Diverticulitis explained; lupus and the liver; COVID's impact on stroke: Upstate Medical University's HealthLink on Air for Sunday, Feb. 19, 2023
Colon and rectal surgeon Kristina Go, MD, discusses diverticulitis. Akshay Patel, an MD/PhD student, shares what he's learned about lupus and the liver. And neurology resident Navreet Kaur, MD, tells about the impact COVID-19 has on stroke.
Host Amber Smith: Coming up next on Upstate's "HealthLink on Air," a colorectal surgeon explains how diverticulitis can be treated and symptoms to watch for.
Kristina Go, MD: ... Patients who have lower abdominal pain, particularly in the left side of their abdomen or belly, associated with fevers and chills, make me more suspicious that they might be having a diverticulitis attack. ...
Host Amber Smith: A researcher shares what he's learned about how lupus affects the liver.
Akshay Patel: ... We're seeing an increase in fatty acids in these livers, which is also a marker of liver inflammation. ...
Host Amber Smith: And we'll hear why stroke patients with COVID had worse outcomes than those who were COVID-free.
Navreet Kaur, MD: ... It leads to damage to the vessels in the brain, can cause inflammation that leads to formation of more clots. And that leads to stroke. ...
Host Amber Smith: All that, and a visit from The Healing Muse, after the news.
This is Upstate Medical University's "HealthLink on Air," your chance to explore health, science and medicine with the experts from Central New York's only academic medical center. I'm your host, Amber Smith.
On this week's show, we'll learn how the liver is affected by lupus. Then we'll explore how COVID impacts strokes. But first, what symptoms might mean you have a case of diverticulitis, and what can you do about it?
From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air."
Diverticulitis becomes more of a problem for people over age 40. And today we'll learn about ways to reduce that risk with Dr. Kristina Go. She's a surgeon at Upstate who specializes in colon and rectal surgery.
Welcome back to "HealthLink on Air," Dr. Go.
Kristina Go, MD: Hi. Nice to see you again.
Host Amber Smith: Let's start by going over the signs and symptoms. How would a person know that they have diverticulitis?
Kristina Go, MD: That really depends on the severity of their symptoms. But generally speaking, patients who have lower abdominal pain, particularly in the left side of their abdomen or belly, associated with fevers and chills, make me more suspicious that they might be having a diverticulitis attack.
Host Amber Smith: What is on the left side? Why would it be on the left more so than the right?
Kristina Go, MD: In the Western world, the most common site of colonic diverticulitis, as in diverticulitis within your large intestine or colon, tends to be in the last part of the colon, called the sigmoid colon, and that tends to be on the patient's lower left side.
Host Amber Smith: So what are the things a doctor might do for someone who's got abdominal pain on the left side to determine if it's diverticulitis or if it's something else?
Kristina Go, MD: The first things that I would approach the patient with, are if they're very sick and look ill, or if they seem to be having pain that is manageable. Barring them looking very sick and ill, really, the way that I would start to approach this patient is asking them a little bit more about when they started to have these symptoms, anything they've tried to make it feel better or worse, basically getting a good history and then, after that, a physical exam to further find out whether this is diverticulitis or something else.
Host Amber Smith: Now I've heard of diverticulosis. Is that the same thing as diverticulitis?
Kristina Go, MD: This is an excellent question because they sound very similar, and they are related to each other, so let's go through a couple of definitions to tease out why you might hear one term, and a physician might use a different one.
Diverticulosis is actually just outpouchings or thinning areas of, in this case, the colon wall, that can occur in a patient's body. So when you are told, say by your gastroenterologist or by another type of doctor, that you have diverticulosis, that's just the presence of this anatomical outpouching.
When inflammation or microperforation, as in something that you might not see by the human eye, or even a visible perforation occurs, that's essentially what diverticulitis is. So it's that inflammation and infection of the colon that can occur when you already have diverticulosis.
Host Amber Smith: Now, do primary care providers generally treat patients with diverticulitis, or at what point might they send someone to a colon and rectal surgeon like yourself?
Kristina Go, MD: A lot of the times, the way that I think about a patient with diverticulitis goes back to the severity of their disease, so perhaps with a patient's first episode of diverticulitis, particularly if it is not very severe, this can be treated by a primary care physician with antibiotics.
Ultimately patients that come to me for further workup might be seeing me because they need a colonoscopy after their diverticulitis episode, or they might be talking about surgery, and we can go into different reasons why a patient would need surgery, either in an elective -- what I mean by elective is a scheduled manner -- or in an emergency manner.
Host Amber Smith: How do you differentiate between a mild case and a more severe case?
Kristina Go, MD: We do have several ways that we approach how diverticulitis presents in a patient. We can talk about mild and severe, but I'd like to take a step back and actually use two different terms.
So, what I say is uncomplicated diverticulitis means that you might see inflammation of the colon that doesn't show a free hole in it, which you might see on either CT scan or based on a patient's physical exam findings. And often that can solely be treated with antibiotics, and the patient gets better and doesn't necessarily need a surgery in the future.
Now, complicated diverticulitis really has a whole host of things that we are looking for in a whole host of categories. So that can mean that a patient might have had a hole in their colon, but the body has been able to wall it off, and instead of having poop or pus sort of free-floating in the the abdomen, you have a pus pocket or an abscess that can be treated. That could also mean a free perforation, like I just said, where unfortunately that's an emergency surgery where somebody might need to be brought to the OR (operating room) within hours of me seeing them.
And then there might be some long-term complications to cause complicated diverticulitis. And that might mean that the colon, while trying to heal in the past, might be narrowed or completely blocked or can cause an abnormal connection to other surrounding parts in the body. That abnormal connection is called a fistula, and so those patients might say, "You know, I notice either passing air or feces in my urine or having recurrent UTIs (urinary tract infections) because their colon and bladder are now abnormally connected to each other. Or in biologically female patients, they might notice a lot of gas or stool coming from their vaginal canal. That would be called a colovaginal fistula. So, we're talking about complicated versus uncomplicated.
When I think about severe, I also think about that whole free perforation where somebody's coming in with, what I would determine is sepsis, and they have very severe abdominal pain. They might have a high temperature and a high heart rate, but a low blood pressure. And when we try to press on their belly, they're so exquisitely tender and in pain that they cannot even withstand being bumped or being jostled a little bit.
Host Amber Smith: This is Upstate's "HealthLink on Air," with your host, Amber Smith. I'm talking with Dr. Kristina Go. She's a surgeon at Upstate who specializes in colon and rectal surgery, and we're talking about diverticulitis.
Do we know what makes one person more susceptible than another to diverticulitis?
Kristina Go, MD: Unfortunately, we really don't. The studies tend to say, "Oh, well what risk factors can we associate with patients that have diverticulitis?" So rather than finding a cause of it, we've noticed that patients who adhere to more of a red meat, or a Western, diet, which really is defined by probably low fruits and vegetables and low fiber, patients who have low physical activity, are considered obese or have a high waist-to-hip ratio. Those characteristics are more associated with having an episode of diverticulitis.
Other things that have been associated with diverticulitis include tobacco use, chronically using an over-the-counter pain medication called nonsteroidal anti-inflammatory drugs, or NSAIDs -- so that includes your Aleves, your ibuprofens -- if you have to use steroids on a long-term basis or even opioids.
As with everything, there seems to be a genetic component because it seems that if you have a sibling who's had diverticulitis, you're more likely to also have diverticulitis. That's hard for me to say because at least when you're siblings, it's pretty likely you have the same environment growing up, so that's very unclear right now, what makes somebody more susceptible.
Host Amber Smith: For someone who has a mild case of diverticulitis, is this something that can be cured, or is it something that they're going to live with, and it'll recur?
Kristina Go, MD: Unfortunately, in the absence of taking out the piece of colon that is susceptible to diverticulitis or has had diverticulitis in the past, there is a high likelihood that you're going to get diverticulitis again.
And with each subsequent episode, the likelihood of you getting another episode goes higher and higher. Now, that doesn't necessarily mean that you're going to have this very severe case with each episode, though. What we have seen is that when you have that free perforation, where poop or pus are free-floating in your belly and need that emergency surgery, that scenario more likely happens on a patient's first episode of diverticulitis.
It's not to say it can happen in a subsequent episode. It's just what we've seen in terms of patterns. But you could have that mild, uncomplicated diverticulitis and be treated with antibiotics or changes in diet during that episode and avoid surgery. That is really what we would consider a soft indication to take out the colon.
Host Amber Smith: So I was going to ask what surgery would involve?
Kristina Go, MD: If I'm seeing a patient who either has had complicated diverticulitis, or they've had simple but recurrent diverticulitis that has now become lifestyle-limiting, the workup would include making sure they have an up-to-date colonoscopy to make sure that this is truly diverticulitis, to make sure that other parts of their colon don't have colon cancer that we need to be thinking about.
And then I counsel the patient about taking out the portion of the colon that has been previously affected, and in the Western world, that is more likely to be that sigmoid colon, or the very last part of the colon.
Host Amber Smith: So when you take out that part, you, I guess, have to sew the two ends together.
Kristina Go, MD: Yeah, that's correct. Absolutely. So, in an elective setting, as in something where we've planned it out, and it's scheduled, I will take out the portion of the colon that is affected, and then the remaining colon is basically placed from point A to point B together, and that reconnection site is called an anastomosis.
Host Amber Smith: And so you sew it back in place; does the tissue grow back together so that it's secure and there's no leaking?
Kristina Go, MD: That's correct. And, of course, with every type of intervention that we do, there is a risk of complications, so when I talk to patients about surgery for the colon, either in the setting of diverticulitis or otherwise, I do tell them that there is a risk of a leak at the reconnection site. For scenarios of diverticulitis and taking out the sigmoid colon, I usually quote them a 5% to 7% chance of anastomotic leak.
Host Amber Smith: And let me ask you about colostomy. Is that something that is a necessity for these patients?
Kristina Go, MD: That really depends on the scenario in which I would be offering a patient an ostomy.
So let's take a step back in terms of the term ostomy.
Ostomy really means making a hole in a hollow organ, so listening to the prefix when you hear terms like urostomy, gastrostomy, colostomy or ileostomy gives you a clue to what part of the anatomy this hole is being made into.
For example, when I use the term colostomy, and I'm making a colostomy, what I'm doing is making an incision through the abdominal wall and feeding a portion of the colon, or large intestine, through that, such that the patient will have poop going through that and being captured in a bag.
Whereas if I'm using the term ileostomy, what I'm saying is that I'm making a hole within the terminal ileum -- that's the last part of your small intestine -- bringing it again through that incision I made in the abdominal wall. And that's really where the portion of bowel that's capturing the poop is being created.
You might be asking, well, what are the scenarios in which I would be making a colostomy in the setting of diverticulitis?
Usually the clinical setting that I would be considering a colostomy is in that patient who comes in very, very sick and septic and needs emergency surgery. And in that case, there might be too much inflammation or other injury to the colon that might make it unsafe for me to be able to place point A and point B together after taking out the area of the colon that has been affected. Another scenario in which we might be considering an ostomy is in an elective setting where I might place point A and point B together, I might see that there's a leak that I need to fix while still in that OR and fix it. But to protect that new connection, because it's at a higher risk of leaking than that 5% to 7% that I quoted, I might protect it by bringing up a loop of the small intestine to basically divert the poop from going through that new reconnection site and avoid that whole septic or abdominal infectious picture.
And if I'm using the small intestine, it's most likely the last part of the small intestine, called the ileum. And so that's why you might hear a colorectal surgeon or a surgeon use the term ileostomy in that setting.
Host Amber Smith: Are those sometimes temporary?
Kristina Go, MD: They tend to be temporary. A lot of the times, if you're having a colostomy because of that emergency surgery, they're a little bit more difficult to put back together, but certainly possible. In the setting of an ileostomy, they tend to be a little bit easier for us to put back together because No. 1, it's planned, and we're bringing up both the upstream and downstream ends, so it's easier for us to find. A lot of the studies, whenever you ask general surgeons and colorectal surgeons how often are ostomies reversed has a lot to do with a surgeon's practice pattern and how comfortable they are in putting them back together.
They tend to more likely be put back together if a patient is then referred to a colorectal surgeon, but general surgeons also know how to do this and are very well versed in it as well.
Host Amber Smith: In terms of prevention, I know you're going to tell us that drinking adequate water and eating a high-fiber diet are important, but getting more specific, how much water does a person need?
Kristina Go, MD: It really depends on the patient, but what I tell patients is, trying to get at least 64 ounces of fluid in every day and taking in at least 30 grams of dietary fiber can help the colon be healthier. Other things that can help in preventing diverticulitis are just really what you hear from many different doctors in terms of your overall state of health. So a high-fruit and -vegetable diet, regular exercise, avoiding smoking -- those are the main things that we've seen are associated with less episodes of diverticulitis.
Host Amber Smith: Now, some people, it's a challenge to get enough fiber. Do the supplements help that you can get over the counter at the pharmacy?
Kristina Go, MD: Absolutely. What I do recommend, and I think everybody I know does it as well, is look at your powdered fiber supplements: your Metamucils, your Benefibers, your Konsyls. The generic terms would be psyllium husk powders, sometimes wheat dextrins. In our current diet, and I am also guilty of this, I'm probably not getting 30 grams of dietary fiber, even if I try very hard to eat a salad and only stick to bran, so I take a tablespoon of one of those types of supplements in the morning with my coffee to help me reach that 30-gram goal.
Host Amber Smith: Before we wrap up, let me ask you about nuts and seeds. Are those forbidden to be eaten by people that are prone to diverticulitis?
Kristina Go, MD: So, not necessarily. The best research that we have seen, it's not very good quality research, but what we've asked of a whole population of patients is to keep a food diary and basically see what they most likely eat and then correlate it with how often these patients are getting diverticulitis.
Now remember, an association doesn't mean causation, so it seems like the patients who more regularly ate popcorn or nuts or seeds seems to have less episodes of diverticulitis. And that could be for all sorts of reasons.
Eating nuts, seeds and popcorn are healthier foods, and so they might just have a healthier lifestyle to begin with. Whereas I do have patients who do tell me, "You know, when I eat this, I notice that I get another episode of diverticulitis." So the science is not robust, and therefore, my advice to them is not particularly sophisticated.
Really, what you want to make sure of and make note of is what are these foods that are triggering you? And if you notice that it is a trigger, avoid them. Otherwise, you don't necessarily need to avoid nuts and seeds for the rest of your life if you notice that that hasn't had any correlation to your episodes of diverticulitis.
Host Amber Smith: Dr. Go, thank you so much for your time. I appreciate it.
Kristina Go, MD: Oh, you're very welcome. Thank you. Have a good day.
Host Amber Smith: My guest has been Dr. Kristina Go. She's a surgeon at Upstate specializing in colon and rectal surgery. I'm Amber Smith for Upstate's "HealthLink on Air."
A researcher takes us into the lab where he's studying lupus --next on Upstate's "HealthLink on Air."
From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air." The National Institutes of Health awarded a grant to an MD/PhD student at Upstate who's researching lupus. Here with me to explain his work is Akshay Patel, who works in the lab of Dr. Andras Perl. Welcome to "HealthLink on Air," Mr. Patel.
Akshay Patel: Thanks for having me.
Host Amber Smith: People may have heard of lupus without knowing exactly what it is. Can you give us a bit of a summary?
Akshay Patel: Sure. So, lupus is an autoimmune disease. It's a shortened form of a much bigger kind of word: systemic lupus erythematosus. That's kind of what I study. Lupus is a broader term.
It's an autoimmune disease. So think of, say you get a cut, like a paper cut or something, And maybe some bacteria or some debris find its way into that cut. This could be devastating for your body. Those bacteria or those pathogens that get in there could cause an infection. Your body has a system, and it's kind of built in, in order to protect you from that happening. And it's the immune system. The immune system comes in, and it is able to clear out the bacteria or the debris or the pathogens. And sometimes the immune system is defective. Sometimes it doesn't work. And sometimes it actually is directed toward the wrong stuff. And in an autoimmune disease, your immune system, which is supposed to protect you from foreign invaders, so to speak, actually ends up attacking you. It attacks yourself.
And that's kind of the basis of what underlies lupus, where the immune system attacks the body. It attacks a variety of different organ systems like the kidney, the heart, the lungs, and, of course, the liver, which is what I study.
Host Amber Smith: Do we know yet what causes lupus?
Akshay Patel: There are a lot of different factors that come into play. Say you have a staph infection, well, it's staph, so you just affect staph, and you don't have the infection anymore. But it's considerably more complicated with lupus. It's multisystemic, multiple different organ systems. And so there are a variety of different factors that come into play to kind of cause lupus. We can think of genetic factors, environmental factors, even hormonal factors. Estrogen is extremely important in the pathogenesis of lupus. Even things like epigenetics, where not only is it the DNA code, but how the DNA itself is modified. All of these things can come together to kind of cause a dysfunction in the immune system.
We'll see an increase in antibodies, which are these proteins that the immune system generates to fight off an infection or to cause -- promote -- an immune response. We'll see a dysfunction in T-cells, which is really where my focus is. T-cells are a particular subset of immune cells, which when they're dysfunctional, can cause an autoimmune attack. As well as we can see the deposition of these things called immune complexes, where those antibodies that I talked about earlier can congregate together, and then that can also cause or facilitate an immune response or immune attack. All of these things come together to then, like I said, kind of attack different organ systems.
Host Amber Smith: This is Upstate's "HealthLink on Air" with your host, Amber Smith. I'm talking with Akshay Patel. He's an MD/PhD student working in the lab of Dr. Andras Perl at Upstate, and we're talking about his research into lupus.
So how did you decide to focus on the impact lupus has on the liver?
Akshay Patel: I kind of fell into it.
Funny story, I guess. I kind of have a mouse phobia. I'm afraid of mice. So, graduate students in the lab typically would go down to the mouse colony and get samples. Typically, it's urine. So lupus affects the kidney. That's a major organ that's affected in lupus, and we're able to actually track renal involvement of lupus by measuring the amount of protein that's in their urine.
But I'm afraid of mice and have a phobia. So I used to find ways to not go down to the mouse colony, and I think Dr. Perl picked up on that. So he said, "Look, you don't have to go down there. There are these histology slides of mouse livers. Take a look at them to see if there's anything interesting." I took a look at them, and I saw that lupus livers had inflammation in them, more so than the non-lupus livers.
The enzyme that I work on, this rab4a enzyme, was linked to the amount of inflammation that was in their livers. And so I quantified it, and then we repeated the experiments, and it was pretty consistent. And that's kind of how I fell into it.
What's also interesting is that, we talked about all of these other manifestations. The skin manifestations, 80% to 90% of lupus patients have some sort of skin manifestation. Renal manifestation, 50 plus percent of lupus patients have some sort of renal involvement. When I started my PhD, we knew that only about 20% of lupus patients had some sort of liver involvement. And I say "only." You know, I don't want to discount the patient's experience, but we have to keep in mind that if we compare it to other manifestations, the liver is very understudied. Now we've learned that the involvement of the liver could be upwards of 30% to 40% of lupus patients. But back then it was understudied. And it was very interesting that this enzyme that we studied was kind of controlling the amount of inflammation that was in lupus livers.
Host Amber Smith: Can you, before we get into this a little bit more, can you review for us what role the liver has in our body? What is it responsible for?
Akshay Patel: Sure. So imagine, you're eating. And imagine your gut is like a tube. So you eat, and your food goes down into your mouth, from your mouth into the esophagus, and the stomach, duodenum, jejunum, ileum, goes into the large intestine. And as this is happening, your intestines are kind of absorbing the nutrients that are in your food. But it doesn't go directly into the blood. There's like a net that catches the nutrients before it goes into the blood. That net is your liver.
So you've got the structure called the portal vein that feeds into the liver nutrients and kind of the foodstuffs and particulates that are essentially being metabolized and digested. And the liver metabolizes all of this stuff, so to speak, and it processes it for your body to use. Drugs, for example, are metabolized by the liver.
And then, if you need sugar all of a sudden, then your liver metabolizes glycogen, breaks it down to create glucose, so your body can use it when you need energy. If you eat too much sugar, the liver then turns it into glycogen, so you can store it for later on. So it does a lot of this metabolism, kind of the heart of metabolism is the liver. It's also my favorite organ. Every time I read about it or look into it, I learn something new about it, all the time. It's important for fatty acid synthesis, fatty acid metabolism. It does a lot of really cool metabolic things.
Host Amber Smith: So where do the enzymes come in?
Akshay Patel: Enzymes, I guess broadly speaking, enzymes kind of facilitate reactions from happening, right?
They use energy to facilitate a reaction from happening, converting some metabolite or some chemical into something else.
The liver is full of such enzymes.
Host Amber Smith: And you mentioned the enzyme that you're studying -- rab4a. Do you know yet why it increases in patients with lupus?
Akshay Patel: Right. So rab4a, we have kind of focused on studying that in T-cells. So lupus is primarily a T-cell driven disease. And probably 10, 15 years ago, our lab, -- I mean, I was in like sixth grade or something at this time, so I wasn't necessarily involved in this -- but other members of the lab previously found that this rab4a is increased in the T-cells of lupus patients. It's downstream of the signaling kind of cascade known as the mTOR cascade. So, mTOR is short for the mechanistic target of a rapamycin, kind of the central hub that senses amino acids and nutrients and metabolites inside of a cell.
And typically it's increased in states of inflammation, increased in states of autoimmunity, really because downstream what it does is it causes cell growth, cell expansion. And we don't want these autoimmune cells to grow and expand. We want them to stop expanding. So you can use something called rapamycin to inhibit mTOR, which then is able to essentially dampen the immune response, and it can control a lupus flare.
But rab4 is one of those things that was downstream of mTOR. The lab has been studying that quite some time now, and it's really, for the purposes of my experiments, it's important for two things. One, it's important for regulating mitophagy. Mitophagy is this process where mitochondria that are dysfunctional turn over. Because you don't want dysfunctional mitochondria that can produce oxidative stress, which we're finding is a trigger of lupus pathogenesis. So what you want is the mitochondria to turn over. You don't want the bad mitochondria staying in there. What rab4 does is it decreases mitophagy. So when you have more rab4, you have less mitophagy. When you have less mitophagy, you have more dysfunctional mitochondria, which then leads to more oxidative stress. So it's kind of one arm of the whole rab4 story.
The other arm of the rab4 story is that it's an enzyme that's responsible for this thing called trafficking, where things are moved from one area of the cell to another area of the cell. And one such protein that is responsible for shuttling around the cell is this thing called CD4, which is on the surface of T-cells. It actually has the ability to bring CD4 from the surface to the T-cell and move it inside and target it for degradation into the lysosome, which inhibits its ability to actually work as an effective T-cell.
So this kind of has these two battling roles, one where it's responsible for promoting oxidative stress. Another one where it's responsible for kind of messing with the immune response.
Host Amber Smith: So, let me ask you this. This rab4a enzyme, if you were able to remove that, would that reduce lupus from developing?
Akshay Patel: That's a great question. That is kind of what we're seeing in mice. So we have this mouse model of lupus called SLE123. It's got three major mutations. SLE1 is a mutation on chromosome one. SLE2 a mutation on chromosome four. SLE3 is a mutation on chromosome seven. When all three of these things come together, you end up with mice that have kind of a critical outcome that is almost exactly like human lupus.
They have auto antibody production. They have renal dysfunction, renal involvement. And we created these mice to have two major genetic changes -- one where rab4a was constitutively activated, which kind of mimics human lupus, where human patients have overactive rab4a, and they have a lot of it.
Then we have this other mouse where we deleted rab4a in T-cells. So rab4a is up in T-cells, causes disease. So we hypothesized rab4a, deleted in T-cells, is going to rescue. It's not going to cause a disease. And for the major things that we look at, the major clinical outcomes that seemed to hold true. They have less autoantibodies, they have less protein in the urine. We call that proteinuria. It's a readout of renal involvement. And when we look at the kidney histology itself, we're seeing that the kidneys don't have as much damage. So I came into this thinking, "Hey, look, the livers are probably protected too."
And kind of that's where things got really wonky because we saw the exact opposite.
Over and over again, we saw that when we deleted rab4a from T-cells, they not only have more liver inflammation, this liver inflammation is marked by T and B cells, which are kind of the hallmark immune cells that are kind of dysfunctional in lupus, and we're seeing an increase in fatty acids in these livers, which is also a marker of liver inflammation. So that was really interesting. Very unexpected. And it was very difficult for us to try to explain it, but we have some ideas.
Host Amber Smith: That's interesting. And going forward, using the grant that you received, are you going to be doing more research that involves the rab4a enzyme?
Akshay Patel: Yeah, absolutely. So, my grant funding was for two years. It's for my final year of my PhD, which is now, and my third year of medical school. So I'm kind of winding down on my experiments. Since I got the grant, we've made quite a bit of progress to kind of explain what's happening.
One is the metabolic side of things. We're seeing fatty liver. And we're seeing that this is downstream of mTOR. We're seeing a very specific protein being increased called SREbp1. It's a sterol regulatory element-binding protein 1, I think is what it stands for. And really it's responsible for fatty acid synthesis. So remember, I said there was more liver inflammation. There was also more fatty acids in these livers. And we're seeing a very specific protein that causes fatty acid accumulation that's building up in the livers of these mice where we deleted rab4a from their T-cells.
And what's interesting is that their fat kind of goes away. This protein that causes fatty acid buildup, it goes away when we treat these mice with rapamycin, which is kind of the hallmark treatment of lupus in humans, is rapamycin. And so it's very interesting to see that what we're seeing in humans, we're able to see it again in mice. And the treatments that we use in humans and in our patients in the clinic also holds true in these mice, where they have this fatty acid buildup, and it's going away as a result of rapamycin.
Then there's also the immune side. Because remember, rab4a is deleted in T-cells, and what we're seeing is that when we delete rab4a in T-cells, there's a very particular cell type that not only is it contracted, so there's less of it. Also what we have is dysfunctional. And that's called the regulatory T-cell, which is kind of the anti-inflammatory immune cell of the body. So it's very weird, again, that we're seeing more of this liver inflammation. We're seeing more of this T-cell and B-cell infiltration into the livers of these mice. And we're seeing a defect in the anti-inflammatory arm of their immune system.
Because really, the immune response is, it's a delicate balance. It has to start off pro-inflammatory to fight off the invader. You can't keep having an immune response over and over again, because that's going to tire out the cells. You have to tell them to take it easy and take a chill pill. And regulatory T-cells do that. But we're finding that if we delete rab4a in T-cells, their regulatory T-cells, they don't have as many, and they don't work as well. The ones that are there don't work as well. So we've done functional studies on that, and I think the missing link between these two arms is soluble mediators of inflammation called cytokines.
Cytokines are like messenger packets where immune cells kind of interact with each other by sending each other notes, like in class. They're sending each other notes. These note packets are called cytokines. They are these proteins that flow in the blood or in the serum, and they bind to receptors on different types of cells to kind of mediate damage. And so that's kind of one area of exploration that I'm currently interested in. And I think we're making some progress there.
Host Amber Smith: It sounds like it. And it sounds like there's a lot to keep you busy working on, too. Thank you so much, Mr. Patel, for taking time to explain this to us.
Akshay Patel: I'm happy to talk about my research. Thanks for having me.
Host Amber Smith: My guest has been Akshay Patel. He's an MD/PhD student working in the lab of Upstate's Dr. Andras Perl. I'm Amber Smith for Upstate's "HealthLink on Air."
Next on Upstate's "HealthLink on Air" -- the impact COVID has on strokes.
From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air."
People who had strokes during the pandemic, and who were also found to be infected with COVID, had worse outcomes than those who were COVID-free, according to research in the journal Neurology. I'll be talking about the possible reasons for this with Dr. Navreet Kaur, who's completing her fourth year of residency in neurology at Upstate. Welcome to "HealthLink on Air," Dr. Kaur.
Navreet Kaur, MD: Good morning.
Host Amber Smith: The paper published in the journal Neurology references the global COVID-19 Stroke Registry. What is that?
Navreet Kaur, MD: The global registry is basically a database, which is IRB (Institutional Review Board) approved research where data is collected and coordinated at a specific site. So this site is affiliated with a center in Switzerland, and they did a couple of studies during the COVID time to obtain this data and research how the things were in the stroke world before pandemic and during pandemic.
Host Amber Smith: So how many institutions across the world are part of the registry? And I'm assuming Upstate is one of them, right?
Navreet Kaur, MD: Yes, Upstate is one of them. So this particular study that we are talking about today involved 105 centers, from roughly 20-plus countries in the world. And then we got the approval from IRB before collecting the data and sending it to the coordinating site.
Host Amber Smith: Now this is a retrospective study, meaning researchers looked back at a group of patients after they received care. What time period did this cover?
Navreet Kaur, MD: This covered the time period from March 2020, which was beginning of the pandemic, till June 2021. So these were the initial time period where everything was new with regards to COVID and stroke care. So these time periods were covered among all the 105 centers from where data was collected.
Host Amber Smith: And which types of patients were included?
Navreet Kaur, MD: All the patients who had acute stroke concerns on admission, which we usually triage with one-sided weakness, numbness, speech trouble, vision trouble. So all those patients that had these symptoms within 24 hours of onset, and then they arrived in the hospital during that time, were screened and were given care based on the criteria they meet with two different therapies.
Host Amber Smith: What are the two different therapies?
Navreet Kaur, MD: One therapy is an intravenous injection. We call it clot-busting medication. That is given within four and a half hours of symptom onset. And another therapy is endovascular therapy, where doctors go all the way into the brain to take out the clot that is blocking large vessels in the brain, causing the stroke symptoms.
Host Amber Smith: Now before we get into the results or the findings, can you give us some background? Do doctors think there's a connection between COVID-19 and stroke?
Navreet Kaur, MD: Yes. I think COVID-19, the general decision is that it affects the lungs the first, that you'll get runny nose, fever, sore throat. But in fact, it does infect the multisystem organs, so it'll have effect on all the organs, primarily brain. It leads to damage to the vessels in the brain, can cause inflammation that leads to formation of more clots. And that leads to stroke. So there is a direct connection.
Host Amber Smith: So this inflammation affects the whole body, not just the lungs, certainly, and not just the neurological?
Navreet Kaur, MD: Yes. So there are different ways that COVID can affect us, so one being that it damages the vessels in the brain. We call it quote-unquote, "endothelial dysfunction." So our brain has small vessels that have the lining with the cells, and when we have any infections, be it COVID or anything else, it affects those vessels.
We discovered that COVID affected us more. It directly damages those blood vessels, and people far more clots that lead to stroke. Another thing being that it can lead to coagulopathy. That prompts us to make more strokes.
Host Amber Smith: And are those conditions that stay with a person forever after they've had COVID?
Navreet Kaur, MD: It is really hard to comment on that, but we do know that short-term effects are there, that predisposes patients to have more strokes. So when we say coagulopathy, just to describe it in a simple way, people will have a problem where they will form clot or break down clots. So both the things are affected. They will form more clots, and then those clots will break up more, and they will go to the other parts of the body affecting us. In stroke, we say that the clots can break into small fragments, go with the blood flow to the brain, causing more strokes.
So that's kind of a cycle of more stroke clots, and then them breaking, giving more strokes.
Host Amber Smith: This is Upstate's "HealthLink on Air" with your host, Amber Smith. I'm talking with Dr. Navreet Kaur about an interesting global study she was involved in that looked at patients who had strokes during the pandemic and compared the outcomes between those who tested positive for COVID and those who were found to be COVID-free.
Now the global COVID-19 stroke registry included more than 15,000 patients from 105 centers. What percentage were found to have COVID-19?
Navreet Kaur, MD: Roughly 5.6% of the patients, a total of 853 patients in the study, were COVID-positive at the time of stroke.
Host Amber Smith: For the treatment, what percent of those got clot-busting medication, and what percent underwent the endovascular procedure you described?
Navreet Kaur, MD: Roughly 38% of the people got the IV medication that we were talking about, the clot-busting medication. And about 61% of the people got the endovascular therapy, where we go all the way up in the brain to take the clot out.
Host Amber Smith: So looking at those with COVID-19, how did their outcomes compare with those who did not have COVID-19?
Navreet Kaur, MD: When we compared the patients with COVID positive and without COVID positive, we saw that the patient who had COVID during the time of the stroke had a worse outcome. So when we say in our stroke world, the worst outcome means their exam is worsening, like they are more weak, they're more numb. And we measure it with doing repeat scans of the brain.
So our threshold for doing a repeat scan is if their stroke scale is worse than more than four points of what was when they came in. So let's say they had a weakness, they had numbness, their stroke scale was 10. And then they got treated for the stroke, and now is 14. And then you see do a CAT scan, and there is a bleed. We say that that's significant. So these patients had more bleeds in the brain. They had poorer outcomes at 24 hours. And when we tracked them across the three-month period, they had worse outcomes as compared to people who were COVID-negative at the time of stroke.
Host Amber Smith: Can you explain or can you speculate why their outcomes were so much worse?
Navreet Kaur, MD: From what we think, is that the same thing we were talking about earlier. More clot formation, more inflammation, more damage. So we realized that these people who were getting treated for stroke had more stroke within the acute short period when they were in the hospital or followed through.
One certain thing was that the clots, they were very difficult to take out. Like we have seen that the patients who required the interventional endovascular therapy, they had more failed outcomes, which we measure with the perfusion, or the amount of blood they are taking back to the brain after we take the clot out. So they were not able to have that good blood supply and perfusion after the surgery, which tells us maybe these clots are different to take out as compared to normal.
Host Amber Smith: Now this study was from a time period before there was a vaccine available. Do you think the results would be different today if the patients testing positive for COVID had previously been vaccinated?
Navreet Kaur, MD: I think that would be very difficult to say as well because COVID has many variants, and some people get more inflammatory response as compared to others. So if we think in a way that patient who got vaccine, they're not that severely sick, perhaps they did not have that amount of damage or inflammation. So their symptoms and stroke symptoms were less severe. But we don't have any data or big study to prove that. So theoretically, maybe yes, they will have lesser stroke, but we need more research to conclude that point.
Host Amber Smith: Have the findings from this paper altered the way you treat patients with stroke who test positive for COVID-19?
Navreet Kaur, MD: We always do the same treatments for our patients, the intravenous therapy within four and a half hours and the endovascular therapy within 24 hours of the symptom onset.
The only thing we think that is a patient who had COVID, we have to be very vigilant that these patients have tendency to form more clots and have more strokes. So we do close monitoring for everyone. So we do them the same treatment. Although they did have worse outcomes in this study, still it's a standard of care and should be given to all the patients. So I think we are doing the things that we do with the known COVID patients as well, and we shall continue to do so until we have more data.
Host Amber Smith: Do you think any of the same concerns that apply to stroke patients who test positive might also apply to a stroke patient who survived COVID but has the lingering long COVID symptoms that we've heard about?
Navreet Kaur, MD: That is a great question. So, COVID, we know that within six months to a year -- and there have been studies to say that -- that people have more tendency to form more clots within first six months to a year of a COVID infection. So perhaps yes.
In this particular study, we did not include the patients who were positive more than seven days before they received this treatment. So we just included the acute patients. But if we think about the inflammatory response that COVID brings to patients' bodies, yes, there is a chance that they are hypercoagulable, which means they have more tendency to form clots within first few months, particularly three to six months of the infection. But again, we don't have any research to prove that.
Host Amber Smith: Dr. Kaur, thank you so much for making time for this interview.
Navreet Kaur, MD: Thank you so much for having me.
My guest has been Dr. Navreet Kaur, who's finishing a four year residency in neurology at Upstate. I'm Amber Smith for Upstate's "HealthLink on Air."
Host Amber Smith: And now, Deirdre Neilen, editor of Upstate Medical University's literary and visual arts journal, The Healing Muse, with this week's selection.
Deirdre Neilen, PhD: Winston Oliver is in his fourth year of medical school here at Upstate Medical University. His poem "Emergency Medicine" is a warning to residents and attendings that their words and actions are being studied closely by their trainees. In this poem, he asks, is this the lesson they wish to teach?
"Pod A" was my destination
if I had remembered correctly,
rummaging through papers
as I passed down a hallway
lit more dimly than the surgical wards.
I approached a short muscular man standing nearby
with a confidence gained by stylish pretense,
an aesthetic rebel among physicians
with a shapely beard and long hair tied back.
"Excuse me. ... I'm a medical student expected at Pod A this evening.
Is there someone here I should speak with?"
"I'm a student too!" He said with a smirk on his face.
"Oh ... yes?" I said as I waited for him to explain his demeanor.
"Nah haha you can wait over there. We're signing out now."
I side-stepped through a mass of physicians
toward a classmate trapped well within Pod A
and asked about the man at the front
so quick to affirm his status.
He turned out to be the overseeing physician --
the one running the department that evening.
He was the one who, even among peers,
almost always ought to be addressed formally as "doctor. "
Brian Smith is a second-year med student at Stanford. He overhears a patient talking and reflects that medicine does not have all the answers in his very short poem "Nihilism on the Wards."
At 2 am, walking out
of the ER, I overhear
a patient say, "I hope it's
a recurrence so that
I can start drinking again."
Who am I to judge?
After all, there's a certain
freedom in despair. If you're
already burnt, might as well
try to walk on coals.
Host Amber Smith: This has been Upstate's "HealthLink on Air," brought to you each week by Upstate Medical University in Syracuse, New York.
Next week on "HealthLink on Air," a new understanding in lung cancer treatment.
If you missed any of today's show, or for more information on a variety of health, science and medical topics, visit our website at HealthLinkonAir.org. Upstate's "HealthLink on Air" is produced by Jim Howe, with sound engineering by Bill Broeckel. This is your host, Amber Smith, thanking you for listening.