This is a three-part series about how getting black spots on my teeth helped me find out I had an iron disorder, and how I found and tested a novel treatment for it. In part 1, we learned that the black spots on my teeth were likely caused by iron overload, a condition in which the body absorbs so much iron it begins attacking its own tissues, and that iron overload is most often caused by a common genetic problem called hereditary hemochromatosis.
Disclaimer: this is not medical advice. Talk to your doctor before making medical decisions.
Genetic tests for hereditary hemochromatosis
The next step in my iron overload journey was to see if I had the genes for HFE hereditary hemochromatosis (HFE HH). I found a copy of my 23andMe report and looked up the line for HFE HH, which said “Variant present,” in scary red text.
What the heck did “Variant present” mean? I knew in general that for a lot of genetic diseases, I could be a “carrier”—someone who didn’t have the disease but could give it to my children if their other parent was also a carrier—or I could have the disease myself. But “Variant present” didn’t tell me which one that was. (Now I see why the FDA wanted 23andMe to run their genetic tests through the FDA approval process before selling them to people!)
Fortunately, I had a copy of my raw 23andMe genetic sequencing data, so I could use this handy guide to known HFE mutations created by Stephen Cobb to find out what “Variant present” meant. But first, I had to get a better understanding of the genetics of HFE hereditary hemochromatosis.
The genetics of HFE hereditary hemochromatosis
Most people with HFE HH are homozygous (have two copies) of C282Y mutation in the HFE gene. Some people with HFE HH have one copy of C282Y and one copy of a different HFE mutation, the most common of which are named H63D and S65C. And 10 – 15% of HH cases are in people with one or zero copies of C282Y, including some with “wild-type” HFE genes with no mutations at all.
Using Stephen Cobb’s guide and my raw 23andMe data, I figured out that I am heterozygous (have one copy) for the extremely common and mostly harmless HFE mutation H63D, which doesn’t usually produce iron overload even in people who have two copies of it (although exceptions exist). I had zero copies of the C282Y gene. My HFE genes were not normal, but they also didn’t say that I had the most common genetic cause of HH. I might still have HH, but at least I hadn’t ignored a genetic test telling me I was at serious risk for developing iron overload!
While I was researching this, I realized that if I did have HH, it would make perfect sense that I had developed iron overload now. First, I had stopped losing blood through menstruation a few years ago. Second, my dietary iron had gone way up recently: I moved in with my partner, who loved to cook for me and especially loved to cook beef (an excellent source of iron). He also cooked dinner almost every night in his favorite cast iron pan (a known treatment for anemia). If I had HH, this is exactly when I would expect it to start to show up. I decided to get tested for iron overload.
Diagnosing iron overload
The first step in diagnosing iron overload is running an iron panel, which is a collection of blood tests that measures three important things about your blood:
- Serum iron: how much iron is floating around in your blood, bound or unbound
- Total iron-binding capacity: how much iron can be bound by the amount of transferrin, an iron-binding protein. in your blood
- Serum ferritin: how much ferritin, an iron-storing protein, is in your blood
Two useful numbers are derived from these measurements:
- Iron saturation or transferrin saturation: what percentage of the iron-binding protein transferrin in your blood is already bound to iron, which is serum iron divided by total iron-binding capacity
- Unsaturated iron-binding capacity: how much iron-binding capacity in your blood is unused, which is the total iron-binding capacity minus the serum iron
Remember, free iron is toxic but your body also needs iron to live. You want enough bound iron to make blood cells and other things, but as little free iron as possible. That means you want a fair bit of unused iron-binding proteins floating around your blood to catch any free iron floating around.
Getting an iron panel
I assumed I’d had an iron panel before, and was surprised to learn that I’d never had one in my life! Doctors rarely order an iron panel, even though it is a cheap and easy test. Doctors often run the CBC (Complete Blood Count) test, which sounds like it would include an iron panel, but it does not. The CBC can tell you if you have anemia but not iron overload.
Most of the HH awareness websites have sections devoted to how to talk your doctor into ordering this cheap, simple, potentially life-saving test, but it’s so hard to get a doctor to authorize an iron panel that there is now a market for direct-to-consumer iron panels. For example, the Iron Disorders Institute now offers an iron panel test that patients in most parts of the U.S. can order online for about $130 (most most insurance providers or national health services are cheaper—if you can get your doctor to order it).
I can confirm the reluctance of doctors to order an iron panel firsthand. Unfortunately, my usual primary care doctor went on vacation just when I wanted this test, so I made an appointment with a random doctor at OneMedical. It took me about 20 minutes to argue the doctor into ordering an iron panel, even with the evidence of the black spots, the paper from the Albanian dentist linking the black spots and the lactoferrin to high iron levels, and the fatigue that lifted when I took lactoferrin. I went to get my blood drawn, and waited for the results of my iron panel.
Interpreting iron panel results
The two most important results from the iron panel for diagnosing iron overload are the iron saturation and the serum ferritin. Iron saturation shows how much transferrin, the iron-binding protein that moves iron around the body, is bound to iron. Ferritin is a different iron-binding protein the body uses to store iron long-term. Ferritin levels in the blood usually (but not always) increase along with the total amount of iron stored in the body.
If both ferritin and iron saturation are high, then that strongly suggests iron overload. Both ferritin and iron saturation sometimes increase for reasons other than iron overload, such as injury, illness, or diet. But when both ferritin and iron saturation are high, and stay that way after retesting, it’s likely that iron overload is the cause.
Normal ranges of ferritin and iron saturation
What levels of ferritin and iron saturation suggest iron overload? Ha ha, good question! Different medical authorities have wildly different “normal” ranges for ferritin (15 – 500 ng/mL), and the ranges for iron saturation vary a lot too (25% – 60%). When it comes to ferritin, it’s extremely unusual to have a part of the blood whose normal range varies by more than 10x. Several researchers suggest that Western diets tend to produce iron overload, and as a result the upper end of the “normal” ranges are actually unhealthy.
After reading the scientific literature, I now have very strong opinions about the acceptable upper limit of serum ferritin. That’s because serum ferritin levels greater than 1000 ng/mL in people who have HH is a strong indicator of liver cirrhosis. It gets worse: people with HH who develop liver cirrhosis have a 30% chance of developing liver cancer. (!!!) Sometimes liver damage can occur at much lower ferritin levels. There’s also no health or performance advantage to serum ferritin levels above 75 – 100 ng/mL. After reading all the relevant papers, my personal opinion is that I agree with the Iron Disorders Institute guidelines of of 50 – 150 ng/mL for serum ferritin and 25% – 35% for iron saturation.
My iron panel results
After a few days, my iron panel results came back with the classic profile of iron overload. Every single measurement was out of normal range, but not by much. At 203 ng/mL serum ferritin and 58% iron saturation, I caught the iron overload early, before it caused any serious damage.
The OneMedical doctor who ordered the iron panel didn’t follow up with me about treatment after my abnormal results. Fortunately, my regular doctor was back from vacation, and was delighted to see that my hunch about iron overload had paid off. We started talking about how to lower my iron levels.
Treating iron overload with phlebotomy
The standard way to lower iron levels is therapeutic phlebotomy—basically, donating blood, except a lot more often than usual. Normally, people in the U.S. are only allowed to give blood once every eight weeks, but people with extreme iron overload may give up to 500 cc (about a pint) of blood TWICE a week! I was astonished to learn that some people can make a pint of new blood every seven days (!!!) if they have enough stored iron in their bodies.
How many blood donations does it take to get iron levels back to safe levels? Well, each 500 cc phlebotomy removes about 200 – 250 mg of iron and lowers serum ferritin by about 30 ng/mL. (A kind of blood donation that only takes out the red blood cells, DRCA, removes around twice as much iron with each donation.) 250 mg might seem like a lot of iron (it’s about the same amount that a newborn baby contains), but a person with iron overload can have as much as 35 grams of excess iron stored in their body. That means up to 175 phlebotomies of 500cc each—about one and half years of twice weekly phlebotomies. People with serum ferritin in my range (200 ng/mL) are advised to give blood every two weeks until ferritin drops to 25 ng/mL, which would probably take 6 donations and remove about 1.5 grams of iron.
The problem with phlebotomy
However, therapeutic phlebotomy doesn’t work for everyone. For example, it might be difficult for people who have:
- Severe needle phobia
- Difficult veins (small, rolling, scarred, etc.)
- Fainting, intense pain, or other bad reactions to phlebotomy
- Both iron overload AND anemia, which happens with repeated transfusions and a few other conditions
- No access to therapeutic phlebotomy
The last point can happen when someone has no access to medical care, but also if their medical provider has an inappropriately high “normal” serum ferritin range. For example, the UK’s National Health Service (NHS) considers ferritin normal up to 400 ng/mL, when the World Health Organization (WHO) recommends 200 ng/mL for non-menstruating people and 150 ng/mL for menstruating people. In my research, I found two people who said they had symptoms of iron overload, but could not get therapeutic phlebotomy because their doctor didn’t think their iron level was high enough. They could not donate blood either: one was disqualified from donating blood for life after a false negative on a screening test, and another had a rare blood type that the blood bank refused to take, since they would almost certainly throw the blood away unused. Strangely, most people are not too keen on self-administered blood-letting.
I was personally leery of phlebotomy because I have postural orthostatic tachycardia syndrome (POTS) as a result of my hypermobile EDS. POTS means that my heart rate goes up too much when I stand up, which makes me feel faint, sick, and occasionally start to black out. POTS gets worse when blood volume drops, as in blood donation.
I did the math and calculated that I’d probably need at least 3 DCRA donations, or 6 regular donations. Also, people undergoing therapeutic phlebotomy often complain about feeling crushing fatigue after the second or third phlebotomy. Between the fatigue I already had and the POTS, I wasn’t thrilled about feeling miserable for 6 – 12 weeks.
The only mainstream alternative to therapeutic phlebotomy is iron chelation therapy—administering substances that bind to iron and remove it from the body. But the standard drugs are expensive and incredibly toxic: side effects included loss of hearing and kidney failure.
At this point, it looked like I had no choice but to risk passing out in some poor phlebotomist’s arms. Did I have any other options?