Graft-versus-Host Disease (GVHD) of the Gastrointestinal Tract and Liver

Presenter: Trent Wang MD, Sylvester Comprehensive Cancer Center at the University of Miami

This video is a recording of the workshop presented at the 2019 Celebrating a Second Chance at Life Survivorship Symposium.

42-minute presentation, followed by 10 minutes of Q&A

Summary:

Graft-versus-Host disease can affect the throat, stomach, pancreas and liver. Symptoms include nausea, loose stools, diarrhea, cramping, weight loss, problems swallowing, yellowing of skin and eyes and/or dark urine. Learn how to manage GVHD of the GI tract.

Highlights:

• Graft-versus-host disease (GVHD) affects approximately 50% of patients who are transplanted with cells from a donor

• There are two types of GVHD: acute and chronic. 

• Of those who develop chronic GVHD, approximately 30% have GVHD in the GI tract and 50% have liver GVHD.

• The median duration of treatment for GVHD is two years.

• Maintaining a healthy lifestyle, making sure your primary care physician and dentist are monitoring you for other issues while you have GVHD, and engaging specialists to ensure good care is important.

Key Points:

02:49  Organs affected by acute GVHD

05:43  30% of patients with chronic GVHD have GI symptoms, and 50% have liver GVHD

07:39  Weight loss, problems swallowing and throat pain are symptoms of chronic GVHD, but it is important to rule out other causes 

14:51  Treatment Options for GI GVHD 

16:57  Strategies to correct weight loss caused by GVHD

17:38  Strategies to treat nausea and taste changes caused by GVHD

26:04  Treatment for cramping and diarrhea caused by GVHD 

28:29  Yellowing of skin, eye and dark urine may indicate GVHD in the liver

31:55  Treatment for GVHD of the liver.

Transcript of Presentation

00:00  Outline of Talk:  Thank you, everyone, for coming. Great. I don't have to talk about myself today. The focus of this lecture, which has some overlap with other lectures you're going to I'm sure, is chronic graft-versus-host of the gastrointestinal tract and liver. This is our outline for the day. We're going to do some definitions. I know you guys know the definitions, but for completion sake we'll have to talk about some of the sub types of graft-versus-host diseases, some of the sub types.

We'll do a little bit of anatomy, and we'll play doctor for a bit. I want you to see how, from the doctor's side, we think about things and when we hear about a complaint, what we go through, the mental exercises. Then we'll go through a lot of these organ systems, through mostly imaginary cases. Don't get too mad at me if it doesn't make perfect sense. We'll have four cases where we go through these complaints, see how we think about it, the treatments, the diagnosis, all of these things. Then we'll wrap up with a few words about where we think the direction is for chronic graft-versus-host disease, the durations of treatment, and all of these things.

01:10  Transplanting a donor’s immune system into a patient can create graft-versus-leukemia or lymphoma effect, but also GVHD:  So, this is my picture of a confused lymphocyte. We all know why we went through this, this donor transplant. Right? We have some kind of cancer, generally speaking, or other thing that requires a new immune system.

It comes with a dose of chemotherapy, usually strong, not always, but a major part of the treatment from this donor bone marrow is a new immune system. A new bone marrow will make all those things, the red cells, the platelets, the white cells, but importantly is this new immune system, which we think will go through our body and be able to recognize cancer, leukemia, lymphoma, and see it as something bad, and zap it. That's what we want. That's called graft-versus-leukemia or lymphoma effect.

The off-target effect or friendly fire is when these new immune system cells, these lymphocytes from the donor, see regular tissue, see our skin or our gut, and also get a little bit confused, and cause tissue damage in that way. So, that's where the term comes from.

02:14  We all know the subtypes. There are two major subtypes that are classically distinguished by 100 days. Are you before 100 days? Are you after 100 days? But the actual distinguishing features are much more complex than that.

There's probably a lot that goes into it, but for acute graft-versus-host disease this is what we classically look at for the skin, the gut, and the liver. Within 100 days we think this is mostly mediated by the T lymphocyte cells from the new immune system that causes damage.

02:49  Organs affected by chronic GVHD:  After 100 days we start thinking about chronic graft-versus-host disease, which is more complex than just the T cells. There's also B cells at play. There's a lot of other features. It's not just the time distinction. It's actually the physiology of how this develops, because we know that through our conditioning regimens, our prophylactic medicines we give, that we can kind of change the frequency or the severity of chronic graft-versus-host. A lot of this is predetermined even at or shortly after the time of transplant. With the chronic graft-versus-host disease organs we have the skin, the mouth, the eyes, Of course, the liver, and the gut, and many more.

With chronic graft-versus-host disease there's also sub-subtypes, like I said. This distinction is less important in terms of treatment. They're treated generally the same, but if someone gets chronic graft-versus-host disease and they didn't have acute before, that's called de novo. It kind of popped up from nowhere. Right?

Someone who had acute graft-versus-host who gets chronic, it depends on whether or not the acute was active or not. If there was active acute, that's called progressive chronic graft-versus-host disease. If it was active and then had resolved by the time the features of chronic started, it's called quiescent. A lot of subtypes.

For the purposes of our talk we're talking about the GI and liver, and these are actually really more hallmarks of acute graft-versus-host disease. We see them more commonly in the acute setting, but Of course, we will talk about the chronic manifestations as well, which are not always totally separable.

04:30  How common is chronic GVHD?:  So, how common is chronic graft-versus-host disease? When we go through these transplants, I think your doctors have given you a lot of different quotes, and they all sound pretty ridiculous. I mean, the common statistic is 10 to 70%. That's wild. That could be nothing to everything. Right? 

It's probably somewhere in between. But this includes all forms of chronic graft-versus-host disease. It can be something very mild, minimally noticeable, that doesn't require treatment, or it can be something that's much more serious and requires aggressive treatment. So, it really depends on where it is and how severe it is.

05:09  Chronic GVHD typically occurs five to seven months after transplant:  It tends to start at a median of about five to seven months after transplant. This means that around the time it starts is actually when we usually are in our taper, the primary taper of where we're trying to stop the tacrolimus or the sirolimus. The immune system is really less inhibited than it was previously. That's why we see these features sometimes. About 30% of these chronic graft-versus-host cases happen in patients who didn't have any acute graft-versus-host, so that's pretty common. Just because there was no acute doesn't mean we're totally in the clear.

05:43  30% of patients with chronic GVHD have GI symptoms, and 50% have liver GVHD.  Of the patients who do have chronic GVHD, 30% of them have chronic GI symptoms, which affect these organs we'll talk about, and 50% of them can have liver GvH.

05:57  What are symptoms of GVHD in the liver?  When I say liver GVH, it usually means some abnormality in liver function. To make the diagnosis of liver GVH is a little bit complicated, because usually it means you have to have other features of GVH. It's so nonspecific to have a liver enzyme that's elevated. It can be from anything, drugs, medications, infections, gallstones. We'll talk about it. So, we're going to focus on these organs that you see here. It's a simplistic picture. We'll talk about the symptoms and signs that we feel we have, that the patients will tell us, how we go about doing a diagnosis, and then we'll talk a little bit about the therapy as well.

06:44  Overview of how the GI system works:  I think at this point most of us know what these organs do or where they are, but just for the, again, review, the esophagus is a kind of pipe that brings food from our mouth to our stomach. It needs to bring the food smoothly down to the stomach, where the first part of the absorption process and breakdown of food happens, which leads to the small intestine, where more digestion happens.

The pancreas secretes a lot of enzymes there to assist with this digestion. Then, from the small intestines, food goes to the large intestines, where a lot of fluid is reabsorbed, and then ultimately out the back.

The liver is a major organ. We see it right here. This has a lot of important functions in the body. It makes a lot of important proteins. It helps with metabolism of anything we take in, including medications.

07:39  Weight loss, problems swallowing and throat pain are symptoms of chronic GVHD, but it is important to rule out other causes:  So, our first case is Ned. He's fake. Ned is a 45-year-old man who had a transplant for leukemia. It was about one year ago. After the transplant he had a little bit of acute skin and upper GI GVHD. The skin GVHD can be just a little bit of red rash that cream takes care of. The upper GVHD of the GI system was some nausea, maybe some fullness that happened. This was treated without systemic immune suppression. These are two very common complaints after a transplant. A little bit of a topical steroid, like a budesonide or a beclomethasone, can do the trick for this very effectively.

A year later he now has weight loss for about three months, and he's feeling that food sometimes doesn't feel like it's getting swallowed properly. It feels like it's getting stuck. Occasionally there's also throat or chest pain, and it doesn't happen all the time. When it first comes up, we sometimes say, "Let's see what happens. Maybe it'll stop. Maybe it won't."

We monitor it. But when he presents to us, we have to kind of think about what else it can be. This is a GVHD lecture. I think number one, two, and three on the list of what it probably is is GVHD, but let's do the exercise anyways.

09:01  Infection, dry esophagus, dysmotility and esophageal narrowing can cause swallowing problems:  One of the main things in patients who go through transplants is infection, and the esophagus is definitely some place that can get infected, so we have to think there. What can the infection be? It can be from viruses, herpes viruses. It can be from candida. It can be from other even more rare infections, but that's in our heads. We're thinking there.

In patients who went through chemotherapy, or radiation, or other tons and tons of treatments before transplant, they may already had dry mouth or effects of that treatment. Sometimes it's actually just from the GVH that may be starting sub-acutely. But if the mouth is dry, sometimes that means the stuff after the mouth is dry. The esophagus is also dry. So, Of course, if the lining is not what it should be, food can get stuck going down.

Acid reflux can contribute to symptoms similar the this, or hiatal hernias. People without transplants get acid reflux as well. We have to think about that.

There can be cases where there's dysmotility, where the nerves that lead food from point A to point B are kind of discombobulated. They don't work as they should. This, again, can be sequelae of treatment that we've had, or infection, or other things. We have to make sure that's not the cause here, that food's not getting stuck because of spasm in the esophagus.

Esophageal narrowing can be from chronic inflammation. The small intestinal bowel overgrowth actually more causes lower GI symptoms. We always have to think about it when there's weight loss, but probably not at the top of the list here. This is just an example.

10:46  Diagnosing GVHD in esophagus: As we are all doctors, we have to do this routine thinking process, where we try to make sure we cross all our T's and dot our I's. The most important thing when we talk to patients is we have to get a good history and find out, make sure we didn't miss any important details. We'll ask, "Is this swallowing only with pills?" Sometimes pills can cause a certain type of esophageal inflammation. It's called pill esophagitis, and the pills can get stuck, certain pills more than others. Is it with solids, or liquids, or both? If it's just solids, that could be a better sign. If it happens with both, it may mean it's more advanced or there's maybe more of an obstruction. Was there prior radiation or other treatments? Are there other signs of infection that we notice? We ask a lot more questions.

Once we've done that, we think about what can help us make this diagnosis. When it comes to swallowing, one of the things that are easy and can be quick to get some results is a barium swallow, where contrast is ingested, and then the radiology team takes pictures of how this contrast goes down from the mouth to the stomach. It can show us the lumen, the lining of this esophagus, and whether or not there may be a tightening somewhere, or if there is spasm, it will look a certain way. Swallow can be very effective to tell us. CT scans if there's a history of lymphoma or other masses that might be pushing extrinsically onto the esophagus.

Then there's more invasive testing. Manometry is if we expect that there is problems with the food moving and the motion's not normal, this is a probe that goes down into the mouth, into the esophagus, and actually near the end of the stomach, and measures whether or not the valves are working from the esophagus to the stomach. It measures pressure. When the esophagus squeezes, it's supposed to be rhythmic. If it's all out of rhythm, that means maybe there is a dysmotility issue. Of course, upper endoscopy, which we'll talk about on the next slide.

12:50  Esophageal web is a characteristic of GI GVHD:  But in Ned's case this picture, let's say it's a representative picture, but not so accurate. Ned was found with an esophageal web in the middle of his esophagus, which can be quite diagnostic for GVHD. This has stricture. We'll pretend it doesn't. This illustration is actually from someone's peptic ulcer disease induced stricture, where the acid from the stomach just pops up and irritates a lining, causes this inflammation and then scarring. In chronic GVHD the rationale's almost the same. There's esophagitis, inflammation along the whole GI tract, and it can cause scarring, these little webs of tissue that don't belong, higher up than you would expect for acid. The endoscopy would make this diagnosis very effectively.

13:37  Diagnosing GVHD in esophagus:  Who here has had an endoscopy? Okay. Not as many as I thought. Endoscopy is done by a gastroenterologist. This is usually an outpatient procedure. There's a little bit of sedation, not too much sedation, but generally you won't remember any of it. If you're lucky, you won't. Okay. It's done with a small camera, or that's what they tell us. It's relatively small. It goes into the mouth for the upper endoscopy. It allows the gastroenterologist to look all the way from the mouth to the stomach and the first part of the small bowel. They get to look at how the tissue is, whether or not there's any unusual findings, if it looks dry, if the color is funny, if there's signs of infection.

 It doesn't just let them look. It also lets them do biopsies, which are very important in cases with GVHD as a suspicion, because the biopsies will be sent for testing to rule out certain infections. In addition to the biopsies, if they see things, certain things they can intervene on immediately, including esophageal webs. They can do therapeutic injections or stretching, which is called dilatation.

14:51  Treatment Options for GI GVHD:  How do we treat it? Let's say we found this. It's complicated. This is an exhaustive list, not too exhaustive. It's a big list, but I just wanted to show all of the options that are running through our heads as we're thinking about how to go about treatment.

15:06  Systemic steroids to treat chronic GVHD:  Systemic corticosteroids are the medications like prednisone, methylprednisolone. They can be pills. They can be IVs. These are the standard of care for chronic GVHD that needs treatment and that needs systemic treatment. This includes very severe disease. This can be disease that affects multiple organs in a pretty moderate degree. But while this may be the most effective option that we generally have, it also has the most side effects in long-term usage.

We all know the side effects of steroids includes skin thinning, bone weakening. It can keep you up at night. It increases infections. It weakens our muscles. There's much more than that. We don't want to stay on steroids for too long, but there's a balance here that we have to keep. So, steroids are always in the mix. We're always thinking about it a little bit. The non-absorbable ones are sometimes used for upper GI or maybe duodenal. Sometimes we add them in addition to the first one.

16:06  Secondary agents to treat chronic GVHD: tacrolimus and sirolimus:  The secondary agents, these are the tacrolimus, the sirolimus. Sometimes more aggressive therapies than that that include chemotherapy agents or agents that we use for autoimmune diseases that kind of have carried over into the GVHD realm. We generally use these when we think we need more than just the steroids or when we have problems lowering the steroid's appropriate doses for safety.

In Ned's case I don't think he necessarily needs the secondary agents yet. The systemic corticosteroids are considered, because when you form an esophageal web, it means there is significant inflammation at some point. Whether it's active or not depends on how the endoscopy looks and other symptoms, but we'll consider that. Endoscopic treatment is something we'll go onto the next slide, but this is probably the mainstay of treatment for a web.

16:57  Strategies to correct weight loss caused by GVHD:  In addition to correcting the web and any inflammation that may be present, we may also want to make sure that we can help gain the weight back. A lot of that has to do with calories. We need calories to heal, to build tissue, to gain weight. Right? It's not so easy. It's easier said than done. So, we need to help with the nausea, the fullness, the appetite, the taste. Of course, since everyone already has a little bit of acid reflux, it may be already there, we have to make sure we manage that. I think a lot of patients after transplant are already on these things that suppress acid, like protonix, pepcid, those kinds of medications.

17:38  Strategies to treat nausea and taste changes caused by GVHD:  Talking about how to manage nausea, taste, appetite, we push pills. Right? That's what doctors always do. You give them a complaint. They give you a pill, so you stop giving them complaints. The anti-nausea pill is the first one we do. This is Zofran, and compazine. We're experienced with this. Taking it about 30 minutes before a meal can help.

Sometimes there's even something called anticipatory nausea, where the smell of food, the thought of food can make you gag by itself. Then sometimes Ativan or benzodiazepines can be more useful for certain types of nausea.

18:14  Strategies to treat feeling full after a few bites:  When we get full easily, Of course, we want small, frequent meals. We don't want to pig out three times a day like we did when we were 20. The frequent meals can help chronically digest throughout the day. We also want cold and chilled foods. It seems to just come and stay down better than warm foods. Of course, sipping liquids and avoiding over-distension of this fragile stomach right now.

18:41   Miracle fruit:  I like miracle fruit. Our dietitian at the University of Miami actually introduced this to me. This is a miracle fruit here. You can buy it from certain I guess places that sell fruit. There's one in Homestead that sells it, but it also comes as a pill, miraculin pill. What this does is it changes the taste of certain foods, and it can make bitter things or metallic things less that way and even make it sweet.

So, the experiment we had was with lemonade. You try it before. You take a little bit of the miracle fruit, which is really expensive, by the way, and then you drink the lemonade again. The lemonade, it tastes like someone added a bunch of sugar to it, so it was very interesting. I think it's worth a try. I did look it up for interactions. I don't think it's a major risk post-transplant. I think if you have it around, why not?

19:34  Acupressure bands and some home remedies may help with nausea:    Acupressure bands, the most common one is Sea-Band, which is sold at grocery stores, Amazon, you name it. These kind of put pressure on the wrist. You usually wear one or two. I've used it on a cruise before. I get nauseous very easily, but it helps me. They do advertise it for chemotherapy. I've had maybe a couple patients try it. The ones who believe in it really believe in it, and the ones who don't. If you've got 20 bucks to lose, you can give that a try. 

Common home remedy, ginger, ginger candies or, actually, ginger, can help with nausea. Of course, we want to make sure you don't go for things that make you nauseous from the first place, any foods that you normally don't like. Strong smells, thick, fatty foods that are difficult to digest as well and may stay in the stomach for longer periods of time.

20:24  Nutritional supplements can help you gain weight:  Nutritional supplementation. To do building, to do healing we need calories. We need proteins. These are the amino acids of life. We need to supplement. These are often marketed as meal replacements, but we are not replacing meals. We're adding. to whatever we eat we add a little bit.

I went on Amazon. I looked up the cost, and how many calories, and the protein of these. They're about the same I think. Whatever you like the taste of or the price of, go for it. Carnation, you have to bring your own milk. That's why the number looks a little bit better. But do it three times a day. Do it more. Do it less.

21:03  Set a calorie goal:  You have to have a calorie goal, and you have to try to meet it to build. Work with your dietitian there. To add to that, snacking a lot is very important, because we can't just rely on meals, especially when our appetite's not good. So, when you snack, make it count. Do high nutrient foods. Do ice cream, shakes, a Greek yogurt with a high protein, pasteurized cheeses. Whatever you like, put it in.

Again, avoiding too much fluid, even though you feel like your doctors are always telling you to drink so-and-so amount of fluids. "What? I can't drink that much." No one can, but you have to try, and hopefully not with the meal.

21:41  Exercise to stimulate hunger:  And exercising. Exercising burns calories, but it also stimulates our metabolism, and it can stimulate the hunger in our body. So, you still have to exercise.

21:53  Dilatation to treat esophageal web:   With Ned's case he had this esophageal web. He underwent dilatation procedure. There's a few different ways to dilate, but this example here, there's a catheter with a balloon on it. They go to the area where the web or a stricture is treated the same way. They go to that area, and they inflate the balloon, and it hopefully safely opens up the area that's tight. They can do it once. Generally, there's good success once, but sometimes they may have to do it more than once. Let's say in his case with focus on nutritional supplementation and all the other things he was able to gain his weight back to his previous baseline. If he didn't, we would give him some steroids.

22:35  Are diarrhea and cramping symptoms of GVHD?  Case two is Jaime, who is 52. He's 130 days after transplant, so he's still fresh. He had some lower GI GVHD that was acute, that means diarrhea, and treated with Prednisone. Improved, tapered, but still occasionally had loose stools. It didn't go away completely. It was never 100%.

On day 130 he had, again, the cramping, diarrhea, eight episodes a day. During this time he also was having the development of some dry eye symptoms, and his mouth was dry all the time, things that sound like chronic GVHD. So, we have to take this very seriously. We never like diarrhea. Okay?

23:17  Causes of diarrhea and cramping other than GVHD:  The considerations now, again, I have to make sure it's not an infection. We have to do the stool tests. We rule out C diff. Everyone who's had antibiotics is at risk for C diff. We have to make sure it's not a virus causing this or other bacteria. We have to make sure you didn't go to a new taco stand, those things. "Who else is sick in the family?", is a common question, because if someone else is sick, it almost gives me some reassurance, but not really.

23:45  New medications, including medications that you're on, ursodiol, magnesium. Who's on that? Everyone. Magnesium causes loose stools by itself. There's two formulations for magnesium that are commonly used. One of them is magnesium oxide. The other one is mag plus protein, which seems to help a lot of patients. So, if you're having trouble with the oxide, the mag plus protein, you can get it online. CellCept is used as an immune suppressant with certain transplant regimens, and this causes diarrhea very similar to actually a GVHD picture, even on biopsy, so it can be very confusing at times.

So, we ask all the questions and the history, and then we do some tests on the blood and the stool. We're looking for a cause of infection in the stool, but in the blood we're also looking to see how hydrated are we? Are we losing tons of fluids and electrolytes or just a little bit? That's why we need to check the blood frequently as well.

24:43  Using colonoscopy or sigmoidoscopy to diagnosis GI GVHD:  When there's diarrhea and this history of GVHD, you're almost always going to get a colonoscopy or a sigmoidoscopy. The difference between the two? The sigmoidoscopy, it can be done at the bedside or in a doctor's office. You don't have to be sedated necessarily for it, and you don't need to prep necessarily for it, which can alleviate a lot of issues with the full colonoscopy, which needs all of the above and goes all the way from here to the other end.

When we're looking for GVHD or infection, a lot of times just looking at the rectum and the sigmoid can give us an idea of how the tissue is. Whoops. So, we generally try to get an endoscopy done. Biopsy is usually done to rule out infection. The one we're most thinking about here is CMV, which treating with steroids would not help CMV. But frequently a biopsy to look for GVHD shows very nonspecific changes, a little bit of inflammation. It doesn't necessarily tell us it is GVHD. It's more of a clinical picture.

25:52  So, Jaime really needs treatment right now. He will need the systemic corticosteroids, and usually in cases like this we give it as an IV, at least for a few days, to make sure that it's being absorbed properly.

26:04  Treatment for cramping and diarrhea caused by GVHD:  Secondary agents - in cases like this, which this is not really acute GVHD, it's not really chronic, it's a little bit of both, it might be what was called overlap. It might be late onset acute GVHD. Secondary agents, starting infliximab, pentostatin, which were used in the past for GVHD that doesn't respond to steroids after a few days, or a newer medication, such as ruxolitinib. This is Jakafi, which there's very good data recently for in this setting. It can provide help when help is needed beyond steroids

26:39  Extracorporeal photopheresis, I won't talk about it in this case. We have a later slide on that. But while we're treating with steroids or going to give some anti-diarrheals, we want to limit the amount of fluid that's lost, the best that we can control it, and make sure that there's enough nutrition going in as well. A little bit of bowel rest is common. Excuse me. But we can't let it go too long without putting some calories in. So, sometimes we need to give parenteral or TPN.

27:15  Jakafi (ruxolitinib) Jaime was started on IV corticosteroids. Seven days later he didn't really have much improvement, although it didn't get too much worse, still having too much diarrhea for our liking. He was started on ruxolitinib, which is not FDA approved for GVHD, although we hope it will be very soon. He was started on this treatment, which is actually a pill, and the other supportive measures to try to limit his diarrhea, which seemed to do the trick. A few weeks later his volume of stool decreased steadily, and he was discharged home. Sorry.

27:52  The steroids were tapered as an outpatient very gradually. I wrote six months, but it can take a while. While on this ruxolitinib drug, the counts fluctuated. In GVHD itself the counts can fluctuate. You can get low white count, low platelets. It can be up and down. Sometimes treatments are adjusted or help periodically. It's not exactly rare. Despite occasional flares, meaning the stool may loosen periodically, the overall prednisone dosage decreased, and his symptoms improved over the next year. So, that's a tough case.

28:29  Yellowing of skin, eye and dark urine may be symptoms GVHD in the liver:  Case three is Maggie, who is a 26-year-old woman. She had a transplant seven months ago, and she turned yellow. Her eyes turned yellow. Her skin was yellow. Her urine became dark. She got abdominal distention and limb swelling. Before all of this she actually was starting to get a little bit of chronic GVHD as well. What do we think this is, when we turn yellow, frequently?

Yeah. Exactly. It's confirmed by the elevated serum bilirubin levels, which doesn't always come from the liver. It can also be from the gallbladder or blockages, but we have to make sure the liver is working here. There's obviously dysfunction when we turn yellow, so we think, "Why?"

29:18 Other potential causes of yellowing, besides liver GVHD:  Liver GVHD can definitely happen, but we have to make sure it's not something that we can correct immediately. When we have increased pressure in some of the liver veins or even arteries that lead to and from the liver, this can be a clot of something similar to that, it can cause this picture.

Medications can cause this picture. Gallbladder dysfunction or stones can do this, especially in someone who's had gallbladder stones before. They can get stuck and cause the bile to build up. Hepatitis, over viruses, including CMV, adenovirus, can cause this picture, and iron overload in patients who have really had a lot of transfusions. This usually doesn't happen so acutely. It's a gradual process, and it can lead to liver cirrhosis, as well as NASH or non-alcoholics steatohepatitis, or fatty liver changes that accumulate over time. But the patients who have preexisting liver issues are more at risk for this.

30:22   So, we do our testing. We ask our questions. We check for a lot of infections through the blood, including the hepatitis viruses. We also do some imaging in cases like this. We do an ultrasound. Ultrasound is very good. It doesn't hurt too much. It's a little bit cold with the jelly, but what it allows us to do is to see the bile ducts and make sure that there's no stones that are obvious there.

If there is a stone, we can call a GI doctor sometimes, if they feel that maybe an endoscopic procedure can clear out the ducts. MRI testing is sometimes needed, especially in cases where we're not sure what's going on, or if there's suspicion for iron overload, we want to see what degree that is. We want to make sure that there's no heart failure. We do an echo quickly to make sure the heart's pumping effectively, because when it doesn't, sometimes fluid can back up and cause congestion in the liver.

31:25  Liver biopsy for GVHD:  For Maggie she had some signs of chronic GVHD already, so as soon as we can exclude the major infections it can put GVHD at the top of our list. But sometimes when there's no other GVHD and it's just the liver enzymes that are abnormal, we may have to do a biopsy. This can be through one of the veins. It can be through the skin, but a liver biopsy done by the interventional radiologist can also provide a lot of insight. Probably not needed in her case.

31:55  First line treatment of GVHD of the liver.  So, treatment for her. It's steroids again. That's getting the be a recurrent theme. IV or oral should be okay, as long as she's able to swallow. Secondary agents in chronic liver GVHD are frequently considered at the same time as steroids, because we know when there's liver involvement, it doesn't tend to go away immediately and all the way gone.

So, we'll consider adding maybe tacrolimus or something called extracorporeal photophoresis, which is light therapy that I'll talk about on the next slide. Ursodiol has been known the help with gallstones, and we use it to prevent liver complications after transplant. Sometimes when we have liver enzyme labs in the setting like this with the obstruction picture, we may restart ursodiol.

32:44  Avoid medications and drugs that can cause more liver damage:  Of course, we want to prevent any ongoing damage to the liver, so we have to limit our alcohol intake, especially at this time. We don't want to drink alcohol. Avoid other drugs that may affect the liver, including Tylenol, certain antibiotics, including tuberculosis treatments. Any new meds, including herbal supplements, which can impact organs, need to be cleared with a doctor to make sure we're not missing that.

33:14  ECP – Extracorporeal photopheresis to treat GVHD:  ECP. Who's heard of ECP before? Not too much. It's very center dependent. I think a lot of transplant centers like ECP. A lot of them don't use it as much. At Miami we use ECP a lot. It's not FDA approved for treatment of GVHD. Almost nothing is. Right? But it is a potentially very effective and on the scale of things relatively less immunosuppressive therapy.

There are a few drawbacks to it of course. One is that you need a catheter inserted, very similar to the transplant catheter, this trifusion [catheter]. It needs to have high flow, so that blood can circulate. There's another type of port that doesn't stick out. It's called a Vortex port, that goes under the skin with two giant lumens that can be accessed, if you don't want anything sticking out.

To undergo ECP treatment you need to be near a center that does it, because you have to be in a physical place with a machine, and it runs for about two hours twice a week. It also takes several weeks to months before we start seeing the effects. So, it's more effective for chronic GVHD that's kind of brewing along.

This is one of our machines, ECP machine. The blood circulates out of our body through the port, goes into the machine, where they kind of separate the white cells. They treat the white cells with a chemical, it's called psoralen, and then further with UVA light. This reaction, although no one exactly knows how it works, is believed to preferentially decrease these aggressive immune system cells that are causing GVHD and spare a lot of the ones that are not. So, that's why we think it probably doesn't impair our immune system as much.

During a treatment the whole blood volume is not being changed, only a percentage, around 10-15% of the blood is being treated. It also has an effect where it cascades through the rest of the body. We don't know exactly how it works. To get a response, like I said, usually we don't even consider checking until at least two months have elapsed, so twice a week for two months. That's a lot of visits.

Maggie went through treatment with high dose prednisone, again. ECP was started as the second agent, so that it adds an additional element of immune suppression and hopefully facilitates steroid tapering. Her bilirubin levels improved, and after four weeks she was at near normal levels.

With liver GVHD hopefully it will be normal, but it doesn't always become normal, especially not quickly. Her prednisone was tapered to lower doses over the next few weeks while the ECP was continued, because we think it's a little bit safer than the high dose of prednisone.

36:12  Case #4 –Patient with nausea, loose stools and is losing weight:  All right. This is our last case. This is Brienne. She is a 65-year-old woman who had a transplant three years ago, had prior acute GVHD, has some chronic GVHD, has been on and off of immune suppression, currently off.

She has very strange, nonspecific complaints. She's occasionally nauseous. Her appetite's not great. Sometimes she has loose stools, not always, and she's been losing weight over the last one to two years, which is concerning, but we've been monitoring it. Her GVHD in the other organs wasn't severe enough where we wanted to give her steroids or treatment yet. However, at a certain point we have to say, "What's going on? Let's do the work up again and try to figure it out."

36:58  Possible causes of nausea, loose stools and weight loss:  These are such nonspecific complaints that we have to really be very comprehensive here. It can be from anything. It can be from diabetes, which again, patients without transplant have. Diabetes with poor control can cause weight loss, loose stools, poor appetite, all of those things. It can be from enzymatic deficiencies due to the pancreas. It can be from all of the things we talked about in the last three patients, with problems with the esophagus, the stomach, the colon, funky infections. Tuberculosis is a classic wasting infection where we lose weight. You have to make sure that's not it, as well as other parasitic infections, bacterial infections. Medications sometimes can cause nausea and weight loss. Of course, we need to make sure that the original disease the transplant was done for is not back.

We go through this same thing, do blood tests, see what degree of deficiencies we have. We look for vitamin deficiencies in the blood, just to see if that can be suggestive of a pancreas issue. We do imaging to rule out all of the above and endoscopes to make sure the upper and the lower GI tracts are normal. 

In her case all of this was normal, except for a very mild increase in the amount of fat content in the stool, which leads us to start looking at the pancreas a little bit. The treatment here, we don't exactly know what's going on, so let's hold off the steroids for just a minute. Of course, we're trying to modify the diet and gain our weight. We're trying to slow down diarrhea when it happens and treat the diabetes, if that was contributing. But we didn't really know the cause.

38:53  Low pancreatic enzymes may cause nausea, loose stools and weight loss:  In her case her stool fat was slightly increased, so let's give it a try of pancreatic enzymes, which are FDA approved for insufficiency. This has been described in literature as a manifestation of chronic GVHD, where the pancreas itself is shrinking a little bit. It doesn't make the normal enzymes it's supposed to or less of it. In addition to making enzymes, the pancreas also affects many endocrine functions. It makes insulin and some other of these things. But in this setting, it's supposed to make these enzymes for digestion. Without it we're not absorbing our vitamins, our proteins, our fats appropriately. It presents often as bulky, oily, foul smelling diarrhea.

A trial of enzyme supplementation doesn't cause much harm, except to the wallet I guess, and is reasonable. So, she went through that. She started the enzymatic supplements. It helped the stools a little bit. There were less stools, but she continued to lose weight and didn't gain, despite our efforts. At this point I think it has to be chalked up to GI GVHD. When we don't have a better answer and we've excluded all the things that we talked about previously, a trial of steroids is reasonable. Let's say she responded to those steroids.

40:17  Summary of Talk:  All right. So, chronic GVHD requires a lot of time. It requires a lot of experts and a multidisciplinary approach, and perseverance from our end, your end and mine. 

The studies have shown that the intensity of immune suppression will generally decrease over time. We think that eventually GVHD will burn out. It takes time, but while we're waiting for it to burn out, we sometimes deal with hiccups along the way. 

The median duration of treatment for someone who has chronic GVHD is two years. That means 50% of patients are still on immune suppression at two years. Among all transplant survivors at seven years 15% of them are still on some degree of immune suppression. That's a marathon.

During this time we want to make sure we minimize any damage to the organs that can be caused by the GVHD, but at the same time try to prevent and treat infections that occur along the way, because the treatment is immune suppression. Right? We need to work hard for this goal. 

With all the treatments we give you guys and all the therapies that are coming out that are new, we just have to make sure we focus on staying healthy, doing things that our primary care doctors want us to do, make sure our bone density is up to par, our endocrine function, treat our diabetes if it's there, make sure we get our chronic usual dental evaluations. They have to also look at the mucosa to make sure there's no secondary cancers, and any other age appropriate cancer screenings, colonoscopies, the mammograms, the pap smears. 

Make friends with people that can help. When any new treatment is needed, if it is needed, to always consider clinical trials, if they're available, because at some point everything was a clinical trial. That's how we further the field. All right? That's it. Thank you.

42:19  Question and Answer Session:  Thank you, Dr. Wang. This concludes our workshop, but if there are some questions available for Dr. Wang, I think there's some time to do that. This mic's really loud. But we're recording this presentation for people who can't be here, and I'm going to monitor this on the website, so if you have a question, I'll just run over. If you can speak into the mic, please.

42:42  Question about spike in liver enzymes that have now come back down to normal.  Question about liver. His liver enzymes all of a sudden spiked, and now they've come back down to normal. Is that then saying that his liver involvement is probably okay?

Trent Wang MD:   For some background, does he have GVHD elsewhere?

Audience:  Yes. Skin and mouth.

43:13  What causes a spike in liver enzymes:  Okay. When the liver enzymes spike, it can be due to so many things. The main thing that causes [it], a lot of times, fluconazole or these medications that we're using to prevent infections or other complications actually cause spikes, so we need to make sure it's not that. Sometimes we switch around medications. If there weren't any significant changes to the immune suppression and they got better on their own, it probably was medication or maybe even some gall sludge, gallstones. If it required a change in immune suppression and then he improved, maybe it was a spike in GVHD. But it's so nonspecific in the setting of liver when the enzymes go up. Really so many things can cause that.

Audience:  He has been told he has sludge in his gallbladder, so-

Trent Wang MD:   It could be that.

44:04  Does sugar cause cancer?  I'm right at 10 months after. Sometimes you can try to eat food, the first bite's great, the second bite you're done. Then, you know, you have your go-to food, like Raisin Bran. I can almost always do Raisin Bran. Ice cream and sugar, that's also a go-to food for me, but my wife gets very concerned about sugar intake. I don't have a sugar problem. I don't have diabetes or anything. I'm fine on my glucose scale, but she is constantly saying, you know, "Sugar feeds cancer. If you eat ice cream-"

Trent Wang MD:  Is she here?

Audience:  No. She's in the next room over. She says, "Sugar feeds cancer, and you're going to increase your chance of getting cancer again."

Trent Wang MD:   In my opinion there's no data that tells me that sugar will increase your chance of the cancer coming back. So, my suggestion is go for it.

Audience:  So, after I leave here I'm going to drag her to see you. Okay?

Trent Wang MD:   Yeah. I'll give her my email.

Audience:  Okay.

45:24  What is a hiatal hernia?  I just wonder if you can explain what exactly a hiatal hernia is, and what kind of effects it has, and if anything should be done about it.

Trent Wang MD: Yeah. A hiatal hernia is when the stomach, which is supposed to be below the diaphragm, where the lungs are, the stomach actually kind of prolapses above the lining, where the diaphragm is. As a result, the valve that normally controls the acid and keeps it in the stomach doesn't work as properly. Anatomically it just got pushed up. So, there's more acid that can flow from the stomach into the esophagus, and it causes sometimes very severe symptoms of acid reflux.

Sometimes surgeons will correct it, if they feel like it, if it's severe enough, but acid suppression is the first treatment that we go for.

46:17  How long does GVHD last?  If it persists, does that mean the transplant failed?  I have a question for you. I'm four years out and still dealing with a lot of cramping and diarrhea. At this point my thoughts or worries in terms of not how long is this going to last, because I'm alive, so I mean, it's not pleasant, but I can deal with it, but what is chronic GVHD going to all these years after? Does it mean anything in the bigger picture, you know, the transplant will fail or anything? I don't know.

Trent Wang MD:   So, that's a good question. Actually, chronic GVHD tells us that there's less likelihood that transplant relapse will happen post-transplant, but in the setting of persistent diarrhea and cramping I think you need to do the full work up. You need to make sure that it's not from another cause. To call it GVHD a lot of times is after we've ruled out the other things. I don't know if you're on immune suppression or the medications and all of these things, but it's very complicated. I think over time it will get better. That's what we hope will happen.

Audience:  Over time do you mean a seven-year timeframe that you were talking about?

Trent Wang MD: I mean time as in years, rather than months. Yeah.

47:47  Audience story about problems with tapering off steroids:  Okay. No problem. Actually, mine is more of a comment. I had a transplant in, well, it was nine years ago in Chicago, and they were of the mindset that I could stay on prednisone, like a low level of like four milligrams a day, for the rest of my life. Then I subsequently moved to Michigan and am being monitored at U of M's transplant center. They're of the belief that you should get off of prednisone. So, believe it or not, it's been two years trying to get me just off of four milligrams a day, and as I was decreasing ... I wanted to respond to your comment about the diarrhea. Oh, my goodness. Even half a milligram difference, I could feel it in my gut. It's just horrible.

For me it seemed like the more my body would get used to a lower dose, then it would improve, but it's very frustrating. It's very frustrating. I just wanted to share that. It was to the point that they actually doubled my prednisone, and then I was taking it every other day, and so now I'm finally down to one milligram every other day, but it's a long process. But it does, at least in my experience, it has improved, so there's hope.

Trent Wang MD:   Thank you.

49:17  Question about how to lower liver enzymes:  Oh. Sorry. I just wanted to find out, for the last two years my liver enzymes have been high and elevated. They don't seem to be coming down. My GVH just recently came back, so I hadn't been on any medications that would cause them to stay high. Is there anything that I can do to bring them down with food, or is it just going to be a medication?

Trent Wang MD:   I'm sorry. Are you on immune suppression?

Audience:  I just started on the first.

Trent Wang MD:   Is it the AST/ALT or is it the bilirubin, if you remember?

Audience:  I'm not sure.

Trent Wang MD: Sometimes the ursodiol, if it's just a little bit of LFT elevation without too much else, ursodiol can be a useful drug here. But it sounds like you started therapy, and hopefully that will take a little bit more time to come down. Over long periods of time we just don't want the liver to keep taking gradual insult, depending on how high the enzymes are. So, eventually it can cause problems if it's unaddressed.