บทถอดความฉบับเต็มของ Familial Hypercholesterolaemia Genomics - Urgent for Primary Care

Hypercholesterolaemia?[00:05:31] Dominic: Thanks. Well, FH is short for familial hypercholesterolemia, so FH for short. And it is a, autosomal dominant genetic disease. So that means, you only need one copy of a FH causing gene to have FH. And FH causes your liver to be less efficient at removing excess cholesterol or LDL cholesterol from your blood. And as you have this from birth, that means you're exposed to high levels of cholesterol over your lifetime. [00:05:58] This gives you marked increased risk of developing coronary heart disease prematurely, which leads to heart attacks and, as you know, sometimes death in many cases.  [00:06:09] Anwar: Can I just chip in there, Dom? I think you, let's put it in perspective premature coronary heart disease 20 fold higher in FH compared to the general population. 50 percent of men with FH will have an MI or stroke by age of 50. 33 percent with FH will have an MI or stroke by 60. That's the reason, isn't it? It really is high risk.  [00:06:33] Claire: That, that's quite scary. so how common is it? And , are there any sort of ethnic considerations or other variations that we need to be aware of? [00:06:40] Dominic: So, FH is I think one of the most common autosomal dominant diseases. It's predicted that there's one in 250 of us in the UK that has FH which equates to 220, 000. And out of that, 220, 000, 92 percent remain undiagnosed. And the reason for that is because it has such a varied phenotype and it's an invisible disease. You really wouldn't know you had FH unless you had a blood test to check your cholesterol, or if unfortunately you present with a heart attack.  [00:07:12] Anwar: Tom, you said phenotype. What is phenotype?  [00:07:14] Dominic: to you first. Thanks, Anwar. So, phenotype, so that's , the characteristics of a variant, what it causes. [00:07:21] So, in FH, you'll have varied levels of high cholesterol dependent on what variant you've inherited and from what gene. So in FH, there are three main genes that FH in LDLR PCSK9 and ApoB. Blimey,  [00:07:36] Claire: that rolls off the tongue.  [00:07:37] Dominic: Yeah.  [00:07:39] Munir Adam: You said it before me. can I just step in there and ask, just in terms of this variable expression, is that why it tends to affect women get far fewer heart attacks and strokes from this. Is that because of that variable expressivity? Is it that it's not expressing itself as much or is it because of the other risk factors that put them at lower risk?  [00:07:58] Dominic: Yes, I think yeah, as I said, a third of women if undiagnosed or treated will have a heart attack by the age of 60 and that slightly lower risk is we're not fully on the show. [00:08:09] We don't fully understand, but potentially is due to life's other risk factors like lifestyle, diet, exercise, et cetera, as well as hormones. And so you often see an increase in heart attacks when women start going through the menopause, I believe.  [00:08:24] Anwar: Just to add to that, you're actually right. [00:08:26] It's a protective role of estrogens. But also as we know, women have later onset of heart disease anyway, that there's some research, you probably know this more than most, but there's an interesting paper I read that suggested maybe difference in the composition and stability of the plaque between men and women. And that's probably why they do it. So they may have more stable plaque, really. [00:08:46] Claire: So what, what's actually going on in the body in relation to sort of biochemical processes?  [00:08:52] Dominic: So, yeah, as I said, there's three main genes that cause FH and they're all involved in basically the liver uh, taking that cholesterol out of the blood. the LDR, gene encodes for the LDL receptor. And if you have changes in the DNA code for that receptor, that will then result in a protein that's less efficient at removing that cholesterol from the blood. [00:09:15] And over time, as I said, it's a lifetime exposure to higher levels of cholesterol that leads to that forming these plaques, particularly around the coronary heart vessels. [00:09:24] Claire: So within a sort of primary care setting when should we be thinking that someone may have FH?  How to detect Familial Hypercholesterolaemia[00:09:31] Dominic: So in primary care, we didn't fully cover this, but, there are you know, across the country, it's 1 in 250 people will have FH. There is evidence that, there are certain populations that have an increased likelihood of having FH, but we know in the UK that in Asian and black communities, potentially there is a marked underdiagnosis. [00:09:52] I think that's something to be aware and vigilant in primary care if that is your population to look out that. And to increase awareness among those communities so we can hopefully reduce this inequality in primary care. [00:10:05] if you're seeing someone who has a really strong family history or a personal history of premature coronary heart disease, that should ring alarm bells, as well as having an unexplained high cholesterol without any clear secondary causes like diabetes, et cetera. there are also physical signs of fh, which are tendon xanthomas, which are really specific to fh. that is a very clear sign that someone has FH as well as a corneal acus with a corneal acus in it is more likely to be FH if they have that when they're under the age of 45. [00:10:38] Claire: There's a lot of big words there. I know a few of them and the first one I don't have a clue what that is.  [00:10:43] Dominic: So these are lumps and bumps on your tendons. Usually you see them around the hands. When I'm assessing patients, I often get them to play the piano and see if you can see any lumps on the tendons around their knuckles. [00:10:53] You can also look at the Achilles and on the knees and on back of the elbows.  [00:10:58] Anwar: They're usually on the extensor tendons. Really, and they're non-tender, aren't they? The other thing you're asking is xanthelasma as

well, aren't you? That's the sort of, lots of yellow bits around the eyes. [00:11:09] Yellow blobs. Yeah, blobs, yeah. See any yellow blobs around the eyes, you always think about it. But I think it's a good point you said, Dom, about corneal the archus. Because you know, people get it as older, but this is about under the age of 45, isn't it? So, always think about it. Exactly. Yeah.  [00:11:25] Munir Adam: It's taken me back to medical school days, actually. That's when, and even when I teach medical students, these are the things they normally look for when they're doing a systemic examination. So, it just goes to show how much valuable stuff we learn in our training, which we just then forget about if we don't make use of. So, this is a good reminder for all of us. [00:11:40] A bit of trivial, fact, that Mona Lisa, we think, had it as well, you know. Because you can see a xanthelosa around her eyes. So, next time you look at Mona Lisa's post, have a look at it. Don't forget xanthelosa.  [00:11:49] Munir Adam: Died young, didn't she?  [00:11:51] Dominic: She did, yeah. Age 37. So yeah, she's often a case study I use when I've done training with primary care. So have a closer look next time you go to the Louvre.  [00:12:01] Munir Adam: Okay. Oh, the question that's going through my mind is why don't we just test Everybody then. Why not just check everyone's lipid profile? Because at the moment we tend to check over 40s, don't we? We offer them a health check. But why not just start, you know, start as early as you can. [00:12:18] Dominic: Yeah, I would love it if we started testing everyone. But unfortunately, at the moment, we don't have a national screening program for FH. And you know, we do have a genetic test that we can offer, but unfortunately, to, be gatekeepers to access to that genetic test, because at the moment with the technology and resources that we have, we just aren't able to offer that to everyone. [00:12:37] That's why it's really important when you are, you know, considering FH that you do effective screening in primary care, you identify, you exclude any secondary causes and ensure that they meet the testing criteria as per the national test directory. And that's the Simon Broome criteria or the Dutch Lippard criteria, or the Welsh score. [00:13:00] Anwar: Again, Dom, you mentioned the Simon Broome criteria, etc. I mean, rather than remember it all if people have got EMIS or system one certainly we know that's on their templates, isn't it? The Arden templates. You can look that through there and it did give you the Simon Broome score. Tom, again, I'm going to ask you a complicated question because Simon Broome is where it's not established, but the world's crisis, there's a different use of it, isn't it? [00:13:25] Dominic: So they're all slightly different. The Welsh score is more similar to the Dutch Lipid Criteria, but it also adjusts for the age of the individual as well. Yeah, because as we, as we get older our cholesterol naturally, you know, does increase. So yeah, it's important that we can adjust for that. [00:13:42] Munir Adam: So just to clarify then, this is the Simon Broom or the Welsh score. Is that to then decide who should be referred for genetic testing? Is that what we're talking about here?  [00:13:52] Dominic: Yes, exactly. So, I mean, this, this is for in primary care. If you have someone in front of you, you think they might have FH. These scores all use the clinical data that you have. So any family history of premature cardiovascular disease or personal history, as well as their cholesterol score and any physical signs. And it uses all these, this criteria to identify whether or not that individual might have FH or a clinical clinical diagnosis of fh. [00:14:20] . And so it for, for Simon Broom, if it gives you a, a result of probable or definite fh, then they would be eligible for genetic testing. And then with the Welsh score of, and Dutch lipid, if it's a score of six and above, they would also be eligible for genetic testing and referral and referral. [00:14:36] Munir Adam: Got it. Thank you. And Anwar, were you saying that both of those tests are available on EMS and system one?  [00:14:41] Anwar: Well, the Simon Broome certainly is and that's the one I tend to use because I'm a simple chap, really. And, you know, you just click on the Arden template . It. And I, I do know Faye has system one and it's on there.  [00:14:51] So you just answer the questions like any template, you don't have to remember it all. I mean people like Dom memorised it but people like us, you and I, we just need to go to the template and then it tells us whether testing is probable or not necessary.  Think about the family[00:15:05] Anwar: But on that note, I mean Dom, I don't know if this is the right time to do it, is that as primary care you are ideally placed to do what we call cascade testing, the rest of the family. [00:15:15] Because that is what we need to be doing rather than spending lots of money doing, you know, testing the whole population and you're looking for a prevalence of one in two 50. So you've actually tested 249 that didn't have it here. If you've got the affected individual, you can then actually start testing their relatives. [00:15:32] And that's much more cost effective. And remember, this is the beauty of primary care. You've got the whole population usually for, you know, families, don't we? We look after families and therefore you, you have a duty of care as a gp. To deal with it yourself, rather than pass it on to lipid clinics or whatever. [00:15:49] Munir Adam: Aren't there finger prick type cholesterol tests that can be done? Do they exist? I'm just thinking about, is it necessarily very expensive to be testing lots lots of people just checking their cholesterol?  [00:16:00] Anwar: Well, it's not just measuring the total cholesterol, the LDL cholesterol as well. So it's actually looking at the differential. [00:16:08]

Dominic: That's absolutely right. Yeah, it's that LDL cholesterol that's really important. So if, if you do get just a total cholesterol that's elevated, you need the full sort of lipid breakdown really to, to properly score someone on Simon Broome and, and the Dutch lipid scores. [00:16:22] Munir Adam: Okay. So if we've hit the criteria, Simon Broome score is high or criteria is high, whichever one we use, and we're now making a decision, right? is somebody who needs to be tested for FH. So,  [00:16:36] Dominic: If, if you're, if you're, if you think that someone has a, has FH and as Anwar has said, the benefit of getting them tested for to identify if they have a known variant that causes FH is that we can then offer cascade testing to the wider family and increase increased detection of FH across the country. [00:16:53] But specialist centers that will do this, they're usually CVD prevention clinics or endocrine and diabetes services. And if you are unsure where to, where they might offer FH testing, you can look on the Heart UK websites and you can search for your area and where, where the closest center is. [00:17:11] Claire: Should this also be available on everyone's local formulary, Dom?  [00:17:15] Dominic: It should be as well, I believe, yeah.  [00:17:17] Anwar: But Dom, that's a very good point about finding the nearest lipid clinic. It's not genetics, it's the nearest lipid clinic and Heart UK, it's a really great tool on there.  [00:17:27] Munir Adam: You know, it's, it's odd really, because I used to deal with high and things a lot before, but now things have specialized so much in primary care. I don't know, Claire, do you, do you deal with high cholesterol?  [00:17:38] Claire: Not particularly. I dabble when we have to do a bit of pathology, but this is why I really keen to kind of get some more information because it's something that, you know, I'd like to feel more comfortable managing within my own clinics and actually taking on as a consideration if you're doing like a systems review and perhaps they've not even come in about that. [00:17:56] It's really important to have that understanding to think about what you're looking for and where you go from there.  [00:18:02] Munir Adam: Exactly. That's exactly what I was thinking because it's not the ones who have already had a suspicious chest pain kind of episode and the ones who are already extremely highly, high HbA1c and poor diabetes. [00:18:13] They've all had their cholesterol down. the ones who are probably walking around thinking they're absolutely healthy, completely unaware that they've got genes that are actually putting them at very high risk, as you guys said, having a heart attack at a young age that we've got to pick up. [00:18:27] So they're not going to be necessarily going to. the cholesterol person in the practice, they could be coming to you or me, even though we don't deal with it. So good reminder for us in that sense.  [00:18:37] Dominic: I guess on that point, Munir is that that's why we need to identify in our, you know, in our populations, in our GP practices, those ones that have had a cholesterol reading and we haven't actually thought, Oh, maybe this is FH. [00:18:49] So we can then test that person and then. And then through cascade testing, identify those one who, you know, who are walking around well with no symptoms, etc. And, and that way we can hopefully prevent any, future heart attacks, etc. In, in those individuals.  [00:19:03] Munir Adam: So just want to push on this point a little bit more. So I've got absolutely clear who, so if somebody happens to have had a cholesterol tested at a young age by chance, You might then, and if the cholesterol comes back high, you might then sort of think about putting in the numbers into the Simon Broome criteria and seeing if they might have FH. But that's, that's only if they happen to have had the cholesterol down by chance. [00:19:24] Are we meant to be proactively testing people other than if we happen to find that they have physical features like You know, xanthelasma, as you said, or xanthoma, tendons and xanthomas.  [00:19:36] Dominic: I think this comes back to family history. So if you, do have a, have an individual joining that, joining your practice and they, you know, if that's something you collect, which I would really advocate for. is really, you know, good family history data. And they do disclose that they have this family history of, of premature cardiovascular disease or a personal history. That's, when you would think, Oh, well, let's check your cholesterol and, and investigate further and maybe do, you know, do a physical examination for those.  [00:20:04] Munir Adam: Thank you for that. Yeah. Cause that's a really important role of, the new patient check, isn't it? Or the routine patient check. Because, you know, we'll say, do you have somebody in the family who's had a heart attack? But sometimes in a half hearted way without really paying attention, it just highlights the importance of that question. [00:20:18] Anwar: But, but also I think what I would say, the family is just more important because things like the tendon xanthomas only occurred in, in the late 30s. You know, if you get someone young, you're not going to get it. So I would Think genomics every time, and you'll be amazed at how many people you will pick up for a decent family history. [00:20:34] Dominic: I think, as I mentioned at the start, that I was involved in a pilot that was working with primary care. And this, this was piloting the use of of resources to help primary care identify FH in, their cohort of patients. [00:20:47] And so for this, we used the UCL Partners Practical FH FH screening. And this really is something that was utilized by the entire primary care workforce. So the idea is a was not of the pilot was that it's, you know, we can utilize your amazing nurses and pharmacists and care coordinators, healthcare assistants to do this

screening with minimal input by the GP. [00:21:09] And so by having really accurate family history data, that, that this would really support this, which is essentially on You know, an audit on emus and system one to identify those high risk patients and then go through in a stepwise process to identify those who may be at risk of having FH and, getting in touch and potentially referring for genetic testing. [00:21:31] Munir Adam: One of the things that worries me a little bit about routinely testing too many people's cholesterol levels. is what happens when it comes back normal. Because it may lead to false reassurance in terms of what they're allowed to do in their lifestyle. [00:21:44] They might not feel under pressure to do anything about trying to remain as healthy. The, thing is that low risk doesn't mean zero risk. When you're, under the age of 40, often your risk markers will come back as being quite low risk, right? [00:21:56] Unless, unless you're then found to have something like FH you're kind of reassuring them even more by saying, Oh, your cholesterol is absolutely fine. So, it may encourage careless behavior,.  [00:22:05] And on the other hand, if it comes back high but they're otherwise not at high risk, and there's something about medicalization in society. What would you say to that?  [00:22:14] Anwar: Koreshi did a study that showed that statins, early, increased life expectancy in FH by 10 years.  [00:22:22] Munir Adam: Wow. Okay.  [00:22:23] Anwar: Okay. But the other thing, it goes back to your point earlier, Munir, people have a choice. I mean, we can't, everybody have, mm-Hmm, , you know, healthy lifestyle all the times. If they wanna do it, they, it's their decision. It professor Humphreys who has done the, it's toolkit on the RCGP website. He was telling me you 10 12 year olds. with blocked arteries So, it's, it's those people we need to pick up. That's what I'm trying to get across. So if we just focus on our role on picking those people up early, treat them aggressively. is what we want to be doing. Management of FH[00:22:52] Anwar: One of the things I find really helpful is to have the NICE guidance on my desktop. I don't forget things. But I think and the middle part of NICE guidance is really where we need to focus on for suspected FH because that's got the guidance for severe hyperlipidemia. [00:23:08] And really the goal is 50 percent reduction the baseline. And, and, and really what they're saying is measuring lipids every 8 to 12 weeks and adjust and titrate the doses. And you could actually add Ezetimibe to increase the reduction of LDO by 65%. But as I say, the important thing is to think about a statin such as atorvastatin or Rosuvastatin. [00:23:33] And, and if you're thinking of atva, you are looking at 40 milligrams or 80 milligrams because they've been shown to reduce LDL Cholesterol by about 50 odd percent Reserves around that same dose as well with 20 to 40 milligrams. So it's about not messing around

with the Pravastatin and Simvastatin just go straight in with the high dose and actually lower that, that lipid level. [00:23:56] So I, I think that was the main thing I wanted to say, and you don't need a lipid clinic  [00:24:00] Munir Adam: for that. Oh, right. That's such an important point, actually, because I think instinctively when you're starting statins on a younger person, you may well decide to opt for the very, very lowest dose you can get away with. [00:24:12] And actually what you're saying is that these are the people who need a good going, high strength statin, at least to begin with, if you seriously want to help them.  [00:24:20] Dominic: Yeah, absolutely. It's because, they've had that, life-long exposure to high cholesterol, and that's what gives them that marked increase of cholesterol of coronary heart disease a young age. So you do treat them aggressively to bring it down to as low as possible, really.  [00:24:34] Anwar: that's more pertinent given the long waiting time some lipid clinics have. So I don't think you wait, you just go in for it.  [00:24:41] Dominic: Let me just say that, , Equally important to the statin though, so it's, you know, it's 50 percent medical treatment, but the other side of things is that it is incredibly important that their diet and lifestyle is as healthy as possible as well. [00:24:54] So that means eating well, you know, avoiding high fat foods and, and ensuring they're exercising within their abilities.  [00:25:02] Munir Adam: Yeah, okay. I think all GP practices should have a little mini gym inside them. Start by, you know, with the staff setting a good example, invite the patients. And I know one practice actually who got funding for a treadmill. One of my friend's practices. Maybe that's the way to go.  Cystic Fibrosis[00:25:17] Munir Adam: Yeah, maybe Okay, cystic fibrosis a different condition again, not much not one that I know very much about that's also a genomic related condition, isn't it? How is that different?  [00:25:30] Anwar: Right? Okay so, As you all know cystic fibrosis is a another genetic condition. It's autosomal recessive it's the CFTR gene. There are many different mutations, by the way, and when we do carrier testing, it's looking to the 50 common variants. It never brings the risk down to zero and we're doing some newborn hill creek, testing now where we're looking for the hundred most common variants, but they may miss the rare variants. [00:25:57] The prevalence is one in 2, 500. And about 1 in 25 are carriers, but that's white caucasians, so the Doms and the Claires of the world, really whereas you and I will be,  [00:26:08] Munir Adam: we got the cholesterol, haven't we?  [00:26:09] Anwar: Well, we've got we've got less cystic fibrosis. We're looking at 1 in 94 of Asians, really. [00:26:15] Munir Adam: Okay.  [00:26:16] Anwar: I think the bottom line is it's a thick mucus that just blocks the various, should we say tubes? So blocking the respiratory tubes, you

get respiratory damage. GI tubes, you get pancreatic insufficiency. Reproductive tubes. That's the way I tend to look at it, really. And, and actually if you look at the test directory, and please people do look at the test directory and if you just put control F and you put cystic fibrosis, it'll bring up the test for cystic fibrosis. [00:26:43] It's under R185, but you don't have to worry about that. I'm just showing off that I prepared for it. They're available to all workers in primary care. don't need referral to genetics. And the test result comes back in eight to 12 weeks. [00:26:58] If a patient's pregnant, then you probably want to do an urgent referral so that we can deal with that. We haven't got much time to play with, really. And, if you go on the the GOSH website or any of your local genetic service website it'll have the blood test ordering form. Just a quick point about blood test ordering. It's really important if you're ordering a carrier test You you're doing it because of the family history of a close relative up to fourth degree, by the way or Something similar in a partner as well Or that you're a partner of a known cf or there's close consanguinous couples and from an ethnic group with a higher Frequency and if that's the case Then you can order the test the test forms on the website and you can download it. [00:27:47] So and, and you just send the test off and they'll send it to the right people. The result will come back about saying the prior risk is, I don't know, one in 400. And then the, then if the risk is higher, they'll say. If the risk is low, it's never negative. You can't say it's negative because there may be some rare variants, but you can decrease the risk. [00:28:09] of cystic fibrosis, and that's what we need to be saying. Now, if you've got a known person with CF in the family, then you would actually highlight that known person. And they could find the specific mutation in that person and then everybody could be tested looking for that mutation. But for screening purposes, you're looking for the commonest mutation. [00:28:31] Munir Adam: Okay. And will it include a link to that? Yeah. Okay. All right. Well, that's an interesting contrast, I suppose, going from an autosomal dominant to an autosomal recessive, which therefore creates that additional consideration that there may be many carriers out there, as opposed to with FH, where there may be people who are actually affected and still might not know that they have it. Take-home messages[00:28:55] Munir Adam: Okay, so to wrap up then, in one or two sentences, Dom, what would you say? Take home messages.  [00:29:02] Dominic: Yeah whenever we do these this type of engagement, we're always saying to people to think genomics. And if there are some terms or, or things that we've spoken about today that you're not aware of, there are many great resources on the genomics education program website to upskill yourself and find out why Genomics is relevant to you, particularly FH, there are some amazing modules. [00:29:21] But again, I would also say I want you to think FH and emphasis on the F. FH is a familial disease. And so when you have someone that you think has FH you really have the power to change and save the, current and future relatives as well. So not just that person in front you. [00:29:38] Munir Adam: Right. I got that. So family history, very important and follow through with it. Anwar, what would you say? Okay.  [00:29:43] Anwar: You have a duty of care to think genomics and it's not as complicated as people make out. There are lots of resources on the DLH website, but more importantly, which you may not know, is the first Thursday of the month between 12.30 and 1 there's a drop in session for you to ask any questions around that. So, really your patient deserves the best care, and that includes thinking of genomics. As I often say, the genie is out of the bottle.  [00:30:08] Munir Adam: OK, thank you. Claire? What do you think? It's good.  [00:30:11] Claire: It's actually been lovely to speak to people who put it in a very practical way that I can take on board immediately and put into my practice. [00:30:17] So another thing that's randomly screamed out to me through this whole conversation as well, some areas we've discussed, a third of are having MIs by kind of the age of 60. And again there's a marked underdiagnosis like you mentioned in kind of black and Asian communities, there's a massive area of health inequality, related to this, that which has come out loud and clear to me, really.  [00:30:38] Munir Adam: There we are. So we're sold on it, right, Claire? So, that's very convincing. Thank you very much. Thanks, Anwar. Thanks, Dom. Thanks, Claire. We're gonna be back next month with the next episode as we continue this all important and often neglected topic of genomics. [00:30:55] I've certainly got some take home messages here. The main thing for me is to make sure I ask a family history. If you guys listening out there are already doing that, well done. If you're like me, you have been skimming past this a little bit, family history. Well, now's the time to change. That's the whole point with these episodes, that you actually do something different after you've heard it and let others know about it as well. [00:31:13] Thank you for listening.