being. While I understand that people want quick fixes and prescriptions, the truth is that the more complicated things are often right. Eating is essential for preventing and mitigating GVHD and promoting healing. Of course, there are times when rest is necessary, but if that's not the case, nutrition and activity should be prioritized. Small movements like bending your knees or flexing your toes can benefit your overall recovery and gut health.

(21:59): Different doctors may manage GVHD differently, and that is ok. Paul Martin is one of the most important thinkers regarding bone marrow transplant and the treatment of GVHD. And he's someone that I find inspirational. And I wanted to show you this quote for a reason, and I'll say the reason at the end. He says, "To date, no consensus has been reached for management of steroid-resistant, acute graft-versus-host disease. The treatment choice has been guided largely by trial and error according to physician experience, ease of use, need for monitoring, risk of toxicity, et cetera."

So, I wanted to show you this quote, not to tell you that we don’t know what we're doing. That's not the case. We know what we're doing and have a good idea. But the different doctors will practice differently. And if your doctor is different from your friend on Facebook's doctor and they do different things, it's okay. And if I say something different than what they're doing, it's okay. But, at the moment, there is yet to be a consensus on everything.

(22:56): Steroids such as methylprednisolone, prednisone, and budesonide are the initial treatment for GI and liver GVHD and are effective for most people. As I already said, treatments are effective for most people. Steroids are the initial mainstay, both oral and first pass.

And it's not non-absorbable. It is. That's an important point. First pass drugs, like budesonide, you take it, it's absorbed, and your liver destroys it. Destroys 90% - 95% of it the first time it comes through. That means there's minimal systemic effect. But if your liver is diseased, there is a systemic effect. Your liver can't destroy it in the way it should.

(23:37): The problem for me is that I often see physicians and patients talk about budesonide as being non-absorbable. It's not true. It is. And in the case of a sick liver, your body will see it.

But the standard of care is oral and first-pass drugs; examples are methylprednisolone, prednisone, and budesonide. And these are typically given for weeks and then tapered over a month. And that's done because we don't want the GVHD to return. Typically, we see a response within seven days. Worsening by five days is considered significant. And strictly speaking, those are the criteria for steroid resistant or refractory GVHD.

(24:16): Beyond steroids, we use ruxolitinib, that's FDA-approved now for acute GVHD. And then there is a list of others, which can be tried, all of which are okay. If there is no response to any of those, I'd encourage you to find a clinical trial.

(24:32): GVHD can be transient, you never see it again, or it can be a life-long problem. General thoughts. GVHD can be transient, and you may never see it again. For some, it's lifelong. And in that case, we begin to think of it as treatment for an autoimmune disease. It can recur. Lifestyle modifications, which your doctors keep talking to you about are so challenging, and challenging because things change over time. Meaning that today, tomatoes are good for you; tomorrow, they're bad for you.

So, I aim for a heart-healthy diet limited by tolerance and illness. I would not aim for burgers, fries, steaks, beer, or spicy food. And I would keep active as much as possible. And here again, I can't stress how important physical activity is. And when I say diverse diet, I'm not talking about an Ale, an IPA, or a Stout. As I mentioned in the beginning, I'm talking about diverse diets, including plants.

(25:24): Chronic GVHD typically occurs after 100 days, is more fibrotic and can affect many more organs. What about after? That's classic chronic GVHD. Or you can also, as I already told you, see late acute GVHD. And this is more fibrotic, and this can involve many more organs. But I'm going to stick to the gut and the liver. And again, there's the overlap. Remember, you can see an acute after or after a hundred days. As I said, it's pretty much the same for most of the guts. And you're not allowed to repeat it; these are dumb organs, right? Nausea, vomiting, diarrhea, bleeding, mucus, not feeling hungry and full. And for the liver, it's the same again, nausea, vomiting, not hungry, feeling full, yellow eyes, dark urine, light stool, swollen stomach.

(26:11): But there are new things. The pancreas can become affected; in that case, the diarrhea can be due to malabsorption. And this smell is horrendous, difficult to impossible to flush.  There's a brown rim in the toilet. And sometimes, patients even tell you they see a layer of oil floating.

(26:31): Patients can lose weight. We call it failure to thrive. They don't do as well as they should. They become frail. And this is incredibly important to deal with. And that's why I listed PT/OT, nutrition, and the whole team.

(26:45): Difficulty swallowing, strictures in the esophagus can occur with GVHD. We see that, and we can dilate them. And for most people, repeated dilations are needed, but they're incredibly effective. It can be done in 15 minutes or 20 minutes and makes a huge difference.

(27:04): What else could it be? The same goes for the gut, viruses, and bacteria. For the liver, the same as before, except now, the liver can throw the whole textbook at you. Anything that any patient can get can occur in any patient. So here for the liver, we must think even more broadly. And I'm going to come back to that.

(27:26): When symptoms occur after 100 days it’s necessary to investigate and analyze the situation again. We should conduct history, blood, and stool tests. Additionally, we must consider the possibility of infection and perform an endoscopy. Finally, we must do a blood test, imaging, and liver biopsy. A biopsy is especially crucial in this case and should be noticed, as emphasized in the textbook.

(27:54): I think it's really important to look at weight and muscle mass for the gut. And your doctors can do things like grip strength to assess muscle mass and frailty. Stool tests for pancreatic function and blood tests for nutrition. And these are things we often neglect but are incredibly important for the quality of life, overall functioning and well-being, and survival and outcome.

(28:20): Questions you should ask your provider in a nice way. Please don't take this list in and yell at them. Always be kinder than necessary. What you have to say is “What else could this be? Are there treatment alternatives? Why am I not responding? Am I on the safest, lowest dose of medicine needed? What are the complications of this medicine? And are we monitoring them?”

I want you to be empowered, and I want you to know what we are thinking, and I want you to know what the best physician should be thinking. And these are the questions you should take to your physician.

(28:53): BMT InfoNet has a list of GVHD providers that you can consult. And at the bottom, I put a list. I was so impressed. Remember I mentioned this organization, which you might not have heard of, called BMT InfoNet.org? They have a directory of GVHD providers, and I would strongly encourage you to go there and use that list to access care that way.

(29:14): Liver biopsies are sometimes needed to properly diagnose liver problems.  I'm going to give you an example, just quickly, of persistence paying off. At NIH, we saw 302 consecutive patients in our Chronic GVHD clinic. Dr. Pavletic is the director of the clinic. And 151 of those patients had hepatic GVHD, based on the NIH consensus criteria. If you've heard of the consensus criteria, I will show you why they are not great.  I'm not knocking them. I was a co-author on the criteria. So, I'm criticizing myself because I was partly responsible for the liver-related criteria. So please don't think I'm being negative. I was involved with this, and I helped derive, and I'm exposing its flaws. My own flaws.

Of the 151 patients with chronic GVHD, 27 we felt needed liver biopsies. And if you look at this table on the extreme left, you'll see two lines. One is clinical GVHD. These are patients who were thought, by us, by NIH criteria, to have clinical GVHD.

(30:21): And then there were patients, 16 of them. That's the total at the end on the extreme right. And again, on the left, no clinical GVHD, 11 of them. And if you looked at liver biopsy, of the 16, 8 had GVHD, but eight did not. So, we were wrong 50% of the time.

And if you look at those, we thought did not have GVHD on biopsy; 8 of them did. So again, we were wrong. And only 3 of them, of those we thought did not have GVHD, did not have GVHD on biopsy. And even more of the 16 - remember, 16 here at the bottom left had a biopsy, liver biopsy, and proven GVHD - of the 16, only 6 had hepatic GVHD alone. Ten had other things -  iron overload, nodular regenerative hyperplasia, and steatosis.

(31:13): If you think about it, all of these patients had their therapies changed because of the liver biopsy. So, a notice of the 302 patients, less than 10% had liver biopsies. So, we're not selling liver biopsies; we're saying you need it. Of the 151, we were so comfortable that only 27 underwent liver biopsy. So, it's not that you need it, but if you need it, it's important. And it's an example of persistence paying off because it changes treatment.

(31:42): A meticulous systemic approach will make the correct diagnosis. And although we try to avoid it, sometimes an invasive procedure is the right choice because the diagnosis is the right choice. The correct diagnosis is so important, and that makes a difference.

(31:58): Future research to help diagnose and treat GVHD. And then you can talk about treatment. So, imagine a future, and I'm listing things here that are in trials in various ways in humans where we don't need bone marrow transplants. Where we have biomarkers, where we don't need a liver biopsy or endoscopy, I would love that. As a federal employee, I would love to sit and drink coffee all day. Remember, I love coffee. So, to have a blood test that could tell us if it was liver GVHD or GI GVHD, or colonic would be a dream. And that is already being worked on. There are clinical trials underway at the moment where people are looking at that.

(32:41): Imagine a personalized treatment. And by personalized, right now, we could talk about the difficulty in knowing how much prednisone to give, how much tacrolimus to give, and what dose is ideal for each patient. And beyond that, the ability to say, oh, for you, with your microbiome, history, and CMV status, this is the drug that will work for you. The ability to personalize it at that level, induce tolerance, knock out those T-cells, and block them. These are studies that are underway.

(33:19): The microbiome is a hot topic, but we should be cautious. A diverse microbiome that produces butyrate helps regulate the immune system and promotes overall health. That is why everyone is so excited. But the problem is, how do we turn that around and take someone who doesn't have a diverse microbiome, who isn't producing butyrates, help them become diverse and help them produce butyrate? That is not so easy. And that's why I'm just putting the break on expectations.

(34:07): Clinical trials are taking place to explore the effectiveness of fecal transplants and plant-based diets in promoting gut bacteria diversity. It's important to note that there aren't necessarily "good" or "bad" bacteria - it's all about achieving a balanced microbiome. This balance is crucial for producing metabolites that keep your immune system healthy and protect your gut barrier. Scientists are also researching ways to deliver essential substances such as butyrate's or modulate the immune system for optimal gut health. These are just a few of the methods being studied in relation to the microbiome.

(35:04): I have to mention the hepatitis C analogy. People spent years and millions of dollars working on different forms of interferon, and then drugs came out that worked. And that changed the whole world for hepatitis C. And I'm so excited because we are doing things in mice that are just unbelievable—science fiction. And I hope this will be in human trials in a year or two. And in two or three years, the future slide will be very different. We'll be talking about things that are possible. And in five to 10 years, it'll be routine.

(35:47): It’s important to build a team of family and friends to help you deal with GVHD.  So, I've gone through a lot. Let's put it together. Building a team, family, and friends is really important. Friends, including your social circle, your church, Synagogue or Mosque. Whatever organization's community you're part of.

(36:04): Find doctors who listen to you, and learn with you, about how to best manage GVHD. Healthcare professionals. And like us or love us, you're stuck with us in the same way that your disease is more than marriage. You can't get divorced; you may as well get engaged with gusto. And we're part of the package. But unfortunately, you can't avoid us. So, if you can't, you want us to be open. You want your doctors to be open to listening to you. You want doctors who learn with you. And even the most expert people who see a lot of GVHD are still learning. We're still learning, as I've tried to show you through the talk. So, I want to learn with my patients.

(36:44): They have to be available and accessible. When you call, they should be able to respond. Not immediately, but within a reasonable timeframe. You must build trust with them, that they're there, and you have a relationship in times of crisis. And that's important because when you suddenly meet someone for the first time in a crisis, it's not the same as someone you've had a relationship with.

(37:06): Ideally, you'd want access to a center of excellence, but that's only possible for some. And that center of excellence is even better if they have experience with your condition. Again, only possible for some. So, what we try and do, which is feasible for most people, is a two-tiered system of care where you have access to the academic center of excellence with experience and a local doctor who's open, caring, available, trustworthy, and will learn with you. And this builds a team that will make the dream work. And I've emphasized throughout my talk that teamwork is incredibly important.

(37:53): Lastly, remember to live. My favorite quote, Maya Angelou, has the line, "Life loves the liver of it." I don't think she was talking to the liver in your abdomen but to the living person. This is the dawn at Chincoteague, where I go to remind myself to live. And in the same way, we're at a new dawn with many of these therapies we've been discussing.

(38:17): I want to thank BMT InfoNet, and the patients; I particularly want to thank Ms. Stewart and her people for putting up with me. And they managed to get more out of me than my mother did. They managed to get work out of me. And I want to thank Dr. Pavletic and Dr. McDonald, who've inspired me. So, with that, I'll take questions.

Question and Answer Session

(38:37): [Lynne Spina]:  Thank you, Dr. Heller, for your excellent presentation. We will now begin the question-and-answer session.

(38:44): Our first question is: Is there any way to prevent GVHD from returning?

(39:08): [Dr. Theo Heller]: That's a fantastic and a million-dollar question. We'd all love to know the answer to that. There are things you can do. Because we don't know definitively, we still have ideas, which doesn't mean there aren't things that help. So, the first and most important thing, as I've emphasized throughout, is being healthy. And that starts with attitude. And I want to be careful with my attitude. If you noticed, I didn't mention it during the talk because I don't think attitude determines whether we live or die. Attitude doesn't determine whether we have GVHD or not. That attitude helps us feel better about ourselves and our day.

(39:49): Second is eating and drinking healthily. The third is being physically active. Fourth is working with your team of physicians.

(39:55): Fifth, there are more detailed things, like, avoiding antibiotics helps your microbiome replenish. Avoiding antibiotics is difficult because you need to be treated if you have an infection and you're immunosuppressed. But there are ways of lessening the impact of antibiotics. Say, take probiotics. But there are ways of mitigating that risk. There are ways to treat it.

(40:27): Remember, I mentioned you'd taper the steroids slowly. We are now, particularly for the people who have long-term GVHD, we're switching steroids up for other medicines sooner. And some of those medicines might be more effective at maintaining GVHD. So, for the people where it does recur, it's essential to consider it. Not to talk about prevention of recurrence, but more to think about it as a disease, like high blood pressure, that you can control but not cure.

(41:03): [Lynne Spina]:  Thank you. Are there any supplements you recommend for immunity?

(41:14): [Dr. Theo Heller]: No, no. Remember I mentioned my hepatitis C patients who took supplements, and people have spent billions of dollars trying to put things into... And the NIH has spent hundreds of millions of your tax dollars trying to find supplements that work. But, if you're not vitamin deficient, if you don't have a deficiency of something, that's important in people with GVHD because people do become deficient in nutrients and vitamins. So that's one of the things to monitor part of the nutrition. If you have a deficiency, it's recommended to take supplements. However, to enhance your immune system, consuming a heart-healthy diet and engaging in physical activity are extremely effective. I understand that it may not be the desired answer, as many people seek a quick fix with supplements. Nevertheless, the reality is that supplements do not make a difference.

(42:08): [Lynne Spina]: Well, thank you for telling it like it is. Do you see long-term issues in the liver with prednisone at a low dose over the years of use?

(42:21): [Dr. Theo Heller]: Not in the liver directly. In people on prednisone long-term, usually at higher doses, there's a problem with weight gain. And excessive weight gain can be associated with fat in the liver. But outside of that, the long-term use of low-dose prednisone has other side effects but is not liver-specific.

(42:46): [Lynne Spina]: Thank you. What are your thoughts regarding being thoughtful about sugar intake? And do you see sugar intake's role in inflammation in GVHD GI people?

(43:03): [Dr. Theo Heller]: This is an excellent question. Refined sugars are a problem. Unrefined sugars are not. So, we have to be very careful how we define sugar. If you're talking about sweet potatoes, roast baked potatoes, not fried, not fries, but the whole potato. Suppose you're talking about cauliflower, broccoli, whole wheat, and whole grains. Whole wheat bread, those sugars are not a problem.

But if you're talking about refined sugars, the kind you find in sodas, candy, processed foods, coffee, tea, and things like that, that's a real problem. Those sugars are inflammatory. Those sugars aggravate inflammation and damage immunity on multiple levels in multiple ways. And I strongly encourage my patients to change their diet and avoid that. That’s part of a heart-healthy diet. So yes, absolutely avoid refined sugars for multiple reasons. But not all sugars. Complex sugars are good for you.

(44:12): [Lynne Spina]: Okay, very good. When you advocate for a plant-based diet, are the advantages associated with both raw and cooked vegetables?

(44:24): [Dr. Theo Heller]: Yes. And when I say plant-based, notice I'm not saying vegan because a vegan diet is associated with certain vitamin deficiencies and oxalate excess. And I'm not saying vegetarian, either, because I think protein richer protein is incredibly important. If you look at people who live into their hundreds and the so-called blue zone diets, and if you look at people who remain healthy long-term, small amounts of meat and moderate amounts of fish are part of that diet. So, when I say plant based, I want to clarify, I'm not talking about vegan. And it can be cooked or raw, yes. But when we talk about raw, salads are raw. And it's important to ensure you're not eating raw fruits or vegetables if you are neutropenic. So again, when I'm encouraging raw food, it depends on neutrophil levels.

(45:24): [Lynne Spina]: Thank you. Although you've spoken about what else it can be, I will combine two questions: the blood tests, imaging, and biopsy. How, specifically, is GI GVHD diagnosed? And how, specifically, is the liver GVHD diagnosed? And is it specifically on certain liver lab work?

(45:55): [Dr. Theo Heller]: That's the problem. Those two questions have hit the nail on the head. Remember I told you that organs are pretty dumb? So, the GI GVHD diagnosis and criteria are based on diarrhea and stool output. But you now know that other things can do the same, which is why the criteria look at context as well, whether there's skin GVHD or liver GVHD with the GI GVHD, in which case you'd be less likely to have an endoscopy and less likely to look. If there's no CMV in the blood or EBV in the blood, if all the infections are ruled out, then you can rely more comfortably on the non-clinical. But if there's any question, it comes to biopsy. And histology is helpful because you see certain histology features typical for GVHD. And then you look at it to see if the whole clinical context makes you comfortable.

(46:53): And I'll make a parallel: Inflammatory bowel disease, ulcerative colitis doesn't have a blood test or anything that tells us ulcerative colitis. It's the history, the findings, the blood test, and the endoscopy. The same is true for GI GVHD.

(47:08): Liver GVHD is more difficult because the blood tests are the same in many conditions. But again, we look at the context, we look at the timing, and that makes us more comfortable. We use our experience to determine whether we need to work it out further or not. We ensure we've ruled out other possible causes, like hepatitis B, CMV, etc.

(47:34): And only if there's a question, then we go to biopsy. There is no specific feature on biopsy, but there are suggestive features like bile duct damage, neutrophil infiltration of the bile duct, and apoptosis. That means cells killing themselves and committing suicide. So, we can see that on the biopsy. So that's a long answer.

Short answer: although there are no specific criteria, looking at the context, the other organs involved, ruling out other things, and when really in doubt, using biopsies make us comfortable with the diagnosis. But that takes a knowledgeable, experienced team. And I know that's not always possible.

(48:16): [Lynne Spina]: Thank you. Okay, the next question is Can you discuss acid reflux associated with GVHD? Is it associated with the use of prednisone? Are there long-term effects with continued use of PPI (Proton Pump Inhibitors)? And have you seen significant hoarseness in voice with acid reflux?

(48:39): [Dr. Theo Heller]: Fantastic question. Acid reflux is incredibly important. When we are stressed, we make it more acid and so, reflux is more likely to occur. It can be so severe that you see hoarseness. PPIs are magic; they are incredible in switching off acid and making us feel better immediately. And patients love it, and physicians love it because physicians feel like they're doing something.

(49:09): But the problem, the downside with PPIs, is there's a reason we have acid in our stomach. That acid is important to protect the microbiome in our colon and keep the colonic bacteria from coming up. So, the long-term use of PPI is associated with changes in the microbiome, and many of those changes are associated with GVHD. So, I don't want to say stop the PPI; I don't want to say don't take a PPI.

(49:40): If you have terrible reflux, to the extent that you're hoarse, there isn't much choice. Once you're out of the significant period of stress, look for other ways to manage the reflux. If you can, go to an H2 receptor antagonist, that's the next class of drugs, which does not change the microbiome as much. See if you can do non-pharmacologic ways of managing your reflux. Smaller meals, not eating for three hours before lying down, things like that. And lastly, if your bone marrow transplant physician is uncomfortable going beyond that, I would request a referral, if possible, to a gastroenterologist who is comfortable with reflux because there are many other options.

(50:35): [Lynne Spina]: Thank you. Can you define PPI?

(50:40): [Dr. Theo Heller]: Oh, sorry. Proton pump inhibitor. It's a class of drugs that switch off the pump in your stomach that makes acid. And some of them are potent. They can shut down acid production completely. The class of drugs is called proton pump inhibitors. And the problem is, you can go to Costco and buy them over the counter. So, people like them because they work. But people at risk with GVHD have to be a bit more thoughtful because of the alterations in the microbiome.

(51:17): [Lynne Spina]: Great, thank you. Next question Is there such a thing as a leaky gut, and can it be treated?

(51:24): [Dr. Theo Heller]: Yeah. Yes. Fantastic question. So leaky gut is chemotherapy or conditioning or dysbiosis, which means an imbalance in the microbiome. So, a shift in the normal balance causes inflammation or damage to the lining of your gut. And the gut is an amazing thing. If you think about it, from mouth to anus, it's outside us. So, we must absorb food, take food into this tube, get it into our systems, but not let anything else in, right? So, it's incredibly sophisticated and incredibly good at only letting nutrients in.

(52:09): But if you damage that barrier, the membranes on the cells, the mucus layer, and the bacteria that protect us, the gut becomes leaky. And now, all sorts of bad, evil humor can leak in and drive right through. Like the Harlem Tunnel, they come straight through into Manhattan and suddenly, floating in our bloodstream, are things that promote inflammation and GVHD. So, the leaky gut is something we're very aware of, very sensitive to, and do everything we can to prevent.

(52:44): [Lynne Spina]: Okay. Next question. For a chronic GVHD patient with liver counts higher than the normal range, what, if any, might be some symptoms that they would experience?

(53:03): [Dr. Theo Heller]: One of the good and bad things about the liver is that liver-associated enzymes don't make you feel bad. There are very few symptoms of just elevated liver enzymes. When the liver becomes quite diseased, then we start to feel tired. We can turn yellow, our stomachs swell, and we can develop bruising and bleeding, but that is the end stage. That's when the liver's quite damaged. And that's why it's important to be aware of those elevated enzymes because there are no symptoms. And to ensure that your doctors thought about it, if it's GVHD, and if you are on good treatment with minimal side effects, we will tolerate slight elevations in the enzymes. They don't have to be normal. So, a slight elevation alone is not an issue if it's been thought through, and the diagnosis is correct.

(53:58): [Lynne Spina]: Okay. Next question. What does mucus in the stool, without diarrhea, indicate?

(54:08): [Dr. Theo Heller]: So, you know, when you get a cold, and your nose starts to run, you make mucus from your nose. The intestine is the same. When it gets a little bit upset or inflamed, it makes mucus. So excessive mucus in the stool, even without diarrhea, suggests some inflammation. And remember, the small bowel is 16 to 32 feet long, and the colon is 6 feet long. So, let's say you have some inflammation 10 feet into the small bowel; there's more than enough time for the rest of the bowel to absorb the water and the liquid. So, you won't have diarrhea, but you could still have mucus. If your doctors have looked at you, worked you out carefully, thought things through, and said it's okay; we don't have to go further, that's okay. But if they have not, and you have not told your doctor, mucus is important to talk to them about because it suggests the equivalent of a cold somewhere in your intestine.

(55:09): [Lynne Spina]: Thank you. How do you keep the balance of the microbiome?

(55:22): [Dr. Theo Heller]: Okay, thank you. It's an unfair thing, again, because our microbiomes are determined mostly by the time we turn three. So, it's how you were delivered, whether you were breastfed or not, or the kind of diet you were fed as a small child. It's the kind of diet you've eaten as an adult. So, a lot comes in where we didn't make the choices. But the exciting thing is that you can restore balance by eating a plant-based diet.

(56:04): So, people are looking at all sorts of steps along the way. Okay, a plant-based diet is very difficult. It's an expensive thing to do. A plant-based diet is much more expensive than going to Mickey D. So, what about other steps?

(56:22): The restoration of the balance is something we are researching very actively. There are prebiotics, meaning that you eat things like plants, which will make the balance right. There are probiotics, which the question referred to, where we take some of those bacteria we are meant to have in excess. And then there are things like stool transplant, where we transplant the whole thing.

(56:48): Let's answer the middle question about probiotics. A nice study from the City of Hope looking at lactobacillus showed it did not make a difference. And we had a patient who was taking probiotics. Don't forget that many people are on immunosuppression; prednisone is an immunosuppressant. So, taking probiotics in that setting is not the same as taking probiotics in a non-immunosuppressant setting. And even in that setting, we don't have it down pat. And we had a patient who came to us and was taking normal amounts of probiotics but was immunosuppressed and had imbalance the other way, an over restoration, and had problems with that.

(57:30): As children, we often hear the story of Goldilocks and the Three Bears, where things are just right. However, finding the perfect balance is impossible in clinical practice, even in mice. While it's exciting to consider the possibilities, we're not at a point where we can confidently push someone in one direction or the other. Therefore, I encourage you to take the more difficult path.

(58:06): [Lynne Spina]: Thank you. That will have to be our last question. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Heller for a very helpful presentation. And thank you, the audience, for your excellent questions. Please get in touch with BMT InfoNet if we can help you in any way.