Connective Tissue Disorders and Lipedema with Karen Herbst, MD

[00:32] Dr. Linda Bluestein: Welcome back, every bendy body, to the Bendy Bodies Podcast with your host and founder, Dr. Linda Bluestein, the Hypermobility MD. Today we're going to be talking with Dr. Karen Herbst. I just have to tell you that Dr. Herbst was referred to recently by one of the world's authorities on mast cell activation syndrome as the world's foremost authority on inflammatory lipodystrophies. So I know you're going to be really excited to hear from her.
[00:57] Dr. Karen Herbst is at the forefront of unraveling the complexities of lipedema, Dercum's disease, and other diseases of adipose connective tissue, focusing not just on lymphatic and vascular comorbidities, but also on metabolic and hormonal factors, dysregulation of the immune system, and the genetics underlying chronic diseases, including hypermobility syndromes and mast cell activation disease. She notably led an NIH-sponsored conference in 2019 to establish the standard of care for lipedema in the United States.
[01:29] Dr. Herbst completed her PhD in cell physiology at the University of Iowa, her medical degree at Rush Medical College, and her residency and combined research and clinical fellowship in metabolism, endocrinology, and nutrition at the University of Washington, an innovative campus known for receiving more federal research dollars than any other US public university.
[01:51] I am so excited to chat with Dr. Herbst today because she has such an incredible background and expertise that will give us insights into the relationship between connective tissue, mast cells, and the immune system. As always, this information is for educational purposes only and is not a substitute for personalized medical advice. Be sure to stick around until the very end so you don't miss any of our special hypermobility hacks. Let's get going. Let's jump into this conversation with Dr. Herbst. I just can't wait to find out about lipedema. What is this exactly, and why is it so commonly misdiagnosed?

[02:22] Karen Herbst, MD: Lipedema is pretty complex. There's not a simple answer to that. I think I could just say that there is some obesity associated with lipedema, and it tends to get misdiagnosed as just regular non-lipedema obesity. And it's also because it sounds like lymphedema — which is why I'm saying "lipedema" to differentiate between the two — where lymphedema, swelling of the legs and possibly of the arms, it gets confused with that too.
[02:59] In a nutshell, lipedema is a disease of the subcutaneous fat tissue. On the outside of the body, it primarily affects the legs and the arms, but it can affect anywhere on the torso as well, just not as commonly. It is a very nodular, fibrotic tissue. And because of its fibrotic content — which results secondary to inflammation — whenever you have inflammation, it ends up resulting in fibrosis, it kind of tethers the tissue. So when it's pressed on, it's very tender. And there's probably also some component of a neuropathy in there as well.
[03:41] So it's increased tissue in the arms and legs, very nodular fibrotic tissue, tender tissue primarily in women, and it tends to start around the time of puberty, which is the time when fat is increasing, but also hormone levels are increasing. It can happen in pregnancy when fat is increasing and hormone levels are increasing, and then also in menopause where hormones tend to be decreasing, but testosterone is increasing and fat is increasing as well.

[04:08] Dr. Linda Bluestein: Okay. And how does that differ from Dercum's disease?

[04:11] Karen Herbst, MD: So Dercum's disease is on the spectrum of lipedema, and the reason I say that is because — I think it was 2016 — I worked with one of my students at the time who's now a doctor, Karen Beltran, and we went back through my charts and said, how many women have I seen with lipedema, how many with Dercum's disease, and what's the difference between the two? And we found that about 6.6% had both. So sometimes it's very difficult to differentiate between the two.
Dercum's disease is more of a grab bag of painful fat. So people who have, for example, multiple lipomas that are non-tender, it runs in their family — familial multiple lipomatosis — and they're fine until they develop some sort of inflammatory condition like obesity, or they undergo a surgery or a trauma, a very stressful event. Then their lipomas become very painful. So it's inflammation plus the multiple lipomas. Or it's somebody who perhaps has an underlying immune dysfunction, so they don't turn off their inflammation very well. They have a traumatic event, their inflammation goes up, they stay inflamed, and the fat tissue is basically where you can appreciate that there's inflammation in the body by feeling the nodules in the tissue.
Dercum's disease is very nodular. Often you get lipomas, you can get angiolipomas, and it often is combined with obesity. It affects more of the torso, whereas lipedema affects more of the legs and the arms. So that's kind of how we differentiate between the two. And also in Dercum's disease, they have more pain conditions like migraines and IBS with significant abdominal pain.

[06:01] Dr. Linda Bluestein: Okay, and of course, this is the Bendy Bodies Podcast, so we talk a lot about connective tissue disorders like hypermobile EDS and related conditions. What is the connection with lipedema and connective tissue and connective tissue disorders?

[06:16] Karen Herbst, MD: It's a great question, and it's one of my favorite things to think about. Fat tissue on the outside of the body is a connective tissue. It's often known as loose connective tissue, but it can also be known as areolar connective tissue. So now I'm at the point where I just call lipedema a connective tissue disease. The reason is because we think of fat as just being a bunch of fat cells, but that's not true. There's a lot of connective tissue in fat, including superficial connective tissue, deep connective tissue, and then all the fibers that make up the nodules, and even the connection between the fat and the skin.
[06:56] I know I was here in Arizona — I came here in about 2013 — and I was in clinic and these ladies were coming in and they were super bendy. And I was like, what do you have? So I started doing the Beighton score and Beighton criteria on my patients, and I started to realize that a lot of these ladies are bendy. Again, in that paper with Karen Beltran, we documented it and it was close to 60%. And then I've just re-documented it in another 100 patients and there's about 75% that are bendy.
[07:37] I think they can become bendy for different reasons. Genes — we're actually starting to look at the genes right now to see how many have mutations in, for example, TNXB or any of the collagens. And I think it can also be secondary to inflammation. I think they're associated because a lot of times when you have connective tissue mutations, you have a loss of elasticity. The tissue doesn't bounce back like a rubber band. And so fat grows and the body just doesn't have that pushback. Fat needs to be pushed because it responds to being pushed and it tends to either not grow or die off when it's pushed.
[08:28] That doesn't mean you can just put everyone in compression and there's your cure for lipedema — because there's so much fibrosis that you can no longer push it like you used to. But if it doesn't have that tension in the skin, it's just going to keep growing and growing, and then you can't lose it. And if you do lose it, you're going to have the sagging skin, just as if somebody who had obesity had bariatric surgery or liposuction.
[08:58] So they occur together. Does one cause the other? I don't know. It's the chicken and the egg. But because fat is a connective tissue, there is a connection between the two. It's just nobody's found it yet, and not a lot of other people are looking at it. We've published now three different papers where we state that about 60% of women have this, and then the latest — not yet published — shows 75%. Why aren't other people looking at it? I have a friend in Spain, and he says it's about 80% in his population.

[09:32] Dr. Linda Bluestein: Percentage of people with lipedema that appear to be on the hypermobility spectrum is what you're saying. Okay, I just want to make sure we understand that. That's really fascinating. Is it possible to have lipedema without obesity, or do they always come together?

[09:50] Karen Herbst, MD: Nope, they don't always come together. I think lipedema is kind of a mixed bag in terms of how you get to a point where we diagnose you with it. We have a lot of very small women who we diagnose as stage 1. Stage 1 means the skin is still really smooth, but you can feel all those little pebbles on the arms and legs. Stage 2, you get more dimpling and more fibrosis where the skin is actually being pulled down because the fibers are contracting. And then stage 3, you're actually forming lobules of skin and tissue.
[10:25] So it's those women with stage 1 that I think may have some other pathway to developing lipedema versus the much larger women who have obesity in stage 2 or stage 3. And it's probably linked to the immune system again.

[10:38] Dr. Linda Bluestein: And what's the difference between lipedema and cellulite, or the connection between them if there is one?

[10:47] Karen Herbst, MD: If you look in the German cellulite literature, or even in the Italian cellulite literature, they put it on the same spectrum. They're both fibrotic, but cellulite tends to occur in places like the buttocks, the posterior thighs, the lateral thighs, sometimes the anterior thighs — a lot of times in the posterior aspect of the body — whereas lipedema is kind of diffuse everywhere. So it's like cellulite on steroids.
[11:23] I don't think that a lot of people talk about lipedema in relation to cellulite because if we do that, insurance companies are going to think, oh, this is just cellulite and they're not going to cover treatment. So we kind of shy away from it, but there are definitely similarities. When I was first trying to understand lipedema, I was reading the cellulite literature.

[11:47] Dr. Linda Bluestein: And do people that have lipedema have other signs and symptoms that we should be aware of?

[11:49] Karen Herbst, MD: They do. They can have many, especially if they have mast cell activation disease or syndrome — then it's widespread. But common things that we tend to cite are easy bruising. The reason for that is part of their underlying pathophysiology is that they have leaky vessels. We showed that in a biopsy study, and then another group out of Austria showed it using a functional assay and AI. So there are at least two studies, there might be a third. That means these vessels are very weak, and that could be due to the connective tissue variation, some sort of mutation, or it could be due just to widespread inflammation. We don't know the difference right now — those studies are too early.
[12:52] There's also pain, as I mentioned. They tend to have pain either all the time or especially at the end of the day when their legs are starting to swell. Often with palpation — their cat walks across their lap and they feel that's painful. Their husband wants to put his arm around her and that's painful. And that's why they're actually seeking treatment, because that reduces their quality of life.
[13:18] And then I did mention swelling. They tend to have swelling by the end of the day. If they stand too long, walking in compression does help. If they sit too long, sometimes they can also get swelling. There is controversy about whether there is edema in lipedema. In the US, we think that there is, and actually we just finished a research study that I think will be very helpful in supporting that. In Germany, there's a group that absolutely denies there's edema in lipedema. So the battle goes on — but that's actually good because it makes you work harder to really prove when things are true.
[13:59] So easy bruising, pain, and swelling are the three most common things.

[14:06] Dr. Linda Bluestein: Now, when you're working up lipedema, what kind of things are you looking for? What kind of lab tests are you doing? What kind of studies are you doing?

[14:14] Karen Herbst, MD: Lipedema remains a clinical diagnosis, which is unfortunate. We don't have a biomarker. We don't have good imaging studies that can help us differentiate between lipedema and non-lipedema fat. There is some really interesting work coming out of Vanderbilt — Shelley Krasinski's work — where they've found increased tissue sodium in the tissue, much more so than in obesity. But that's not available for regular clinical diagnosis at this time.
[14:46] When I look at labs, the lipid panels tend to be awesome. The hemoglobin A1C or other indices of prediabetes or diabetes are completely normal. CBC is normal, a comprehensive metabolic panel is normal. Every once in a while I get a CH50 or CH100, which just looks at the whole complement pathway — that often is elevated. But I've done some intense work in the complement pathway itself through Cincinnati Children's Hospital, and there was really nothing consistent that I could find. So I kind of gave up on that.
[15:27] We do know that complement actually mediates the interaction between the macrophage and the adipocyte, so I'm sure that complement is involved somehow — we just don't understand more than that.
[16:10] So for labs, I like to get a CBC with differential, a comprehensive metabolic panel, a fasting insulin level and a hemoglobin A1C, and a lipid panel. The reason for that is metabolic disease often occurs concurrently with lipedema, and I want to try to get that metabolic disease under control because it is my opinion that insulin resistance and inflammation of any kind promotes the growth of lipedema. So I'm not looking for anything lipedema-specific in labs — I'm really looking for other diseases associated with it.
[16:18] I also ask them about allergies. That's a big deal. They say, I don't have any allergies to medication. I say, well, what are you allergic to? Anything in the environment or food? Oh yeah, I'm allergic to — and they start listing. And I think, okay, mast cell. Now I'm onto mast cell. And they often have a component of autonomic dysfunction when they have mast cell. On exam, you're bending them. I often send them to allergists. I like them to get tested for food because if they're eating something that they shouldn't, that's increasing their inflammation. But I usually don't do those labs myself — I really like them to do the patch testing or the prick test. So I wish I had something I could tell you that would be great for identifying lipedema, but we just don't have it yet.

[17:05] Dr. Linda Bluestein: Well, I was smiling when you were talking about complement because the kallikrein gene research out of the Norris lab just came out, and of course there's a connection to the complement system there too. And I'd love to ask — when you mentioned, I think you used the word "awesome" when you talked about the lipid panel — are you finding certain patterns with that?

[17:29] Karen Herbst, MD: Not really. We actually published a paper showing that as you increase in stage, but also increase in weight and BMI, the lipid panel does get a little off. The HDLs tend to decrease a little bit, the triglycerides increase a little bit, and the LDLs, I think, stay the same or increase a little bit too. It's not dramatic. And these women who have BMIs of 40 or higher don't have diabetes. So the subcutaneous adipose tissue is somewhat protective against prediabetes and diabetes.

[18:11] Dr. Linda Bluestein: Interesting. Okay, and in terms of autoimmune disease, what's the relationship between lipedema and autoimmune disease, if there is one?

[18:19] Karen Herbst, MD: I wish I knew. If I get an ANA, it's generally negative unless they have an associated disease. It's not due to the lipedema. So if they do have an autoimmune component, it's not going to show up as an ANA. There's probably something else going on that we just don't understand.

[18:40] Dr. Linda Bluestein: Okay. And does lipedema always progress, or does it sometimes just stay stable?

[18:49] Karen Herbst, MD: That's a great question. I'm laughing because that's also a point of contention. I think what often happens with lipedema is that there can be an increase in weight and BMI over time, but I think that's really due to inflammation rather than primarily due to lipedema. Because if you can do bariatric surgery or give them a GLP-1 agonist, you can get a lot of that weight off.
[19:15] A lot of women with lipedema are very smart. They know themselves very well. They're usually very careful — especially if they know they have lipedema — with what they eat and how they exercise. There are a lot of them that can just stay in the same stage. And if they do progress — say they're in stage 1 and they start looking like a stage 2 — they can just work a little bit harder on their diet, keep up their exercise, and get it to go back.
[19:57] Manual therapies are also helpful to maintain it, like manual lymphatic drainage — in some, not all. Deep tissue therapy to treat the fibrotic component seems to be very helpful, and that can help somebody stay in the same stage or the same place their whole life. So the answer is no, you do not need to progress. Can you progress? Yes, oftentimes due to the presence of inflammation from many sources.

[20:25] Dr. Linda Bluestein: Okay. And let's dig a little bit more specifically into what you were just saying about nutrition. I know you've published a lot of really great papers on the topic of treatment of lipedema and nutrition specifically. What are some of the things that you think are most important for people to do?

[20:43] Karen Herbst, MD: I would say the most important thing for nutrition in lipedema is to eat well. There are all sorts of different ways to eat. The ladies who seem to do the best are either on an anti-inflammatory plant-based diet — and these are very, very careful eaters, they don't stray off the diet, they love it, they're anti-inflammatory, and that works for them. Other eating plans that are very successful include the keto diet and variations thereof. Intermittent fasting is very helpful as well, and a lot of women combine keto with intermittent fasting.
[21:29] The only problem I have with keto is that more women go off the keto diet and regain weight than the women who are on the plant-based anti-inflammatory diet. I think that a lot of the women who choose the plant-based anti-inflammatory diet, that's how they like to eat, that's how they grew up eating, and they're very comfortable in that space. You can find the same thing with women who are on the ketogenic diet, but it just seems like so many come in and say, oh, that didn't work for me. And I say, well, why didn't the keto work for you? Well, Christmas came along and I had a few carbs, and then I went off. So I find it's a little bit harder to do keto, especially if nobody else in the family is doing keto at the same time.

[22:19] Dr. Linda Bluestein: Yeah, that definitely makes sense. And when you're talking about anti-inflammatory plant-based, what about fish? Would that play a role?

[22:28] Karen Herbst, MD: Absolutely. Pescatarian is in the same space. And sometimes people on anti-inflammatory diets eat meat as well. Maybe not beef very often because that has very saturated fats. I think fats are really important in lipedema because all membranes are made of fatty acids, and if you have a lot of omega-6 fatty acids, that stiffens up the fat cell membrane, which isn't good. So I like people to take in more omega-3 fatty acids, and I like to run an essential fatty acid profile to get a look at kind of where people are. Not perfect, but at least it's something.

[23:10] Dr. Linda Bluestein: Can you elaborate on the omega-6? A lot of people are probably familiar with omega-3 and know what some of those sources are, but could you give us some examples of where you would find a lot of omega-6 versus omega-3?

[23:25] Karen Herbst, MD: Well, vegetable oils that are not olive oil or coconut oil — I would say that's the main source. Soy oils, which are in everything, and other vegetable oils would be a big source of omega-6s. But let me say this, because this is really cool. I was at the International Lipedema Conference in Potsdam, Germany in October, and there was an investigator from Italy, Saverio Cinti, and he did a lecture on microscopy on lipedema fat cells.
He noticed three very important things. One, that there were a lot of large adipocytes in the tissue, and large adipocytes are known to be present in conditions such as obesity and diabetes. Often those large adipocytes become sick, hypoxic, and then they die off, and macrophages come in and eat them and form a circle around them — it looks like a crown. We call that a crown-like structure of macrophages. But you don't see that in lipedema. What he found was that the fat cells were big and they were fine. They had a coating of perilipin on the inside. And perilipin, if you have perilipin, that means you are an alive fat cell. A fat cell that is alive and doing well.
[25:05] So why do the fat cells in lipedema become really large but they don't die off like the fat cells in diabetes? That's one thing to think about. It may have something to do with it being a different kind of fat cell, or it may have something to do with the lipid composition of the fat cell. Interesting to look at further.
[25:27] He also found that a lot of the blood vessels — especially the endothelial cells — were dying. He said in his 45 years of doing electron microscopy, he had never in his life seen anything like it.
[25:48] And the third thing he found was a lot of calcification in the tissue, including around every fat cell. So lipedema tissue is not only fibrotic but also calcified. No wonder it's not very metabolically available to undergo lipolysis or to release its fat. We don't know where the calcium comes from. He's trying to get the paper published, and we'll know more about what he has to say there. I find that to be a fascinating link to what we're talking about with the omega-6s and omega-3s and those fat cells. I'm nerding out on it.

[26:38] Dr. Linda Bluestein: Yeah, for sure. And I wanted to come back to intermittent fasting. When people do this, are you talking about time-restricted eating, or actually going days without eating? Can you elaborate on what people are finding success with?

[26:57] Karen Herbst, MD: What I see in terms of fasting in women who are successful at it and who have lipedema is that either it's time-restricted — so they're not eating until like 10 in the morning or noon — but also some of them go on 3-day fasts. When they don't feel good and feel like they're in a flare, they will do a 3-day fast. As they go through the 3-day fast, they feel better and better and better. Then they go back to their eating plan. And often they combine that with time-restricted eating as well.

[27:33] Dr. Linda Bluestein: Now, when they're doing that 3-day fast, they're drinking water, I'm sure. What, if anything, is being consumed besides plain water?

[27:44] Karen Herbst, MD: Some of them drink bone broth, herbal teas — usually clear liquids, basically. But primarily they focus on water and non-sugared electrolyte mixes.

[28:02] Dr. Linda Bluestein: That's like a 3-day colonoscopy prep, I think.

[28:07] Karen Herbst, MD: Yeah, pretty much. But it really makes you wonder why they have to do that. What is it — they have a higher threshold for a signal that happens without lipedema overnight. So overnight we fast and maybe we turn on a signal, but they're not turning it on. It takes them 3 days to turn it on. And often they don't go into ketosis very quickly either. It can take like 48 hours to go into ketosis. So that third day seems to be relatively important. And it's not something I'm recommending for everybody.
[28:49] It's really — there's not a lot that do it, but the ones that do seem to be very successful and able to keep their weight down. So it's a very anti-inflammatory state they're putting themselves into. They must have inflammation going on, and when their inflammation levels rise too high and they can really feel it, that's when they do the fast and get that inflammation back down. It would be nice to know why their inflammation is going up.

[29:22] Dr. Linda Bluestein: So when people do this — they do it for like 3 days when they're feeling more in a flare, and I can definitely relate to that with my own patients — how durable are those effects? Like how long are they feeling some relief?

[29:34] Karen Herbst, MD: That varies. The very rare one will repeat it sometimes weekly. A monthly 3-day fast would be more common, and others might do it fewer times per year. They really just look for that flare signal. The ones that do it more often just know they're going to flare, so they do it on a regular basis. It has to be personalized per person.
[30:14] I would love to do a fasting study on women with lipedema because it's a cheap way to do it, there are very few side effects. And I think what we're trying to do is give a signal to the fat cells that they don't need to be around anymore. I'm not sure that the lipedema cells are getting that signal the way a non-lipedema fat cell would — a non-lipedema fat cell would get a signal earlier.
[30:50] And if you change the fatty acids in the membrane, you also change the ability of the receptors to find their antigen or whatever they bind to, because there are clathrin-coated pits that receptors tend to get into for protection. But if they're not in a protective pit, they can get cleaved off by inflammatory enzymes. So could it be that the calcification around these fat cells is secondary to just chronic inflammation that has cleaved off all these receptors? So those fat cells are sitting there just taking up fat, but they have no knowledge of what's going on in their environment. They have no connection to the environment anymore. They're just happily taking up fat. It's a thought. They need a bigger signal in order to release the fat.

[31:54] Dr. Linda Bluestein: And not eating for 3 days would, in theory, at the very least give that big signal. So interesting.

[32:02] Karen Herbst, MD: Yeah, maybe that signal is just a decrease in inflammation.

[32:05] Dr. Linda Bluestein: No, that's okay. I'm excited about all of this because it's so fascinating and so rarely talked about — at least I didn't know a whole lot about it until I started preparing for this interview. Really, really interesting. And in your experience, the women that are doing this on a regular basis, they're not feeling terribly hypoglycemic? I mean, obviously a lot of these people may be somewhere on the dysautonomia spectrum, so they are needing to take in good amounts of fluid and things like that, but otherwise they're feeling okay?

[32:37] Karen Herbst, MD: They feel great. As the days go on, they feel better and better. I've never done a 3-day fast myself — I do some timed eating — but I would be interested in doing one just to see if I feel better as the 3 days go on. Maybe somebody else wouldn't feel better. I would suggest that if you don't feel good doing a longer fast, don't do it, and work with a healthcare provider to figure out what's best for you and what's healthy for you.

[33:08] Dr. Linda Bluestein: And what about saturated fat limitations? Are there restrictions that you recommend?

[33:15] Karen Herbst, MD: I try not to restrict because a lot of women with lipedema have a history of disordered eating. Anytime you bring up, okay, I want you not to eat this, and you start restricting, that can trigger them. Not all of them, but some. And there's no data whatsoever that would justify doing that. So I think eating healthy fats — especially olive oil, which I really like, coconut oil, avocados, nuts, the usual healthy fats — and trying to stay away from the more saturated fats that you would find in beef, potato chips, and vegetable oils and things like that.

[33:59] Dr. Linda Bluestein: Okay, wonderful. We're going to take a quick break, and when we come back, we are going to dive more into treatment, and we're going to talk specifically about medications and surgery. So we'll be right back.
[34:45] Okay, we're back. Super excited about this treatment section because I know a lot of people had so many questions. We're going to get to medications and surgery in a minute, but I first want to talk about supplements. Are there any supplements that you commonly recommend? What are your favorites and what should we know about that?

[35:05] Karen Herbst, MD: I do have some favorite supplements. Because there's microvascular disease, I tried to think of supplements that are going to target that and decrease the inflammation around the vessel. We're stopping the leakage of fluid into that interstitial space because that seems to be overwhelming the lymphatic vessels. It also seems to be generating an increase in the glycosaminoglycans that then bind up that water and form a gel. So the flow through the interstitial space is slow, and then everything just compounds.
[35:43] When I see a woman with lipedema, one of the things I do is look at her veins in her legs. I just use a thermal camera — I'm not a vein specialist — and with a thermal camera, I can do it super quick. First I look for spider veins: 80% of women with lipedema have spider veins. Then I look for varicose veins. If I see them, I'm going to refer them on to a vascular specialist and get a better baseline idea of what their veins look like.
[36:13] But I'll also start recommending diosmin, which comes from the rind of citrus fruit. So if you're allergic to citrus, it's probably not a good idea to take it. Diosmin is well known to decrease inflammation around the veins. I'm hoping that's also happening around the microvessels. And because it decreases inflammation in general, it improves lymphatic pumping — inflammation in general in the body slows lymphatic pumping, which is why people who develop obesity and inflammation along with that have slow lymphatic pumping and are at great risk for obesity-related lymphedema. So I'd say diosmin is kind of my go-to.
[36:57] Fatigue and brain fog are prevalent in the lipedema population, and I'm thinking maybe they have some underlying mitochondrial dysfunction. So I often give them nicotinamide riboside, which we know kind of revives your mitochondria. Along with it, I give them a B vitamin — unless they have MTHFR mutations, then it's a methylated B. And then also a good CoQ10.
[37:29] From there, it's really personalized. Berberine — if they look insulin resistant, have inflammation or metabolic disease, I often recommend berberine because of its insulin-sensitizing effects. It's also a mild GLP-1 enhancer; it increases GLP-1. And then just good things for connective tissue like vitamin C. I like them to at least take a little vitamin C.
[38:01] I used to recommend selenium — everyone knows me for selenium — but it's easy to get your selenium levels too high. So I try not to give extra unless they really want to try it, and then I measure their blood level. If it's low or low-normal, I'm okay with it, but I don't want them to go over because of the few studies showing that increasing selenium levels can increase insulin resistance.
[38:31] We did publish on a whole range of supplements that could potentially be used for lipedema, but there are really no studies on it. Alexandre Amado from Brazil did publish a little bit on anti-inflammatories and lipedema, and he has some proprietary blends that he uses. But I like people to get it from their food. I don't want to over-supplement people. For people eating plant-based or just a low-carb type of eating plan, I tend to encourage rainbow-colored fruits and vegetables to get all those bioflavonoids.

[39:22] Dr. Linda Bluestein: Yeah. And if they have mast cell activation syndrome, then of course you have to take that into consideration as well, and the potential for excipients in the supplements.

[39:32] Karen Herbst, MD: So crazy, right? And I usually say, get the cleanest supplement you can, but all supplements have excipients. You could get the powders and put them in your own little capsules if you want to — it's just a lot of work. I used to supplement a lot more, and I supplement a lot less now and try to do it through food, exercise, manual-type therapies, and tools. Women get a lot of tools — muscle massagers that they use at home. So you're really manipulating the tissue from the outside, trying to eat healthily and get anti-inflammatories through your food, and then moving to keep the fluid moving out of the legs using that calf muscle pump.

[40:16] Dr. Linda Bluestein: Excellent. And a couple of the things that I had read in some of the papers you had written were DHEA and yohimbine.

[40:23] Karen Herbst, MD: Yes. So DHEA is an androgen. The question is, are androgens good for lipedema? There are a number of women who have transitioned from male to female, and the question is, I'm in a family with lipedema, am I going to get lipedema? Very possible if the right genes are there. And we don't even know what those genes are — nobody's found a gene for lipedema, nobody's found 2 or 5 or 10 genes for lipedema. I think the genes are going to start coming out one by one, kind of like hypermobile Ehlers-Danlos. There was a really great family study out of Australia, beautiful families, and they couldn't find a gene. So it's going to be difficult.
[41:14] But back to DHEA. I think men are protected from lipedema more than women. So is it the androgens that are helpful, and could DHEA be helpful? As an endocrinologist, we were trained: do not give DHEA unless they really need it, unless they're really low, because there can be some issues — especially if you take too much, it can increase your testosterone levels. But the reason a woman with lipedema would take DHEA is that it increases lipolysis in fat cells, so the thought is you can decrease some of your fat tissue.
[41:58] I know of a woman who takes DHEA and has for years, and she has maintained the same stage of lipedema, but she's also a plant-based eater and an avid exerciser. She also has a really good mindfulness practice, which I think is really important in lipedema because of the years of not knowing what you have and how women get treated when they have too much fat tissue on their body. But I digress.
[42:28] So I think DHEA is okay. I just feel like in that case it would be a good idea to work with a healthcare provider and get your DHEA level measured and not go too high above normal.
[42:43] And then yohimbine — I'm laughing because I always try these supplements. I tried DHEA for a while just to see what happens. I tried yohimbine and I was in clinic — I would take yohimbine, I'd be wearing my white coat, and then all of a sudden I'd be like, oh my God, and I would just take it off because I would go into this massive sweat.
[43:08] Yohimbine is often used by bodybuilders. Going through the literature, the best time to take yohimbine would be right before you exercise — that seems to be where it works best. It has a really short half-life and it can decrease fat tissue if you take it. It acts synergistically with exercise. So this would be something you would pulse, not something you would take all the time. And it is activating your sympathetic nervous system, so you have to worry about things like heart palpitations, especially if you have baseline tachycardia with autonomic dysfunction.

[43:45] Dr. Linda Bluestein: And in people who have fatigue — which I know sounds like that is a lot of your patients, it's definitely a lot of my patients as well — do you find that the DHEA sometimes helps with that?

[43:55] Karen Herbst, MD: Yeah, I have noticed that it does, but not in everybody. That may reflect that some people are starting at a lower level, so they're noticing that increase, whereas others are not.

[44:07] Dr. Linda Bluestein: Okay, let's move on to medications. What medications do you recommend?

[44:15] Karen Herbst, MD: So one of my favorite medications is dextroamphetamine, and I actually published a paper on this. The reason I did it is because of the literature on phentermine — and I'm not as big a fan of phentermine as I am of dextroamphetamine, because phentermine tends to have to be used at higher levels and is then at greater risk for downregulating the adrenergic receptors that it binds to, thereby losing its effectiveness. So you have to take holidays, whereas with dextroamphetamine you don't. You can use it at much lower levels. You can get the brand Zenzedi, which has fewer excipient ingredients — so that's one I would use in my mast cell patients.
[45:04] What we showed was that over 90% of women with lipedema said their lipedema got better taking dextroamphetamine. If you had a medication like that, it would be a blockbuster, like the GLP-1s. They lost weight, they had a lot more energy, focus, and motivation, and they were more active in their lives. There was a very tiny reduction in sleep — almost negligible — and nobody abused it either. They weren't ordering it ahead of time and taking extra.
[45:39] I use doses as low as 2.5 milligrams. I tend to use that for my very sensitive patients with Dercum's disease who have mast cell issues and are usually bedridden. A 2.5 milligram dose can get people out of bed and living their lives again, which is just incredible. Then 5 milligrams is also common, 10 more common, and 20 is probably the most common dose that I use. I do not like to go higher. When I looked at the literature on what would help edema, 25 milligrams was the highest dose they used, but I like 20 because I can give them two 10-milligram tablets a day. That was from the literature by Streeton — they have the Streeton test where they try to figure out whether you're a water excretor or salt excretor.
[46:38] I said, they're using that medication, let me try that. And it's just been incredible, the result with that.
[46:44] The second medication I often use, which is not very well known, is pentoxifylline. That is an old drug from the 1970s, an old cardiac med called Trental. It's a great anti-inflammatory. I tend to use that more in patients with Dercum's disease and often more in men who have Dercum's disease because in Dercum's disease, it's a very painful disease. And the way men's pain pathway works is that their glial cells in their central nervous system interact with their nerves. The glial cells are like your macrophages or monocytes of your central nervous system, whereas women tend to have pain that occurs more through their T cells than their glial cells. The glial cells respond very well to pentoxifylline for some reason. I haven't delved deep into that yet, but I'm planning on it.
[47:44] I have used it in women in very low doses. It does cause headache and GI upset, so unfortunately it's not good for mast cell patients with very sensitive mast cell. Does not work.
[47:56] I use metformin often, especially if there's metabolic disease, because metformin decreases fibrosis in the tissue — and so does pentoxifylline.
[48:07] And then the elephant in the room: I do use GLP-1 agonists. And those have just been incredible — just incredible transformations in people's lives. Sometimes I combine a GLP-1 agonist — at a low dose — with a small dose of amphetamine, and they just seem to work synergistically.

[48:37] Dr. Linda Bluestein: Are you running into problems with insurance for the GLP-1 agonists and/or adverse effects?

[48:38] Karen Herbst, MD: Insurance is becoming harder and harder. If I have someone who does have diabetes and we give them the GLP-1 agonist, their hemoglobin A1C comes down, they lose weight, and then the insurance company says they don't have diabetes anymore so we're going to withdraw it — which is ridiculous, because it's a chronic disease. And it's hard to get it approved.
[49:07] It's been a little bit easier to get Zepbound approved recently because it's newer and there are still coupons. But yes, insurance is a big deal. I wish it weren't as hard, but I understand these are expensive medications and so many people are taking them and the insurance companies are trying to push back.
[49:31] Side effects: a lot of my patients learn to manage their constipation, and some of them have almost no side effects. And some of them don't respond to GLP-1 agonists — not that many, but I've had a number of them. I didn't believe it, so I said, well, you only tried the semaglutide, let's put you on the tirzepatide. And sure enough, they didn't respond. I don't know why — maybe there are some mutations in the insulin receptor or the GLP-1 receptor. But they don't complain. They are so happy to have lost the weight and they regulate their gut because they are so motivated.
[50:12] Have you had a lot of trouble with GLP-1 side effects?

[50:22] Dr. Linda Bluestein: I have a lot of patients with gastroparesis and I haven't really ventured into that a lot yet. So I was very curious about, with your patients, what you consider to be definite contraindications to the GLP-1s?

[50:45] Karen Herbst, MD: I have a number of patients with gastroparesis as well. I have started GLP-1s in a few of them, and I do low dose. I'm very reluctant to keep increasing them because of their guts. So I want them to get very, very used to a dose before they go up, and then we often alternate. Like, if they start at 0.25, we'll go to 0.25 alternating with 0.5. We're not just jumping to the highest dose as fast as we can. I think that's asking for trouble.

[51:19] Dr. Linda Bluestein: Right, right. And this is a great example of why the 7-minute visit is so problematic, right? This is a lot to try to cover in these short visits that a lot of people are experiencing.

[51:36] Karen Herbst, MD: Yeah, I'm in a cash-based practice because of that. I barely get done in an hour. And now I've got a new comprehensive appointment where I do an ultrasound at the same time. We're quantitating lipedema using ultrasound parameters from two different publications because we just need a little bit of extra information for insurance companies. We need to find a way to really document lipedema quantitatively rather than just qualitatively. And it's so much fun to look inside people's bodies and show them. I say, where else do you want me to look? And they say, will you look here? Yeah, let's do it. I'm enjoying it.

[52:21] Dr. Linda Bluestein: That's great. And with the EDS population — the trifecta of EDS, POTS or some form of dysautonomia, and mast cell activation disease — these are definitely complex interwoven conditions that are very time-consuming to tease out. I definitely want to find out about surgery. Are there surgeries that are helpful for this?

[52:47] Karen Herbst, MD: Yes. I wish we had medications that really could get rid of the lipedema. Usually the medications are getting rid of the non-lipedema tissue, and I think it just takes so long to get rid of lipedema tissue because it's so fibrotic. There may be other reasons like the calcification, but we do know the fibrosis exists — it's like a cage inside the tissue. We don't have anything yet and we need long-term studies. I looked on clinicaltrials.gov and there's not a single GLP-1 study on lipedema registered. I don't think that's going to happen anytime soon, and I don't know if the companies even want to go into it because they have enough to do with people who have non-lipedema obesity.
[53:42] But surgery seems to be very helpful. In general, this is liposuction, and there are different kinds. One is called tumescent liposuction, and they use PAL — power-assisted liposuction — where the cannula vibrates and loosens things up in the tissue a little bit more. The tumescent fluid that they infuse into the tissue softens everything up so that they can suck it out through the cannulas a little bit easier.
Then there's water jet-assisted liposuction, which takes jets of water, shoots it at the fat tissue to knock it down, and then sucks it out. And there are variations on tumescent liposuction — for example, VASER and SmartLipo. But the most common ones are tumescent with PAL or water jet-assisted liposuction.
[54:40] It was initially very difficult to get these surgeries covered by insurance companies, but now it seems to be slightly easier. It's still a very long process, and insurance companies have developed policies that you have to follow in order to be considered for coverage.
[54:59] When women do get the liposuction, they often experience a dramatic reduction in pain, a dramatic reduction in heaviness of their legs due to the fluid that accumulates with standing. Their easy bruising goes down, which is amazing. Their activity levels go up and their mood goes up too. They're just happier — they feel better, they look better.
The women who have problems with surgery are the ones with inflammation. If they have metabolic disease or something like MCAS that's gone untreated, or some other source of inflammation we may not even know about, they tend to get worse and start to grow fat more on areas of the body that weren't treated — the abdomen, the shoulders, the back, the breasts, the arms. That's really unfortunate because they've done so much work to get the surgery and then they just start growing again.
[56:08] That's why I am vigilant about improving metabolic disease before anyone has surgery. Sometimes other factors supersede the reduction in metabolic disease and women go for the surgeries anyway, and then it's a scramble to work with them. But it would be a good idea at that point to start a GLP-1 agonist just to keep their inflammation down as much as possible.

[56:35] Dr. Linda Bluestein: So before surgery, are there certain things that you're doing to assess a person's inflammation?

[56:41] Karen Herbst, MD: Usually I run a fasting insulin and glucose, and then I calculate a HOMA assessment to see if they have insulin resistance. I run a hemoglobin A1C and a CRP level, and that's about it — which probably isn't sufficient, but we don't have good evidence in the literature that we should be running anything else.
[57:01] Recently we've been checking ACEs questionnaires, which looks at childhood trauma, and it seems to be a little bit higher in the lipedema population, likely because these young girls developed increased fat tissue, felt self-conscious, and maybe got bullied or made fun of. What that literature suggests is that with childhood trauma, CRP levels are not elevated, but IL-6 and TNF-alpha are elevated. So maybe we should be looking at things like that. But sometimes insurance doesn't cover those levels, so I'd be asking people to get them and then — where's my data? How do I tell the insurance company that they need these tests done? Unless they self-pay, it's not as easy as I would like it to be.

[57:52] Dr. Linda Bluestein: And if somebody is contemplating a different surgery in the same region — for example, a total knee replacement — and they have lipedema, would you think that they would be at increased risk of complications?

[58:06] Karen Herbst, MD: That's a very interesting question, and we just had a research webinar on that. A lot of women have gotten turned down for knee surgery because they have too much fat tissue around their knees. So they're walking around bone on bone, unable to get surgery. In that case, with that particular surgeon, it would be a good idea to get liposuction around the knee first — remove as much fat tissue as possible to allow that surgeon better access.
[58:36] There's also a weight issue. You have to look at optimizing nutrition and exercise and maybe weight loss medications like GLP-1s or others. And then there are some women who have surgeons that just go ahead and replace the knee, and they really haven't had any problems. So it's very dependent on the surgeon.
[59:01] I do think it is harder to get into the knee if there's a lot of fat tissue around it, and I would personally advocate for some focused liposuction to allow the surgeon better access. But I don't think there are any complications beyond that unless there's a huge increase in weight, which the surgeons don't like with knee replacements.

[59:25] Dr. Linda Bluestein: Right, right. They worry about infection risk and a lot of other things — DVTs and PEs and things like that.

[59:31] Karen Herbst, MD: Yeah, DVTs.

[59:34] Dr. Linda Bluestein: In terms of tools — you've kind of mentioned this already a little bit earlier — what are some tools that can be helpful, and which ones?

[59:43] Karen Herbst, MD: Muscle massagers seem to be the latest greatest tool and most women have them. They say it really helps — it helps decrease the fibrosis and the tissue congestion. That's probably the water bound up to glycosaminoglycans forming a gel in the tissue. Over time it may be helpful with decreasing fibrosis, but it definitely helps free up movement, which is really good.
[1:00:11] Whole body vibration machines are very popular. I like them myself. They increase blood flow, increase lymph flow, build bone and muscle. One of the things we worry about with the new GLP-1 agonists, bariatric surgery, or other dramatic weight loss programs is that you're going to lose muscle mass at the same time as fat mass. We know that muscle eats fat, so we don't want that. We don't want women to lose strength. So I think whole body vibration is a really great tool to maintain muscle mass. And it's so easy to do.
[1:00:55] Other tools are rollers. I love a flat roller. Often I give a flat roller to my patients and say, try it out on your thigh. And they're rolling their thigh and they just keep rolling and rolling, finding everything they can. They're like, oh my God, this feels so good. I think it just helps teach fat tissue that it needs to be smooth, needs to stay in its place, needs to go down, needs to flow better. I like it better than some of the more bumpy tools that, if you press them on the tissue, go deep immediately. I like to do it in layers, and with a flat roller you can roll gently or you can roll really deep and push hard and everything in between. So you can do it to your own ability to tolerate it.
[1:02:00] Then I have them put the flat roller behind their knee and bend their knee, because that's where lymph can get really congested and where there are lymph nodes. I have them bend it on their arm too, because again that's where lymph nodes are, and then under the arm. I kind of have them clear everything, and then they can just go at it and use that roller. It's something you can do while talking on the phone, watching television, sitting outside. So flat rollers, whole body vibration, muscle massagers. I used to recommend gua sha tools, and a lot of women still use gua sha tools — the flat tools for scraping. That's all I can think of right now.

[1:02:28] Dr. Linda Bluestein: And when it comes to the vibration plates, are there certain things you're recommending that people do on them? Because I've seen a whole host of exercise protocols. And of course I'm sure you have this too, where patients can be very limited in what they're able to do because of joint pain and chronic fatigue and things like that. So is there something in particular that's most important when looking at the usage of a vibration plate?

[1:02:58] Karen Herbst, MD: I want them to use it however they feel comfortable. If they are still working and come home exhausted, if they can just sit down and put their feet up on the whole body vibration machine and vibrate their calves — because the calves are where fluid tends to accumulate most, since when you stand that's where the highest pressure is in your venous system — if they can just vibrate their calves, I'm really happy.
[1:03:25] I actually have a very small trampoline under my desk even right now, and I can bounce my feet up and down, which anybody can do at work or when you get home. I have them sit on the whole body vibration machine if they feel comfortable. I don't want them to get any damage to their spine, but a lot of them at low frequency feel really comfortable on the machine sitting.
[1:03:48] And then standing, I like you to move around because you can actually move where the vibration extends to on the body. If you just bend your knees, it'll stay in your calves. If you straighten your legs, it'll go up to your abdomen. If you straighten your legs and lean back, it'll go even further up onto your chest and even onto your head. And then if they want, they could put their arms on the machine, sit next to it, and just put their arms on it and get some whole body vibration of their arms. So whatever they feel comfortable doing. And when you're standing on it, you can do squats, you could pull on resistance bands, you could just do all sorts of things if you want to elevate the experience.

[1:04:28] Dr. Linda Bluestein: Okay. Last question before we get into the hypermobility hack — and I could probably ask you hours and hours more, but I want to respect your time. What about mast cells and hormones, and are there certain ways in which they impact lipedema that we should be aware of?

[1:04:45] Karen Herbst, MD: Yes. There are some data in the literature suggesting that estrogens can make lipedema worse, especially through inflammation. One of the pathways I think estrogen does this is through mast cells. Estrogen can directly activate mast cells and turn them on. So if a woman is estrogen dominant for whatever reason — and that could be just because she has excess fat tissue, because fat cells generate aromatase, and aromatase changes androgens into estrogen — almost by definition, many women who have excess fat on their body could be estrogen dominant. And estrogen also potentiates the immunoglobulin E activation of mast cells. So it's activating mast cells through two different pathways.
[1:05:40] The question always comes up: if I have lipedema, can I go on the birth control pill? Or can I go on hormone replacement therapy? We don't have the answer to that, but anecdotally, what I have seen over the years is that women who start hormones of any kind tend to gain a little bit of weight and then stabilize and they're fine. And when they go off the hormones, they gain a little bit of weight and then stabilize.
[1:06:13] So if you can prepare for that — you know you're going to go onto hormones, so really be diligent with what food you're eating, diligent with your movement, keep the stress down — and then go on the hormones. When you come off, repeat that same pattern. I think it's okay. I have given my blessing for many women to go on the birth control pill. I like the ones that are a steady dose — I don't like the ones that fluctuate because that really pulses the mast cells and perhaps other immune cells.
[1:06:48] And then hormone replacement therapy. I found it very interesting in my training as an endocrinologist that when we gave men testosterone, we watched them diligently, made sure they didn't go too high, and were very careful with them. With women, we gave them hormones and said, there you go, and sent them on their way. Now there are bioidentical hormone specialists who do watch their patients very carefully, and I'm sure there are some allopathic physicians that also watch their patients very carefully, and I applaud that.
[1:07:21] But what I usually say is: keep your estrogen in the low-normal range. Don't go crazy, don't be at the high range or above normal. Make sure that you balance estrogen with progesterone to protect the uterine lining. And then monitor your testosterone levels as well, because if you have super low testosterone, that testosterone-estrogen ratio is off. Keep testosterone within the normal range as well. Don't over-replace that either.

[1:07:48] Dr. Linda Bluestein: That's fabulous information. Thank you so much for sharing all of that. I like to end every episode with a hypermobility hack, and I'm sure you have one you can share with us.

[1:08:02] Karen Herbst, MD: So I'm a big fan of compression garments. I like how they shape the body and give support. And I don't know if you know this, but I have hypermobile EDS.

[1:08:12] Dr. Linda Bluestein: I did not know that.

[1:08:16] Karen Herbst, MD: Yes, I do. And the funny thing is, I was diagnosed in 2016. I was going through the Beighton criteria for all of my patients — I would do everything and say, this is how you do this, that's how you do that — but I wasn't thinking that I had hypermobility myself. I have hEDS, but I don't know why I have it. It could be due to inflammation or something else. I know I don't have the kallikrein mutation, nor do I have the MTHFR mutation. So I obviously have something else, because I've already looked at my genes.
[1:08:55] One of the things I did early on was look through the hypermobility literature about fat, and there's not a lot. And you say "the trifecta" — I think you should add lipedema in there, because it's just so common that there are some abnormalities of fat tissue. In men, what I notice is they get a big amount of flank fat and they often have striae on their low back. Big flanks, big flank fat, striae on the low back — there's your fat. In women who have hypermobility and aren't showing a lot of lipedema signs, it's on the abdomen. Some abnormal tissue on the abdomen — and that's often found in vascular EDS. And then just a little bit of increased fat on the calves. Not a lot that you can see, but when you pinch it up, you can get a kind of a glob of it. And that would be type 5 lipedema — the type 5 is very rare and you only see it on the calves.
[1:10:02] So compression becomes very important in that case. You want to compress the calves for sure, and abdominal compression — or anywhere that there's increased or abnormal fat tissue, especially what looks just like cellulite — I think that needs to be compressed as well, because there's inflammation in that tissue. Compression reduces pain and improves fluid flux, whisks out inflammatory mediators, shapes the body really nicely, and I think it's just really supportive, especially as we age.

[1:10:39] Dr. Linda Bluestein: Okay, well, I love that. Thank you so much, Dr. Herbst, for joining me today. This was such a fantastic conversation, and I know that the listeners are going to find this incredibly helpful. Before you go, can you let us know if you have any projects that you're involved in right now that you want us to be aware of, and also where we can find you?

[1:10:59] Karen Herbst, MD: Sure. I have just switched practices. I am brand new with the Roxbury Institute — the home base is in Beverly Hills, but I am located in Tucson, Arizona. I am working on a number of papers trying to get them all written up and out in the literature. But we are planning a study on cavitation for lipedema with Karen Ashforth starting in January 2025. Cavitation is basically sound waves that go through the tissue and loosen everything up. So that might be another great tool for women to use.
I am also heavily into the genetics, and my goal is not to do large population-based genetic studies or even family studies right now. What I'm using genetics for is to improve the health of people. We're looking for things like deficiencies or obvious changes in the inflammatory milieu that we can do something about. And a lot of my patients, when I tell them about it, are just jumping on board because they're excited too. We use a direct-to-consumer company, so we are empowering women with lipedema to go through their own genomes and improve their quality of lives. And we are their cheering section.

[1:12:25] Dr. Linda Bluestein: That's incredible. Are you able to share what company you're using for that?

[1:12:30] Karen Herbst, MD: I'm using Sequencing.com.

[1:12:30] Dr. Linda Bluestein: I'm very familiar with them. A lot of patients have found them and are using them as well.

[1:12:39] Karen Herbst, MD: They do have some issues — they're not perfect — and we are actively working with them. I'm working with Denise Morrow. She's a patient of mine. She should be a PhD. She's one of the most incredible people I've ever met. She's been working on her genetics for two years and she's having these breakthroughs. In fact, I'm going to get on with her again this afternoon — I was on with her this morning and she's showing me all her breakthroughs. Once we've solved this problem — and we're trying to create an Excel spreadsheet that will really amplify the experience of people using that platform — I think it's going to be very exciting.

[1:13:17] Dr. Linda Bluestein: Okay, incredible. Well, thank you so much again. It was so great to chat with you today.

[1:13:23] Karen Herbst, MD: You too. Thank you for the invitation.

[1:13:28] Dr. Linda Bluestein: Wow, that was such a fantastic conversation with Dr. Herbst. I feel like lipedema is such a rarely talked about subject and affects so many people. So I'm sure you enjoyed it. Share this conversation with your friends, with your family, and anyone else that you think might be interested.
[1:13:47] Thank you again so much for listening to this week's episode of the Bendy Bodies with the Hypermobility MD podcast. You can really help us spread the word about joint hypermobility, lipedema, Ehlers-Danlos syndromes, mast cell activation syndrome, and all of these interconnected conditions by sharing the podcast. This really helps raise awareness about these complex conditions.
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