 So last year a patient named David came to see me for the first time. He was 34 years old and had been a vegetarian for about 15 years and He was experiencing some pretty significant health problems. So he decided to start eating meat again He did some research and he ended up on a paleo diet He did that for about a year and a half before he first came to see me and he felt great for the first nine months But right around then he started to feel worse again He was tired, his joints hurt, he had palpitations, brain fog, and low libido He saw about six different doctors before I saw him and he was diagnosed with everything from depression to chronic fatigue syndrome And he was prescribed antidepressants given lots of different drugs and supplements to take but nothing worked I ran a full blood panel on David as I always do with my new patients and I discovered that he had iron overload So I sent him to his family physician to get some genetic testing so that insurance would cover it and It turned out that he had a single copy of the genetic mutation that causes haemochromatosis But according to conventional wisdom you have to have two copies of this mutated gene in order for disease to develop So his doctor sent him away and said there's nothing to worry about Unfortunately, this wasn't an isolated occurrence Haemochromatosis is the most common genetic disorder in North America affecting about one in 200 people And that's a prevalence about 10 times that of cystic fibrosis Haemochromatosis is associated with significant morbidity and mortality and yet few people have even heard of it In fact, haemochromatosis is often misdiagnosed or simply just missed according to a 1996 Center for Disease Control survey Patients with haemochromatosis see an average of three doctors over an average of nine years before they get an accurate diagnosis And this is definitely consistent with my experience clinically Out of about 40 people that I've diagnosed with iron overload only two or three were previously aware that they had it Compounding the problem is that even mild iron overload or high normal levels of iron can be associated with increased risk of disease and death This makes it hard because even if a doctor finds high normal or Slightly elevated iron levels They very well may not do anything about it because they were taught in medical school that there's nothing to be concerned about with High normal iron or or mild iron overload Now iron is essential to all life without it life on the planet would cease to exist Plants would wither and die and animals and humans would suffocate Plants require iron to make chlorophyll and humans require it to make hemoglobin and myoglobin Hemoglobin is a protein that delivers oxygen to the cells and tissues And myoglobin is a protein that stores oxygen in the muscles which allows them to do work Other proteins also contain heme such as cytochromes that produce energy atp the primary energy currency in the cell And proteins that are required for dna synthesis Irons also needed for connective tissue to produce neurotransmitters and to maintain healthy immune function Now there's no doubt that too little iron is a serious problem a much more serious problem than too much iron In terms of disease statistics Iron deficiency anemia affects up to two billion people worldwide and this is particularly true in the developing world Without enough iron we become short of breath fatigued and our brain and immune systems can function properly But too much iron can also cause harm as little as 450 milligrams of iron can be toxic And too much iron in the form of diet and supplements can accumulate in our tissues Literally causing our organs to rust and this is especially true in the pancreas liver The joints the heart and the brain There are several medical conditions that can lead to iron overload Some of which I've listed on this slide Among the more common are hereditary hemochromatosis African ciderosis beta thalassemia sickle cell anemia alcohol abuse and viral hepatitis And among the less common are cideroblastic anemia Dismetabolic iron overload syndrome And glucose 6 phosphate dehydrogenase or g6pd Classic hereditary hemochromatosis is an autosomal recessive disorder Involving a mutation of both copies of the hfe gene on chromosome number six An autosomal recessive disorder is a is a genetic disorder that requires two copies of the genetic mutation for the disease to develop And there are two major forms of classic hereditary hemochromatosis One is c282 y which involves The replacement of cysteine with tyrosine and the other is h63d which involves the replacement of histidine with aspartic acid Since the discovery of c282 y mutation in the early 1990s At least 20 other mutations of the hfe gene that can lead to iron overload have had been identified But unfortunately their effects are not really well understood at this point We've also discovered mutations on other genes that can cause iron overload like transferrin receptor 2 ferroportin 1 chromosome number 19 Hepsidon and cda2 And these have not been well characterized either at this stage The estimates for prevalence of hemochromatosis mutations vary depending on the study you look at But according to one large review in the american journal of epidemiology About 0.4 percent or 1 in 200 are homozygous for the c282 y mutation Which means they have two copies of the mutated gene Anywhere from zero percent in asia to nine percent in north america and northern europe Are heterozygous for c282 y which means they're carriers of or have a single copy of the mutated gene for hemochromatosis For that particular mutation of that causes hemochromatosis more specifically 1.5 percent are homozygous for the h63d mutation From five to 22 percent are heterozygous or carriers of the h63d mutation And then five percent are what are known as compound heterozygous That means they have a single copy of the c282 y Mutation and a single copy of the h63d mutation So as I mentioned earlier in the presentation a common misconception is that people who are heterozygous for these mutations or carriers of them Aren't affected by disease and don't have an increased risk of death But a significant amount of recent research suggests that this isn't true This slide lists several different studies indicating that people who are carriers of this of these mutations can have elevated iron indices And also increase risk of disease and death So there are four studies of iron loading showing That carriers can have elevated iron saturation and ferritin levels There are four studies on cardiovascular disease showing that carriers can have between 2.3 to 6.6 times the risk of cardiovascular disease There are three studies on cancer showing that carriers have between 1.6 to 8.7 times the risk for cancer And and there's one study showing that carriers have an increased risk of death prior to the age of 65 In fact iron saturation alone as a marker has has been shown to predict increased risk of death In a study of 45 000 danish subject they looked at mortality levels according to baseline iron saturation Measurements and they found that survival was significantly reduced in those with iron saturation levels above higher than 50 percent And that those with iron saturation levels above 80 percent had a 2.2 fold increased risk of early death It's well known that hemochromatosis is associated with a very long list of other diseases and conditions Including liver disease, diabetes, metabolic syndrome, gout and cardiovascular disease, metabolically Neurological diseases include Alzheimer's, dementia, Parkinson's, epilepsy and RLS or Lou Gehrig's disease Endocrine conditions include impotence, infertility, hypogonadism, hypothyroidism Immune conditions would include asthma, inflammatory bowel disease, rheumatoid arthritis, lupus, psoriasis lung disease, cancer And then there are musculoskeletal conditions like osteoporosis and osteoarthritis and this is just a partial list It's it's actually quite a long list when you look at the full one But less well known is that even mild and high Mild iron overload and high normal levels of iron are associated with metabolic cardiovascular and neurodegenerative problems For example several studies suggest that iron overload is associated with diabetes and impaired glucose tolerance And this is thought to involve several different mechanisms The accumulation of iron reduces insulin production and decreases insulin sensitivity in the liver And iron deposition in the muscle decreases glucose uptake in the muscles Even high normal levels of iron have been shown to disrupt glucose tolerance and insulin sensitivity In a study of a thousand finished men glucose levels rose as body iron stores increased They divided the study population into quintiles or fifths and the increase In glucose levels was detected in the two highest quintiles for ferritin, which was the way they used to the marker They used to quantify iron stores So in people with ferritin levels between 143 and 216 and with ferritin levels above 216 They detected a slight increase in in blood glucose levels Now keep in mind that The ferritin lab range for men goes up to 400 So people in the quint in the fourth quintile with levels between 143 and 216 And a substantial number in the fifth quintile with levels above 216 were still in the normal range of ferritin And yet they had elevated blood glucose compared to people with lower ferritin levels Other interesting lines of evidence that support this connection between iron overload and metabolic disease is the include the observation that increased iron predicts Diabetes development of diabetes in the future that frequent blood donors have lower incidence of diabetes That elevated ferritin people with elevated ferritin are more likely to have hypertensive retinopathy Which is a a condition affecting the eyes In people with high blood sugar and diabetes And that those with high blood pressure have a higher prevalence of iron overload Of course, none of this proves causality. We're talking about Associations and as as i'm sure many of you know by now correlation is not causation However, there are some other lines of evidence that suggests that there may be a causal relationship between Iron overload and metabolic disease For example reduction of iron in people who who are iron loaded can restore glucose tolerance and insulin sensitivity In one trial of 25 patients with high ferritin diabetes. They separated participants into two groups One group had three therapeutic phlebotomies a week And that was over three weeks and a phlebotomy is the the removal of blood Like when you go to donate blood for example the red cross, but just done therapeutically And the other group had no treatment and in the group that had the bloodletting They the researchers observed decreased hemoglobin a1c levels, which is a measure A way of measuring average blood sugar over the prior three months And decreased C peptide levels, which is a marker used to To screen for diabetes They also had increased insulin sensitivity compared to the controls and what was especially striking about this study is that these changes persisted for up to a year after Those three phlebotomies That occurred over three week period another study of 65 patients with metabolic syndrome Phlebotomy decreased blood pressure resting heart rate fasting glucose hemoglobin a1c And the LDL to HDL ratio And this effect is not limited to people with blood sugar issues like diabetes or impaired glucose tolerance In a study of healthy volunteers with normal glucose and ferritin levels The researchers found decreased two-hour post-meal blood sugar and insulin levels One month after a single phlebotomy a single removal of blood And iron depletion to near iron deficiency Therapeutically that decreased fasting and post-meal blood sugar and insulin sensitivity and increased insulin sensitivity Excuse me in a group of patients with non-alcoholic fatty liver disease Even though they didn't have increased iron levels at baseline or any genetic mutations that lead to iron overload Another study found that induction of near iron deficiency Using phlebotomy and patients without iron overload reduced the average number of gout attacks They experienced from 6.4 per year to 2 per year And that near iron deficiency prevented relapse in 58 percent of these patients with gout And significantly reduced the frequency and severity of gout in 48 percent of them Iron overload has been shown to increase the risk of death from cardiovascular disease in a study of close to 3,500 u.s. Adults 27 percent had LDL cholesterol levels above 160 milligrams per deciliter And 1.64 percent had iron saturation levels above 55 percent Now if they only had elevated LDL or iron saturation their relative risk of death from heart disease increased by 40 percent or 57 percent respectively But if they had both Elevated LDL cholesterol and elevated iron saturation their relative risk of death from cardiovascular disease increased by 521 percent So quite a dramatic difference there The probable mechanism that explains the connection between iron overload and cardiovascular disease involves the oxidation Of lipids and free fatty acids by iron Free fatty acid oxidation reduces glucose uptake which in turn promotes gluconeogenesis in the liver and causes insulin resistance Iron is also a powerful catalyst for free radical production And free radical production contributes to oxidative damage and inflammation This explains why iron overload is associated with increased levels of oxidized LDL One study of 40 male patients found that those with iron overload had 40 percent higher oxidized LDL levels than those with normal iron levels Along with higher levels of other markers associated with cardiovascular disease like cholesterol ester transfer protein LPPLA2 and triglycerides They also had lower levels of HDL and reduced activity of important antioxidant enzymes Even people that are at high risk of cardiovascular disease that are not iron loaded may benefit from iron reduction In this study of 31 carbohydrate and tolerant patients With normal iron levels induction of near iron deficiency with phlebotomy Increased HDL and reduced fasting glucose total and LDL cholesterol triglycerides and fibrinogen And the effects of this improvement were reversed after a six-month period of iron repletion where their iron levels were returned to normal Some researchers believe that iron explains the difference observed in in the incidence of heart disease between men and women We've known for some time that pre menopausal women have lower rates of heart disease than men And that this advantage disappears when they enter menopause The early hypothesis was that estrogen was what explained this difference it was believed that As estrogen was protective and as women entered menopause their estrogen levels typically dropped so they got More heart disease, but when this was tested clinically It went terribly wrong as as you may know about from the following the hormone replacement trials or hrt debacle So they gave postmenopausal women estrogen and instead of lowering their risk as was predicted it actually doubled their risk of heart disease The iron hypothesis may be what explains this this uh beneficial effect of iron depletion on heart disease risk, so men begin acquiring iron The iron hypothesis is an alternative alternative explanation for what explains this difference in heart disease risk observed between men and pre menopausal women men begin accumulating iron from the beginning and Just accumulate it throughout our entire lives whereas women don't Accumulate as much due to continual losses during menstruation and then larger losses during childbirth Women with diabetes Lupus and polycystic ovarian syndrome all have equal rates of heart disease to men and postmenopausal women So what do these conditions have in common? They are all associated with increased iron levels In addition to the cardiovascular and endocrine problems we've discussed iron can also cause oxidative stress and neuronal damage in the central nervous system Brain iron levels increase with age even without genetic mutations that lead to iron overload And excessive iron has been found in the brain of parkinson's patients and then plaques of patients with Alzheimer's Iron overload in the brain can contribute to other central nervous system conditions like ms ALS or lugaric disease Huntington's disease stroke and cerebral hemorrhage And studies have found that the iron key later a drug that that carries iron out of the body Called dyspheria oxamine slows the progression of dementia iron's role in the oxidation of LDL may explain the common pathological mechanism between cardiovascular disease and neurodegenerative conditions And this is especially true in people with the apoE4 mutation We know that apoE4 carriers have an increased risk of both cardiovascular disease and neurodegenerative conditions And that people with apoE4 are more susceptible to oxidative damage and have higher oxidized LDL levels Than people who don't have that mutation This suggests that apoE4 carriers are probably more vulnerable to the harmful effects of iron overload and it may explain why Iron overload is more common in people with cardiovascular disease and Alzheimer's disease Now let's talk a little bit about diagnosis the signs and symptoms of iron overload include extreme fatigue Joint pain impotence or loss of libido skin bronzing, which is sometimes mistaken for jaundice palpitations depression and abdominal pain And as you can see from this list many most of these symptoms all of these symptoms in fact are are quite non specific Meaning they could be attributed to any number of problems And this is one of the things that makes iron overload so difficult to diagnose clinically As far as blood test goes serum iron is not a very reliable marker It can actually be low in hereditary hemochromatosis And this is unfortunate because when doctors do measure iron, which is not very often they often only do Serum iron instead of a complete iron panel. So a lot of people with iron overload will be missed for that reason Iron saturation, which is also called transferrin saturation measures the percentage of iron that's bound to Transparen Transparen is a protein that transports iron through the body and withholds it from pathogens because pathogens utilize iron and It's a source of energy for them And each molecule Of transferrin can be bound to two atoms of iron. So a normal transferrin or iron saturation level is below 45% some clinicians myself included generally like to see it below 45% T IBC or total iron binding capacity measures the capacity to bind transferrin with iron And U IBC or unsaturated iron binding capacity measures the remaining amount of transferrin That's not already bound to iron These are inverse markers. So If iron overload is present, you'll see a value below the lab range rather than above for these markers And U IBC is much more reliable than T IBC As a marker and in fact it's equal to iron saturation in terms of its predictive value for iron overload And I've just listed the ranges here for T IBC and U IBC ferritin is the long-term storage form of iron found in every just about every cell in the body And it's a huge molecule contains up to 400 atoms of iron And the lab range for ferritin is up to 400 in men And 150 in women But I would argue based on my research and some of the studies we've covered in this presentation That you that the upper limit should be somewhere around 200 in men and 100 in women But be careful in assuming that elevated ferritin always indicates iron overload because ferritin is also an acute phase reactant Which is a type of protein that's elevated in the inflammatory response So if you see elevated ferritin with normal iron saturation and U IBC It's likely that you're looking at some kind of inflammatory process rather than iron overload Soluble transferrin receptor is a little known marker that can be used to determine whether elevated ferritin is due to inflammation or iron overload If there's any question about that Soluble transferrin receptor decreases with reduced cellular need for iron And unlike ferritin, it's not affected by inflammation So because it decreases with reduced cellular need for iron This is another inverse marker just like T IBC and U IBC So if if soluble transferrin receptor is low, that suggests that iron overload is present if it's normal Or even towards the high end of the range when ferritin is elevated It suggests that ferritin is is probably the ferritin elevation is being caused by inflammation As a side note, this is also a really good marker to use for diagnosing anemia If it's high, it would suggest that iron levels are low And sometimes if someone has anemia and inflammation Their iron levels will appear to be normal or their ferritin levels will appear to be normal because the inflammation is increasing it Whereas it and if It would normally be low because their iron stores are depleted And then if you use soluble transferrin receptor and find that it's high That actually can clarify the situation there as well So if a patient has persistently high Iron levels, I think it's a good idea to run a DNA analysis that looks for the three most common mutations of the HFV gene Which are C282Y and H63D that we've already discussed and then the third one, which we haven't mentioned yet is S65C As I mentioned before As I mentioned before there are several other mutations of the HFE gene that lead to iron overload, but There's no way of of testing for those outside of a research setting, unfortunately The good news is that these three common mutations cover about 90 percent of people with iron overload So, um, you know, nine and ten people that have a genetic mutation that causes iron overload will have one of these three So you'll you'll get the majority of them I do recommend the genetic testing because it it informs the treatment Moving forward and it can help the clinician and the patient plan But it's really important to understand that it's a mistake to assume that a negative Genetic test means that there's no problem Uh elevated iron itself is a problem regardless of what the cause is, you know Whether it's genetic in origin or due to excess supplementation or some unidentified Or another medical condition or some unidentified cause and it's really important to treat high iron levels regardless of whether there's a genetic mutation It's also a mistake to assume that carriers of these mutations are not at risk as we covered earlier in the presentation Carriers or people that are heterozygous for have a single copy of these mutations do have increased risk of disease and death and a higher probability of having increased iron levels Now this is not nearly as pronounced as it would be in someone that's homozygous for the mutations and most heterozygous carriers will never develop disease But based on the evidence we've reviewed, I think it definitely makes sense to be cautious Okay, so here's a A flow chart a diagram for how to do a workup for iron overload in the clinic If a patient comes in and has iron saturation Okay, here's a little flow chart for how to do a workup for iron overload in the clinic So if a patient presents with iron saturation levels of above 50 percent or ferritin above 200 if they're male or above 100 if they're female I'll ask them to discontinue any iron supplements if they've been taking them and vitamin c which can increase iron absorption And then we'll do a retest in about a month If their iron levels are normal, then we'll just monitor them yearly if they're elevated again I'll do the hfe genetic test And if they're negative or they're a carrier meaning they have a single copy I'll put them on a program of blood donation and other iron reduction strategies to try to get ferritin down in a range of maybe 50 to 150 for men or Or maybe 40 to 60 70 for women and get iron saturation below 45 percent If the genetic test is positive and they're homozygous for the mutation then They need they and their ferritin levels are very high. Maybe 700 800 And up they will probably need a prescription for therapeutic phlebotomy Um, and that's the difference between that and just donating blood as it can be done more frequently and the goal in those cases is to get Ferritin down into that same range Often they'll actually try to get a little bit lower than that maybe 25 To begin with and then keep it in the range of 50 to 150 and iron saturation below 45 percent So let's talk about prevention and treatment The first question you might be asking is should healthy people limit iron intake in their diet? Well, the the body tightly regulates iron and most people just excrete any excess that they might take in So I don't think it's necessary for for most people to limit iron in their diet That said, we know that genetic mutations that contribute to iron overload are common And so I do recommend avoiding iron supplements for that reason and doing regular Screening for for iron maybe once a year I also think it's probably a good idea for um, at least men and post-menopausal women to donate blood Between one and three times a year There's there's no harm in doing that. It's actually providing a great service and it will reduce the likelihood that You'll accumulate any excess iron But what do you do if you already have excess iron? Well, there are only two ways of getting rid of iron once it's stored in the body And those are phlebotomy or the removal of blood and chelation Phlebotomy is the really the treatment of choice because chelation with drugs at least can lead to some pretty nasty side effects Therapeutic phlebotomy involves the removal of one unit of blood And a unit of blood is about 200 to 250 milligrams It's straightforward and safe There are a few risks and the typical frequency Is about one to two times a week when it's when it's done by prescription Until ferritin is about 25 nanograms per milliliter and Provided hemoglobin stays above 12.5 And then once that level is reached they'll usually put the people on a schedule where they're getting a Phlebotomy maybe once every two months to maintain ferritin in the range of 50 to 150 in iron saturation below 45 percent The phlebotomy is also possible for patients without hereditary hemochromatosis that you know the full-scale homozygous form They can do it without a prescription Simply by donating blood at a place like the red cross or local hospital And they'll also remove one unit of blood which is the same as they would do in a therapeutic phlebotomy But in this case the maximum frequency is once usually once every 56 to 59 days And this is to prevent People from inadvertently giving themselves anemia making themselves anemic by withdrawing too much blood too quickly A frequency of once every 56 days may or may not be enough Depending on how quickly you accumulate blood between accumulate iron between phlebotomies if you have iron overload Unfortunately blood donation is not an option for some people Those who have anemia or hemoglobin levels below 12.5 aren't eligible because blood donation would make that worse People who've lived in the uk At a certain period of time are not eligible due to concerns about mad cow disease Some states in the u.s. Don't allow people with tattoos to donate blood So in these cases Kulation must be used as I mentioned Kulation with drugs is is kind of a last resort because of its potential The potential side effects But luckily there are other Natural keelators available that are pretty effective in most cases But don't have any of the side effects associated with Drug chelation and one of those is lactoferrin Animals and humans both produce lactoferrin. It's found in secretions like saliva and tears that are exposed to pathogens And in breast milk lactoferrin suppresses the growth of iron dependent bacteria, which protects the baby from infection Studies have shown that lactoferrin can remove iron. That's already stored in the body and apolactoferrin would be the preferred form in this case A life extension foundation has one That's and the recommended dose would be 300 milligrams one to two times a day between meals Phytic acid or an acetalhexaphosphate also known as ip6 Does inhibit iron absorption But this is only true of iron that's found in in plants rather than a heme iron, which is found in animal products And it doesn't remove iron. That's already stored in the body like lactoferrin does. So it's not an alternative for lactoferrin In addition to removing accumulated iron, you'd want to follow three steps to reduce iron levels Step one would be to reduce your iron intake and of course avoiding all supplements Reducing the intake of iron rich foods, which I've listed here on this slide like beef liver muscles red meat shrimp pork Clams are have a significant amount of iron. I didn't list them on this slide and chicken and salmon much less so And you'd want to use ceramic or steel cookware instead of cast iron. That's step number three Number two you want to avoid Things that enhance iron absorption. So these include alcohol, which you'd want to limit to maybe two drinks a week Supplemental vitamin C, which you'd limit to 200 milligrams between meals Bittain hydrochloric acid, which you should probably avoid completely And high doses of zinc which interferes with copper and iron metabolism and supplemental beta carotene, which Not only may increase iron absorption. It may increase cancer risk as well Step three is to include things that inhibit iron absorption and there are several Foods or compounds that can inhibit the absorption of plant Forms of iron like tannins and tea and coffee oxalates and sweet potato and spinach eggs phytic acid and greens and nuts And phosphates But there is one compound that we know of that can inhibit both plant And animal forms of iron heme and non heme And that's calcium. So the recommended dose Here would be 300 milligrams of calcium with meals But you would want to monitor your serum calcium levels and pay attention for any signs of excess calcium because Although calcium will help Inhibit iron absorption getting too much calcium can actually increase the risk of heart disease by other mechanisms So you don't want to substitute one problem for another Okay, that's the end. So for References from this presentation and copies of some of the charts you can go to chris crescer.com slash ahs 12 And you can learn more about my work there and you can also sign up for my free Email newsletter that covers topics like this. So thanks for listening. I hope you enjoy the presentation