This is the transcript of the seminar on assessing the degree of iron overload in suspected haemochromatosis with Dr Bill Griffiths.

[00:00:00] Neil McClements (CEO, Haemochromatosis UK): [00:00:00] There we go. Perfect. 

[00:00:10] Dr Bill Griffiths (Consultant Hepatologist): [00:00:10] Right. Okay. As I said, thank you very much for inviting me to talk on this subject this morning. Welcome everybody. I'm just going to start the talk by just talking briefly about haemochromatosis, I'm going to talk about ways that we can evaluate the degree of iron overload in haemochromatosis, but also in general, because we have patients obviously presenting with haemochromatosis or different genetic forms of haemochromatosis.

[00:00:40] And it's useful to know, the degree of iron deposition in these patients.


[00:01:00]If we look at the common form of hereditary hemochromatosis, so thinking mainly about C282Y homozygotes, but could apply to other forms. We have this sort of iceberg, if you like. So we have, at the bottom, the genetic predisposition, which you're born with. And then over time, we get expression that's evident in the bloods, but not necessarily evident clinically.

[00:01:29] So the earliest signs will be this rise in transferring saturation, perhaps in the twenties, if you're a male, perhaps a bit later, if you're a female and then gradually over time, but also, with other factors and obviously with females there are iron losses, but in general terms, for example, excess alcohol, and we know that there are also some genetic modifiers, we can go on to see symptoms develop as the iron overload progresses and eventually organ [00:02:00] damage.

[00:02:00] And we know we don't want to get to this stage if possible, and preferably not even this stage, because if we intervene early, we can prevent this arrow going in this direction.

[00:02:14] So, how do we quantify excess iron? Well, the sort of tried and tested method is just to measure the serum ferritin, which is pretty good. But we'll elaborate on that a little bit later, historically one would have done a liver biopsy to confirm haemochromatosis. And measure the amount of iron in the tissue and then do a sort of ratio, to look up something called the hepatic iron index.

[00:02:48] And there was this sort of magic figure of 1.9. If you had more than 1.9, then you'd got hereditary hemochromatosis. And if you're below 1.9, you had iron because you were drinking too much or some other [00:03:00] reason, but this was very historical and we don't really use this anymore. More recently however, we have been looking at MRI in particular because there are techniques with MRI, which I'll talk about that allow us to measure iron in the liver in particular.

[00:03:15] MRI can also pick up on and other organs such as the heart, the brain, not so good in, in some of the areas where iron can be deposited in haemochromatosis, but we can talk about that as well at the end. And then the other way of sort of measuring the amount of iron present is by removing blood and then seeing how much blood is needed to be removed to normalize the ferritin levels, sort of connotative phlebotomy method, which is retrospective, but can give you some information.

[00:03:51] So, let's look at serum ferritin first, we know that, in haemochromatosis [00:04:00] there is this, correlation really with the amount of iron in the body. So, whereas transferrin saturation is really just a marker of excess iron coming in from the gut and loading on to a very specific the molecule, which is just present in the blood.

[00:04:17] And there's really only about a thousand of your total body iron actually bound to transferin. Ferritin does correlate well,with the body iron stores, and we have these diagnostic thresholds in females and males. And we say that if the ferritin is above that level, then we'd be concerned. There might be excess iron in the context of someone with proven haemochromatosis, genetically proven hemochromatosis.

[00:04:39] We also know that the ferritin level falls fairly predictably with venesection. Although those of you who've had venesection know that it's a bit of a stuttering line back down to baseline down to normal. But on average, about a 50 microgram per liter drop her units of blood removed.

[00:04:59] Now we also [00:05:00] know that ferritin is elevated in other situations, and this is where it becomes a bit problematic to necessarily rely on it and ferritin can vary, and this can depend on other conditions that might be present. So it can vary with alcohol any inflammatory condition. If someone's developed diabetes or related problems to do with fatty liver and  there are one or two other situations where ferritin can be raised.

[00:05:25] So  it's not specific for iron overload, but if it's a sort of a clean situation where you haven't got those other factors present and you've got your, particularly homozygosity for C282Y, then it's pretty reliable. So a while ago, we did look at, some patients in Cambridge and so this was a cohort.

[00:05:48] This is going back some years. Now there's quite a few more since then, but just shows what we were doing because we're doing a lot more liver biopsy back then. And this clinic I set up in 2000, most of these [00:06:00] patients would be in the sort of 2000 to 2010 period when we were doing biopsy more, certainly a lot more than we're doing now.

[00:06:07] So I had a bit of data to look at and you can see in the top graph, you know, there were a fair proportion of patients just did a biopsy wasn't indicated but you can see varying ranges of liver fibrosis along the X axis, culminating in psoriasis. I've also added the compound heterozygous form, which generally is a milder form, but occasionally we do see more severe scarring, but this is

[00:06:33] almost exclusively when there are other liver conditions present such as due to alcohol or obesity. And then if we look at, the amount of iron that,in the biopsy itself, once we start to get  a ferritin level above a thousand, we start to see scarring develop in the liver, and once we get an iron grade, [00:07:00] up to about three, we start to see scarring develop in the liver.

[00:07:03] So really you have to sort of start to develop quite a bit of iron in your liver before it scars. And you can get away with a sort of a grade, two iron or a ferritin below a thousand and not really get much in the way of scarring. So, small amounts of iron is relatively safe, but once we get these, these higher levels and we start to see scarring.

[00:07:23] So it just cause a little bit of an indication of how ferritin and how we used to use liver biopsy for assessing on.Now in terms of the liver, just to give you a bit of background,  the liver is made up of hexagonal units, which you would only see under the microscope and in hemochromatosis we talk about what's called a periportal distribution of iron.

[00:07:50] And if you look at this cartoon of the liver, you can see that there are these things called portal tracks dotted around, and then the central vein in the middle. And so periportal [00:08:00] means that the iron will be sort of initially seen around the portal tracks and would sort of get wider and wider and eventually go to the central vein, fill out the whole liver.

[00:08:11] What's called a hexagonal section of liver. And as I said, historically, we used to quantify the amount of iron in liver by, sort of measurement technique using the tissue but liver biopsy is invasive and is prone to sampling error. So this is an example of a liver biopsy showing the iron quite nicely with the stain.

[00:08:34] And you can almost see these hexagonal units as well. And you can see that it's concentrated in certain areas, which will be the periportal areas. We know from looking at, explanted livers from, from patients with iron overload, who've had liver transplant if you look across the whole liver, there are some areas where there are more iron some areas where there are less.

[00:08:54] So, you wouldn't necessarily get an accurate feel for the amount of [00:09:00] iron in the whole liver based on a biopsy. So, this is where we start to think about techniques that might look at the whole liver, so MRI, how does it work? Well, this is just a very rough guide to how we detect a signal using MRI.

[00:09:17] Patient goes into this tube and is placed in a strong magnetic field, the radio-frequency excites protons and in particularly in water. And then when it excites these protons, they sort of release some energy and that's detected by the scanner basically. And  the sort of rate at which it picks up these energy waves can depend on whether there's iron present.

[00:09:43] So it happens quicker if iron present and then that's all converted into an image. And this is the sort of image you might get in haemochromatosis so the signal in the liver is quite dark[00:10:00] because the iron has caused everything to be lost very quickly.

[00:10:04] Whereas if you look at muscle, there's a lighter color and spleen is even lighter than that. So we're looking at the sort of blackness in the liver when we look at an MRI of a patient with iron overload.Now MRI is useful to look at a patient with an elevated ferritin where you might not necessarily have your standard form of haemochromatosis.

[00:10:27] I'm just giving this case. In fact, as an example of how MRI is useful to sort of help delineate what might be going on. So this is a normal MRI for reference, and you can see that the liver is similar intensity to muscle on this, what's called a T2 weighted image. In our standard sort of haemochromatosis patient, like I just showed you, we've got this fairly black liver.

[00:10:53] And then this particular patient who had a ferritin about 3000, interestingly, a normal [00:11:00] transferrin saturation had not only iron in the liver, but also on the spleen. He didn't have any known haematological condition and we went on to do a liver biopsy. Now this biopsy does show excess iron and again, using this stain you see the iron in blue, but the iron is distributed slightly differently, to

[00:11:23] it would be in a haemochromatosis because we're seeing it concentrated mostly in these cells, which are called Kupffer cells. Now, these are white cells or macrophages that tend to gobble up red cells and store iron and then release it back for the bone marrow to use but sometimes the iron gets locked in these cells in this particular condition.

[00:11:47] And this is why you see the spleen look dark because the spleen is full of macrophages. So this is pretty much a condition where iron is locked in macrophages, and you may not be familiar with it, but this is something called [00:12:00] ferroportin disease. Which is an entirely different condition to HFE haemochromatosis, but just shows how when we use MRI, we might detect this sort of condition.

[00:12:12] I don't want to bore you with too much detail about this condition, but it is very different because it's inherited in a different way, also more dominant rather than recessive for HFE. So you just basically pass on one copy of the mutation and that gives you the condition. You pass that onto the next generation and so on.

[00:12:32] It can occur in all populations across the world. And whereas in HFE, we have this raised transferrin saturation at the outset. It's normal in this particular case, the iron is very much stuck in these macrophage cells but it's a generally a mild condition, but it's one that we do pick up occasionaly.

[00:12:59] I just going to [00:13:00] give you a very, very brief overview of how we actually quantify iron in the liver. I've shown that we can demonstrate it, but actually what we want to do is know how much is in there. And you may have come across these various terms, which is why I've put this slide in because you sometimes see people talk about T2.

[00:13:19] T2*,R2,R2* and it's all to do with how that signal that the MR Scanner gets back from wherever it's trying to receive the signal. So for example, one part of the liver. And, the T refers to the time. So it's the time with which the signal comes back. And the T2* is because actually  in reality things are slightly different to what they are in theory.

[00:13:51] So the T2* is really your real T2 or observed T2. And R is basically the [00:14:00] inverse. So R is how quickly the signal relaxes. And so you end up with this R2 and again, R2* depends on the sort  observed. So when we look at techniques that measure liver ion, they often refer R2 or R2* or T2.

[00:14:18] It's all pretty much the same thing. But depending on whether they use the normal time or the start time, if you like, you might get slightly different readings and then you map the liver. So you basically get all the signals from the liver, avoid the blood vessels so that you get the full liver, or we call the parenchyma, the solid bit of the liver.

[00:14:38] And then that is converted through an equation in determining the liver on concentration. And this has all been sort of calibrated some years back. So that in fact, any MR scanner can do this using software. Although there are some companies that do this technique as well, but it can be done on any MR [00:15:00] scanner basically.

[00:15:01]  Then we have this sort of  value which the normal range is up to about 1.8 milligrams per gram, for argument's sake 2, you know, would be a sort of cutoff if you like. So with this knowledge and with our ability to have done this in Cambridge for some years. And we wanted to sort of look at MRI and quantification, see how that compared with ferritin and some other measures of iron overload.

[00:15:32] So this is a fairly recent study where we presented this at European liver meeting last year. We took 93 patients who had either raised serum ferritin or had HFE diagnosed. This was sort of a mixture of patients, some of which had HFE haemochromatosis, some were homozygotes, some were compound heterozygotes and then a fair few,  [00:16:00] were wild type or just simple heterozygotes, but had other liver conditions making the ferritin elevated.

[00:16:09] We did exclude patients with sort of extreme cirrhosis and hematological disease. And then we looked at the risk factors for liver disease, and then we sort of basically studied this data set to see if any patterns emerged.

[00:16:28]  So, of these 93, we had 45 homozygotes, 23 compound heterozygotes and 25 sort of other, if you like.

[00:16:41]The homozygotes were broadly half female, half male, the ferritin range is quite a wide range. A mean of just over a thousand, transferrin saturation, again  we'll see some variability, but the mean was about 81%. [00:17:00] And the MR Liver iron concentration for this group. Again, a range from normal to pretty high, around 10 milligrams per gram.

[00:17:08] Remember upper limits of about 1.8, a mean about five. So, you know, that is definitely a significant amount of iron in the liver without a doubt. When we look to the compound heterozygotes, they had a similar ferritin level, almost the same, In fact, as the homozygotes, transferrin saturation was lower around 51.

[00:17:31] And the liver iron concentration was about half of what we saw in the homozygotes. So the average was about 2.4 and I'll come on to a bit more detail about this group in a minute, and then not dissimilar there is this other group again, similar ferritin, overall mean ferritin level around thousand.

[00:17:58] Transferrin saturation [00:18:00] verging more in the sort of normal range. MR liver iron concentration only just above normal. And remember, these are patients with an average ferritin or over a thousand, so really only just elevated and not particularly significant mean, but the odd one with a significant range.

[00:18:20] And we also found that if you had liver risk factors such as alcohol or obesity, then the ferritin levels were higher than those without, with sort of similar liver iron concentrations, we did some statistics on this and this came back significant. So the next thing we did was we correlated ferritin with liver iron concentration in the homozygotes.

[00:18:47] And I'd say the correlation was not brilliant. It was only just what we call  moderately positive. So this is an R value using something called a Pearson coefficient, which is a [00:19:00] statistical method for measuring correlation. So not a great correlation and in fact, it was certainly worse in the compound heterozygotes and the other group and the transferrin saturation

[00:19:13] in fact, did not correlate at all really. The liver iron concentration, as I said, was, higher in the homozygotes than the other groups. And this next table just shows, sort of table showing the different ranges. So you've got the ferritin down this one, this side of the table, and then across, you've got the different concentrations with the means.

[00:19:40] So you could probably just look at the means and you've got homozygotes, the compounds and the other. So it just shows that for each ferritin range, you're seeing these higher values in the homozygotes. And slightly higher values in the compounds and compared with the wild type and the simple heterozygotes.

[00:19:58] And obviously as the ferritin goes up, you're [00:20:00] seeing higher values of liver, iron concentration with a bit of, not the trend, not quite following when you get to the sort of extreme ends, but we know that again, you know, ferritin may be manipulated by other factors. And then this sort of does also point to the fact that ferritin is not a perfect correlation with liver iron concentration, which we think is probably better.

[00:20:26] And this shows quite nicelythe sort of scatter plot, if you like of  the homozygotes with their liver iron concentration on the Y axis and ferritin on the X axis. So it's going  sort of reinforcing the same point that you've got these generally high liver iron concentrations for any given ferritin level and that the compounds and the heterozygous, the simples and the wild types are certainly in a much lower sort of range for any given ferritin value.

[00:20:56] But obviously with some scatter.

[00:21:01] [00:21:00] Now, when we looked at the risk factors for liver disease these were more relevant in the patients who did not have homozygous gene for HFE. So they were present in some of the homozygotes, but at a lower level and we're looking, we're concentrating mainly on patients with ferritin above a thousand here, but you can see that increasingly comes into play

[00:21:25] when you look at the other groups, so there's a take home from that, if you have a patient with a high ferritin and they're not homozygous for HFE, then you really should be looking for other factors that might be influencing the ferritin level which in turn is going to overestimate the amount of iron.

[00:21:46] We went on to do one further bit of analysis.Sorry, a couple of further bits of analysis. We did just look at a little bit more to do with, certain ferritin and liver iron concentrations. [00:22:00] So, interestingly, if you look at these non-homozygotes, even if the ferritin is above 500, a fair proportion had a normal liver iron concentration.

[00:22:13] So again, it's just showing that, high ferritin doesn't necessarily equate to high iron and again, this was sort of demonstrated in even higher ferritin groups. So ferritin above a thousand, a third of this simple heterozygous wild type group had normal liver iron concentration. And then if you look at the compound heterozygotes, all of them above a thousand

[00:22:37] had significant liver iron concentration. So I think compound heterozygotes need to be looked at separately. And if the ferritin is above a thousand, then you probably are going to be looking at significant liver iron, but below a thousand you may certainly not have significant liver iron.

[00:22:55] Just a bit of further analysis. And then we looked at this[00:23:00] idea of measuring iron through the amount of blood. And we took the patients who'd actually had venesection. So there were 20 patients who’d had venesection, 18 homozygous, two compound heterozygotes, and they were,for just simplicity.

[00:23:20] looked at when the ferritin got to below a hundred, rather than necessarily a much lower range. It measured the amount of blood that was removed by going through the clinical records and calculating from the units and the frequency and the total number of visits, basically. So, the range was 55 to 28 individual phlebotomies with between half and one unit, sometimes three-quarters of the unit.

[00:23:46] So a little bit crew, but it gives us a value that we can use. And in fact, the liver iron concentration as measured by MRI did correlate well with total venesection volume as shown on the next slide, [00:24:00] which shows, this is a little bit, plotted slide, but basically you got the, the ferritin level going across the bottom and then you've got the, the liver iron concentration and the total venesection volume on the two Y axes.

[00:24:17] And you can see that basically the lines sort of correlate quite well, and so,  it does look as though MR Liver iron concentration is giving you better information than serum ferritin, because it correlates well with this  method of calculating iron, which we think is reasonably accurate.

[00:24:41] So conclusions from this study were that liver risk factor are more common in non homozygotes and contribute to serum ferritin. And this is particularly relevant when the ferritin is above a thousand, the liver iron concentration can [00:25:00] be normal despite the ferritin being above 500, but if you're above a thousand and are a compound heterozygote, then you are likely to have, significant iron overload.

[00:25:12] When I say significant, I mean, greater than two, but you could argue that 2.1/ 2.2 is not totally dramatic. And then, further conclusions, overall is the data supports venesecting homozygous, even with the raised ferritin, even some of those homozygous with the ferritin, just above the normal range, had significant liver iron.

[00:25:39] So you can't ignore ferritin in homozygotes.The liver iron concentration however did not correlate as well with ferritin as we thought it might, but it does certainly with Quantitative phlebotomy or total venesection volume. [00:26:00] So we think that MR Liver  concentration is probably better than ferritin in determining iron overload, but you wouldn't necessarily need to do it in a homozygote because we know that a raised ferritin is going to indicate iron overload in those patients.

[00:26:17] However, I think that it can be useful in non homozygotes and in general sort of in terms of investigating high ferritin levels.

[00:26:30] So in summary, sorry, that was quite a lot of data. But the bottom line really here is that Serum ferritin is a reasonable guide to iron overload and homozygotes. Non-homozygotes, ferritin can overestimate the degree of iron overload. We know that MRI is useful in quantifying iron in the liver and can do it fairly accurately [00:27:00] and it's probably more accurate than ferritin and that it can assist with venesection decision making.

[00:27:10] And as I said, the compound heterozygotes just need a little bit more attention because they are prone to loading iron, just not generally reaching the point where they develop sort of the real symptoms and signs you get with the homozygotes. And we also know that MRI.

[00:27:31] By doing MRI and suspected iron overload that can help determine the patients that might need to have additional genetic testing. So I'm just going to finish by showing you this paper, which is pretty hot off the press.And hasn't come out in its full form yet, but this is from a colleague of mine in Austria called Heinz Zola in Innsbrook who has just published a paper, showing that MR liver iron is useful

 [00:28:00] for selecting patients where you might want to do over and above genetic testing. So not just HFE genotype and this goes on to look at other genes that can cause haemochromatosis. And this involves over 400 patients who had HIV testing and MR to calculateliver iron, included in that were 41 homozygotes.

[00:28:28] There were 200 patients, out with the homozygotes who had on overloade MRI and 256 had elevated T saturation. They went on and did what's called next generation sequencing. So that's basically looking at a panel of genes, including HFE to see whether there are any genetic alterations that could explain iron overload in those patients.

[00:28:53] And they did find mutations. Obviously most of them were in HFE, but there also some, and this is a gene and the [00:29:00] transferrin receptor two gene were just the ones they highlighted, but there would have been some other genes and they had a sort of a reasonable pickup. If you like,  other conditions, small numbers.

[00:29:12] And they also showed that if you had mutations in other genes, then it was associated with low spleen iron. Take that how you will but not necessarily a raised transferrin saturation. So that last bit, I would need to look through the paper and just try and understand that a bit better.

[00:29:31] But, it's just showing that, we are looking at liver iron a bit more, as I said, I think homozygotes, it's not really necessary.You might want to do it just for the sake of it, but I don't think it's going to really alter what you are going to do to the patient. I think if you're dealing with the non-homozygotes it’s much more useful because ferritin is just not a [00:30:00] very accurate guide in those patients.

[00:30:03] So that gives you a little bit of a flavor of the sort of stuff we've been doing in Cambridge to try and look at  measuring iron in patients. And we've got plenty of time for questions because we've got until 12 o'clock. So my last slide is this one: questions. Thank you.

[00:30:23] Neil McClements (CEO, Haemochromatosis UK): [00:30:23] Bill. Thank you very much. That was a very,very detailed presentation in a very short period of time.

[00:30:29] A lot of information there, we've already started to get some questions coming in.So just as a reminder, if people do want to ask a question to Dr. Griffis, you're very welcome to if you could drop that into the Q and A feature on zoom, that would be really helpful. So anyway, whilst people are pondering, their questions, we've got three questions that have come in.

[00:30:53] The first one, Bill, if I could put this to you, we [00:31:00] know that the liver often bears the brunt of on overload and many of us have liver scans. However, if we are fortunate enough not to have own deposited in our livers, how do we know where it’s ended up? Is there a pattern to iron deposition?

[00:31:16] Dr Bill Griffiths (Consultant Hepatologist): [00:31:16] Yes.

[00:31:16] No, that's a good question. So, invariably in haemochromatosis, iron will go into the liver first, the gut drains blood to the liver and with increased iron coming in through the gut, which is basically the defect in haemochromatosis. You can't regulate your iron absorption. The liver will pick up the iron first without a doubt.

[00:31:41] Iron is consistently deposited in other organs as we know. But it would hit the liver first in my opinion. And then it's the question of where else it might end up. It does seem to get into the joints. As we [00:32:00] know fairly easily. We can't really see that with MRI. We only know that from historical

[00:32:09] examination of the sign avium under the microscope, which is the lining of the joint. In severe cases, we do see iron in other organs, hearts, pancreas, some endocrine organs. I don't think anyone has demonstrated iron in the brain in haemochromatosis on MRI. I'm prepared to be pretty wrong. But that's a sort of distribution we'd be looking at, but it really would be a case of the severity dictating where the iron's going to end up ultimately.

[00:32:45] And certainly the liver's going to get hit initially. And in any patient with iron that's in other organs, apart from maybe the joints, you're going to have absolute saturation of iron [00:33:00] in the liver by then, or before that happens. I hope that helps answer that question.

[00:33:07] Neil McClements (CEO, Haemochromatosis UK): [00:33:07] That's great. Thank you very much, second question we've received.

[00:33:11] As in the advances made in the treatment for prostate cancer, the MRIs provided physicians with the ability to target specific areas for further exploration, enabling less invasive biopsies to take place. My question is will the MRI be able to target equally certain areas in our bodies where  iron loading is high and can this then further provide a therapy for those as an alternative to venesection.

[00:33:40] So can an MRI be used as an alternative to venesection.

[00:33:46] Dr Bill Griffiths (Consultant Hepatologist): [00:33:46] So I think this is maybe just confusing, two different types of conditioning, if you like. So with the prostates, what they're referring to is that they're able to sort of see particularly nodules within the prostate that might be [00:34:00] cancerous and then target them

[00:34:02] with some form of radiotherapy or what have you. So, that's really using the imaging to, to find a focus that needs treatment. Whereas with haemochromatosis, we know that iron is going to be deposited in the liver in a fairly diffused way. There might be some areas that have a bit more, some areas that have a bit less, but MRI is going to balance that out when it does its calculation and you wouldn't treat one area, that's got more iron than another.

[00:34:29] You're just treating the whole liver and the whole body as a whole. So, it doesn't really work the same way. Yes, we can pick up MR and some other organs, but again, that's not going to dictate a different treatment.

[00:34:47] Neil McClements (CEO, Haemochromatosis UK): [00:34:47] That's great. Yes. Thank you. Sally has asked a question, you mentioned the correlation of ferritin levels with obesity.

[00:34:56] Could you expand on this?

[00:34:59] Dr Bill Griffiths (Consultant Hepatologist): [00:34:59] Yeah,  [00:35:00] this is quite a complex area I have to say. So we know that something called insulin resistance or all sorts of pre-diabetes can cause a raised ferritin and so anyone with obesity and other features that go with that, what we call the metabolic syndrome.

[00:35:21] So that's hypertension, high blood pressure, cholesterol, diabetes, fatty liver. These things all go together, we tend to see raised ferritin in that context. There is something to do with insulin signaling and ferritin production, which is sort of understood to some extent at a molecular level, but not fully.

[00:35:46]We know that, in fact, people have tried to venesect, Diabetic patients without necessarily iron overload and that improves insulin sensitivity. So there is this sort of [00:36:00] complex interplay between ferritin, insulin, resistance and iron, but it's not all fully understood, but we know that ferritin goes up in pre-diabetes in obesity and fatty liver, and it's all sort of interrelated.

[00:36:22] Neil McClements (CEO, Haemochromatosis UK): [00:36:22] Thank you that that's a very thorough answer to Sally's question. Vanessa has just put a question up. Vanessa's asking, how often do you think homozygotes, like myself should have a fiber scan done?

[00:36:42] Dr Bill Griffiths (Consultant Hepatologist): [00:36:42] Okay. That's that's a good question. Let's start from the beginning here. So if we have a homozygote, okay. We know that if the ferritin is less than a thousand, the alt is normal.  [00:37:00] The liver reading is normal and there's no enlargement of the liver. We know from a study that was done in 1998, just after the HFE gene was discovered.

[00:37:12] Those patients have no risk of liver fibrosis, basically. So the ferritin below a thousand normal liver reading, no enlargement to the liver, we don't actually need to do any liver assessment because we know the risk is extremely small of having any scarring. And these are only reason for doing a fiber scan is cause we're concerned.

[00:37:28] There might be some liver scarring. So if we exclude that group, we're then into the next group, which have ferritin above a thousand or abnormal liver reading or liver enlargement, I would personally do a fiber scan at that stage at diagnosis at the beginning of this process to see whether there's any sign of liver scarring.

[00:37:48] Now the data on fiber scan in haemochromatosis is still a little bit in its infancy. But there are studies out there that, and really just [00:38:00] need to look at the data suggests that if the fiber scan is normal, then that's reassuring. If it's raised, then there could be liver scarring, but it's not very specific.

[00:38:10] So a raised fiber scan, I would normally do a biopsy, but, perhaps if it's only slightly raised, I might not. And then I might repeat it after an interval just to make sure it's not getting worse because we are moving away from liver biopsy, we used to always do liver biopsy at the outset, apart from that initial group, with the ferritin less than a thousand normal liver tests.

[00:38:35] So, we have to use fibers scan a bit with caution and haemochromatosis because the data isn't so great, so I use it as a bit of a guide and I also look at ultrasound. So liver ultrasound is useful to give any indication there might be significant liver scarring. But if again, the ultrasound is normal or just shows a bit of fatty liver, [00:39:00] then it's not really telling us an awful lot, but it is a bit reassuring.

[00:39:04] So it's going to be very much individual case by case as to whether you would repeat a fiber scan.If you have a fairly normal fiber scan from the outset and you treat the patient and there aren't any other obvious risk factors for liver disease, then I wouldn't repeat it. I would say that, you know, we've cleared the iron.

[00:39:26] This patient is not going to develop any problems they are not drinking to excess they are not obese,why repeat the fiber scan?You know, just leave it. Just go onto maintenance venesection. And that's  that, and just attend to any other issues, but not need to worry about liver scan. So that is the sort of rough answer, but I'm happy to elaborate on that if you or anyone else wants to ask further questions on that subject it's a good question.

[00:39:55] And, as I said, fiber scan is coming more into [00:40:00] play. We're just in the process of writing some new European guidelines, actually, which will have fiber scan in there, but again, I'm hesitant about how much reliance to put on it. And this is the problem, the data is just not fantastic and it's much better for things like fatty liver.

[00:40:19] My personal view is that you can translate that data quite well because we know that haemochromatosis is not particularly inflammatory, it's not going to skew the readings that much. I think it's a good thing to be doing in patients where there is a possible concern, but the repeating of the scan is really down to whether you're worried about it getting worse.

[00:40:46] Neil McClements (CEO, Haemochromatosis UK): [00:40:46] Interesting. For those people who are listening, you're maybe not familiar with what fiber scan is. Actually, it's a sort of an alternative to doing a liver biopsy. It's just sort of a form of ultrasound. You sort of lie on a bed and the sonographer or the [00:41:00] consultant, basically places the wand over the liver.

[00:41:02] And it fires a few rounds of signal at the liver and makes the liver wobble. So it's really a sort of wobbliness test. Isn't it?

[00:41:12] Dr Bill Griffiths (Consultant Hepatologist): [00:41:12] Yeah. There is some physics involved but yeah, that's about right? Yeah. So it's good. It's actually a very, very good technique.

[00:41:24] Because the liver is very accessible for this because of where it is near the ribs. It's quite a uniform organ. You couldn't really do it in a lot of the other organs. They do do it in the spleen and there is some evidence to do with splenic stiffness but that's a separate issue not to do with haemochromatosis.

[00:41:45] And yes, it works quite well because the stiffer, the tissue, the faster the wave travels through. And so you can get this reading that can indicate whether there is scarring, which makes the liver stiffer.

[00:41:59] Neil McClements (CEO, Haemochromatosis UK): [00:41:59] And for [00:42:00] those people who may be watching from Northern Ireland, Dutch state, until very recently had one fiber scan machine for a population of 1.8 million, they've now actually got four fiber scan machines and that's quite a significant development because people have been waiting a very long time up to two years.

[00:42:20] To have a liver biopsy done, so for those of you here in Northern Ireland if you haven't already been called in for a fiber scan you may well get a letter in the next few months inviting you to attend for that diagnostic.We've got a couple more questions come in from anonymous.

[00:42:39] So should I be concerned and what are the consequences of having a higher than normal Tsat for example, 58%.

[00:42:50] Dr Bill Griffiths (Consultant Hepatologist): [00:42:50] So I'm guessing this is in the context of someone who's had venesection as a maintenance, potentially, because this is an issue that's come [00:43:00] up recently since the paper was published in 2017, by a French group who suggested that If you run a high TSat, you're more prone to joint problems and other things.

[00:43:12] There was a slight floor in that study because it kind of picked out really the more severe patients to begin with in my view. So I wouldn't worry about a Tsat of 58% personally. It's obviously at the outset of your doing diagnosis, then it's helpful because it points in the direction of doing HFE gene testing.

[00:43:33] But if it's an established haemochromatosis patient is on maintenance, then if the ferritin is low and the Tsat is 58%, it wouldn't worry me personally, unfortunately, that French paper has made its way through, into guidelines a bit as well.I think there's differing opinion about how much weight to put on a Tsat.

[00:43:59] It really [00:44:00] needs a better study. To be honest, it needs kind of more like  a prospective study where you just take everyone who's running a Tsat of above 50 or whatever, and anyone who's running below and they're just seeing, but they have to start out equal. So these patient groups would have to have the same rates of joint disease, the same rates of liver disease for it to really be meaningful.

[00:44:28] And if you wanted to venesect someone to get their Tsat continually below 45 or 50%, you'd have to do a fair amount of venesect in some patients. And it's just not warranted. Really you'd end up making them anemic.

[00:44:46] Neil McClements (CEO, Haemochromatosis UK): [00:44:46] Interesting. I think there's this issue of Tsat has been quite a hot topic this week.

[00:44:50] Ted Fitzsimmons has some clear views about it, which were just blatantly different.

[00:44:56] Dr Bill Griffiths (Consultant Hepatologist): [00:44:56] That's it Yeah. So that's where, [00:45:00] we are. And I think, haematologists and hepatologists have slightly different views. Some people have different views. I don't think it's something to be totally obsessed about personally.

[00:45:18] And it varies, you know, you can measure a Tsat in one person one day and measure it the next day. It will be completely different. It's not a completely robust test if you like.

[00:45:32] Neil McClements (CEO, Haemochromatosis UK): [00:45:32] Okay. Let's move back onto liver matters. Carolyn says GH patients have a long list of weird and wonderful symptoms, even when ferritin is less than a thousand.

[00:45:45] So if it's unlikely, with lower numbers on is deposited in other organs. Can we attribute the symptoms to a liver out of balance? And can you give some examples of symptoms we may have as a result of that?

[00:46:00] [00:45:59] Dr Bill Griffiths (Consultant Hepatologist): [00:45:59] So I think it does depend on again, homozygotes versus compound versus other, ferritins below a thousand, you're entitled to have symptoms because we know that there could be significant iron loading particularly in the homozygotes.

[00:46:15] And therefore you may have symptoms like fatigue and joint pains are very common in that group, the ferritins  below a thousand, just really a marker of whether there's likely to be liver scarring. And it's also seeming use from the data that I've looked at  in the non homozygotes as to whether there's significant liver, iron overload.

[00:46:37] And therefore, whether people are likely to have symptoms, I think symptoms are not likely to be present if the liver isn't already loaded with iron, but it's a very difficult area because you never quite know whether a symptom is due to the haemochromatosis in the patient. You sometimes get a better idea when you venesect someone, you [00:47:00] see if the symptoms improved, but then again, you don't know if there's a bit of a placebo effect or something else would come along in the meantime to make that better.

[00:47:07] So it's tricky. I think every patient has, has to be taken on their individual merits. Really. You have to look at the symptoms. You have to look at the symptoms that are really more specific to haemochromatosis than the ones that may not be. You have to look at whether that patient has significant liver iron,you know, so you have to look at the whole thing.

[00:47:32] Basically. You have to look at the patient, the symptoms, the iron indices, the liver inflammation. And then, you know, decide about treatment and then follow that patient through and see where you get to with the symptoms. The symptoms don't seem to be obviously related haemochromatosis. You've treated the patient, they're ongoing, you know, look for other causes.

[00:47:55] But it can be difficult because the symptoms are [00:48:00] common and they're found in lots of people who haven't got haemochromatosis. And so, you know, it does become difficult. So it's very much an individual. Patient by patient evaluation.

[00:48:11] Neil McClements (CEO, Haemochromatosis UK): [00:48:11] Mm, and something which has come up quite a bit on our Facebook support group over recent days.

[00:48:17] And I think this is to some degree driven by the weather. Is people experiencing PCT, as a consequence of iron overload. I mean, what are your thoughts around using dermatological diagnostics to help diagnose iron overload? I mean, if someone's got PCT and they present to a dermatologist, is that a meaningful way of trying to establish whether they have iron overload?

[00:48:45] Dr Bill Griffiths (Consultant Hepatologist): [00:48:45] I think that, PCT is obviously quite rare, but it's quite a specific disorder, where the skin is affected, particularly when it's sunny. So the symptoms tend to be worse in the summer and better in the [00:49:00] winter, but it's also associated with iron overload because there was a link between iron and porphyrin metabolism and the P for PCT

[00:49:10] is to to with Porphyrin, which has to do with red blood cell formation. So it's a bit complicated at a sort of a molecular level, but we know that patients who are predisposed to having PCT are more likely to present when they have iron overload. So there's a reasonable pickup of haemochromatosis and patients with PCT and venesection and normalizing the serum ferritin.

[00:49:35] is a way of reducing the risk of getting the rash that's associated with PCT. So, I mean, it's not very common, I think can only think of two or three patients I've had over the years that I've venesected that has prevented them having the problem, basically. So it's definitely important to look for iron overload in that condition.

[00:50:01] [00:50:00] Neil McClements (CEO, Haemochromatosis UK): [00:50:01] That's great. Thank you. And for anyone who's interested in a bit more about skin conditions and the haemochromatosis we have actually, earlier this year published a new booklet, which is available our membership pack. So if you don't know what PCT is or what it looks like, got lots of photos of it.

[00:50:16] So you can go and have a look, see if your experience that, particularly at the moment with the sunny weather. We have a question from Sally, Sally forgive me, Sally. I think you are a hematology specialist's nurse and Sally asks this question. She says Dr Griffiths, in terms of the need for further liver imaging concentrating a liver function, would you particularly concentrate on alt or would any of the liver enzymes out of range?

[00:50:46] Prompt for imaging?

[00:50:50] Dr Bill Griffiths (Consultant Hepatologist): [00:50:50] Yeah, it's mainly alt cause that's the one that was studied when, you know, when the HFE gene was discovered, a lot of the original research [00:51:00] looked at . So alt or AST is typically raised when the liver is loaded with iron and typically improves when you treat a patient with venesection.

[00:51:11] So ,the alt might just be a marker of liver. Or it might be a marker of fatty liver or both. So, that's where I think liver ultrasound comes in helpful and it comes in handy initially when you've got to raise alt and then you have to think about whether there's a fatty liver presence, and one of the interesting things with haemochromatosis is it’s

[00:51:40] initially managed by both hematologists and gastroenterologist and hepatologist. And if you're a hematologist, you'll have a certain angle on it. And if you're a hepatologist, an angle on it. So we obviously think about the liver a lot. Just to let you know, there's a networking exercise going on at the moment in the [00:52:00] UK.

[00:52:00] So we're pulling together, basically all the hematologists, gastroenterologists, hepatologists, rheumatologists, geneticists, anyone who's clinicians looking after patients of haemochromatosis are sort of forming a group. We want to kind of standardize the investigation and management and condition across

[00:52:23] Different hospitals, where people are being seen by different specialties, basically and often it's the case. If you're seen by one specialty you think less about one organ than the other and it's true with other conditions as well, where different specialties are involved in a patient because it affects different organs, different systems.

[00:52:43]  We want to try and get some common ground, you know, so that everyone agrees what the approach of the. So hopefully that's helpful. And again, the UK guidelines, which were published in 2018 and I'm sure are on the [00:53:00] hemochromatosis UK website have some information about evaluating the liver and hemochromatosis.


[00:53:10] Neil McClements (CEO, Haemochromatosis UK): [00:53:10]  This may be asking how long is a bit of string, but this cross-disciplinary initiative. I mean where might the patient community see the first fruits of that collaboration? Do you think?

[00:53:23] Dr Bill Griffiths (Consultant Hepatologist): [00:53:23] I think Neil, you're going to hear about this pretty soon. If you haven't already obviously it's going to form under the what's called

[00:53:32] The Basel umbrella. So that's the British association of study of liver umbrella. And it’s going  to meet and discuss the topics that need addressing, the unmet need issues, if you like. And then,there's going to be a bit of data collection and auditing. [00:54:00] So there's quite a few things that I'm interested in trying to Improve.

[00:54:04] If you like, so access to services, consistency of services, access to blood donation. You know the geographical pockets in this country where patients are probably not getting the expert advice and trying to sort of get everyone up to the same standard. So there's, there's quite a lot to do really.

[00:54:26] And I think we're going to be working very closely with Neil and his organization for improving care and much of the stuff, you know, Neil and all you've already done. But, it's really just  getting these clinicians together because we've never really had a proper network formed previously.

[00:54:44] So I think this will be a good way forward.

[00:54:49] Neil McClements (CEO, Haemochromatosis UK): [00:54:49] think the first meeting is actually imminent isn't it in the next week or two,so this is actually happening. It's just going to take a bit of time to work through the [00:55:00] process,

[00:55:00] Dr Bill Griffiths (Consultant Hepatologist): [00:55:00] Right? Yep. Okay.

[00:55:03] Neil McClements (CEO, Haemochromatosis UK): [00:55:03] Great. Well, we've run to time.

[00:55:06] So I just wanted to thank Dr. Griffiths again for a very illuminating presentation and for being so thoughtful in answering questions  for those watching, if you wanted to watch this again, or if you had friends and family who might want to watch this session, we are recording it.

[00:55:30] As soon as we get time, hopefully next week, we'll get it edited and up onto the haemochromatosis UK website and also onto our YouTube channel. And just finally, I wanted to just make good quick plug for one of our events, which is happening tomorrow. Vicky, our amazing membership administrator is going to throw herself out of a plane tomorrow morning with a parachute I hasten to add.

[00:55:59] She's doing a [00:56:00] sponsored sky dive to help raise awareness for world haemochromatosis week. So if anybody's watching this and has found this session to be a value I know that Vicki would love to have a donation. So if you go to our website on iron or and give Vicki a little bit of support.

[00:56:19] I understand if we raise another 500 pounds, the plane's going to go 5,000 feet higher than they'd originally planned. So, that will make for a much more spectacular sky dive. So if anybody's interested in supporting Vicky please do. But for now, I just wanted to say thank you very much for everyone who's attended.

[00:56:37] And to Dr. Griffiths. Thank you again. And we wish everyone well for the rest of the week.

[00:56:43] Dr Bill Griffiths (Consultant Hepatologist): [00:56:43] Thank you Neil.