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Core etiology of ME/CFS: Fe toxicity?

Discussion in 'General ME/CFS Discussion' started by alethea, Oct 31, 2017.

  1. alethea


    I recently wrote an email to Whitney Dafoe’s parents with my thoughts on ME/CFS, and wanted to share them here, as well.

    I’m a fellow sufferer with a much less severe case of ME/CFS. I’ve been studying it (and healing myself) for years, and I’ve come to believe it is a form of iron poisoning.

    I’ll paste some information that I’ve recently found that describes the metabolic phenomenon in some detail. It actually comes from a veterinary website; my apologies, but unfortunately, there is simply not (yet) anyone studying this angle in humans. The article contains principles that I believe are true for humans in a chronic sense, even though what is described is an acute canine condition. I’ve bolded the details I feel are most salient.

    The short version is this: Too much iron causes metabolic acidosis; inhibition of the Krebs cycle; lipid peroxidation and subsequent mitochondrial damage; hypotension, orthostatic intolerance, hypokalemic hypersensitivity, and general pH imbalance; and central nervous system dysfunction.

    In me, the final clue was when my skin bronzed — a hallmark symptom of iron overload.

    Unfortunately, no iron test I have ever taken came back abnormal. Not ferritin, not transferrin, not TIBC. Nothing. I also do not have hereditary hemochromatosis (although I do “carry” one of the HH genes - H63D). It’s as if there is simply no way to get around this disease remaining invisible in mainstream medical terms. Although I suppose if the body is in fact “hiding” iron, we shouldn’t expect to see it in serum testing. The damage may be being done not by the iron we're accustomed to measuring, but by free iron. I have not attempted a FerriScan MRI, but I suppose that could be one way to detect this(?). The whole idea of magnetic resonance imaging became unsavory once I figured out my body was full of iron.

    I believe I’ve had mildly compromised iron metabolism from birth. Then, viral and fungal exposures caused my body to “hoard” or “sequester” Fe, as a protective mechanism. The precise ways in which the body does this, I do not understand. But since iron can drive bacterial, viral, and fungal virulence, it makes sense.

    Once iron has been sequestered, it's difficult to get it out. There is no normal mechanism for iron excretion.

    At any rate, the life-changing therapy for me was high-dose thiamine. Many different forms and very large doses may need to be trialed; dis-use weakens the thiamine enzymes, and thiamine transport may be damaged by antibiotics, antifungals, or viral exposures. Thiamine (see Derrick Lonsdale) returned my CNS to proper functioning, and provided the energy required for the Na/K pump. To support the thiamine, I’ve found I need manganese. Thiamine worked for a while, and then stopped working when my manganese bottomed out. It seems thiamine gets the oxidative metabolism up and running, but then manganese (MnSOD) is needed to clean up the metabolic waste.

    In fact, I’ve read (Ralph Catalase) that the absorption of iron in the body is dependent on manganese. It could be that the body knows it needs Mn to clean up after oxidative metabolism and will only allow entrance to Fe if there is sufficient Mn. If this were the case, the low manganese induced by Lyme disease could be dysregulating iron. And Glyphosate (RoundUp), which has a special ability to destroy manganese metabolism (see Stephanie Seneff), is making everything worse. But where does the iron that enters the body unregulated go? What are the effects of dysregulated iron metabolism? ME/CFS, autoimmune illness, neurodegenerative disease, and cancer. Some days I think it's all one illness, we’re just expressing it in different ways.

    If it is indeed “likely that iron was essential for developing aerobic life on Earth,” then perhaps dysregulated iron is not only catastrophic but is the mother of all catastrophe.

    And yet we (in the US) are adding toxic amounts of unbound iron to our food! And not just our food — our pets’ food, too.

    When excess iron disrupts oxidative phosphorylation by interfering in the electron transport chain, thus prompting anaerobic metabolism (the Warburg Effect), it may play a role in the genesis of cancer — another illness with a special response to thiamine supplementation (smaller doses of thiamine appear to increase tumor growth, while massive doses inhibit it, as if cancer cells themselves were starved for thiamine). But this is perhaps another topic for another day.

    To recover, I’ve also needed to support my Glycine Cleavage system (oxalate metabolism) — which was genetically weak to begin with. This process, if weak, allows for the formation of endogenous oxalates, which help to “trap” the iron. It requires B1, B2, B3, B6 (all in their “active” forms), as well as their co-factors. So to support B1, I need calcium, cobalt (B12), manganese, and magnesium. I also need vitamin A and zinc. Thiamine deficiency cannot be fully resolved without also addressing folate deficiency (they share a transporter). Also required is ALA, which should be used with caution if mercury is present.

    I’ve also needed massive amounts of electrolytes on occasion, especially when actively “iron dumping.” I believe the iron is bound to oxalates, so dumping iron requires we also support oxalate metabolism. Oxalates (oxalic acid) is extremely acidic (used to remove rust) (you see its affinity for iron); maintaining pH homeostasis can be a constant struggle until things normalize. In fact, an acidic body will not allow the release of iron or oxalate.

    Once health is stabilized, the Krebs cycle is supported, the metabolism is aerobic again, and acid-base balance is restored, active iron chelators can be introduced: EGCG, IP-6, curcumin. I would not recommend these as initial therapies. IP-6, in particular, can bind to zinc and to other minerals that you will need to get the metabolism up and running. Lactoferrin (the “apo” variety) and colostrum have also been hugely helpful to me, in addition to probiotics that contain b. animalis subsp lactis (helps degrade oxalate).

    Side note: It can be helpful to try to reduce the fight-or-flight response (“sympathetic dominance”). While under attack — or perceived attack — the body will continue to hoard iron. For this reason, things such as lavender essential oil and meditation, which I initially laughed off, have actually proved helpful. One of my core personality traits — hypervigilance — probably does not serve me, with regard to iron metabolism. Trauma survivors may also find they have unknowingly hoarded iron, and emotional healing can help with its release. One of my mantras in dealing with this illness has been: I forgive everyone everything, and I love all that lives.

    But it’s worth noting that the mechanisms involved here are not all conscious. It is the central (autonomic) nervous system that is involved. The iron causes organic acids to accumulate, and this depletes thiamine, which induces a mild hypoxia (oxygen starvation) in the brain. The resulting changes in metabolism are not under conscious control.

    I hope this helps. I pray for you all every day.
    xo Alethea

    Toxicology Brief: The toxicity of iron, an essential element
    Iron is the most abundant trace mineral in the body and is an essential element in most biological systems.1,2 It is likely that iron was essential for developing aerobic life on Earth.3 But iron is toxic to cells in excessive amounts. Acute iron poisoning is common and potentially lethal in dogs, cats, and many other animals. Iron is also a leading cause of unintentional poisoning deaths in children less than 6 years old.

    Normal iron content and storage

    About 70% of the iron in mammals is found in hemoglobin, and about 5% to 10% is found in myoglobin. When bound to normal hemoglobin and myoglobin, iron is in the ferrous (Fe2+ ) form.1,2,4 Up to 25% of iron in the body is in the ferric (Fe3+ ) form and is stored in hemosiderin, ferritin, and transferrin in the liver, spleen, and bone marrow.1,2,5 Ferric iron is used in iron-containing enzymes, such as peroxidase, catalase, and cytochrome-c.


    One reason iron toxicosis is such an important problem is that the general public is often unaware of the potential toxicity of products that are considered natural and necessary for our health.6

    Another reason is that many pharmaceutical preparations contain iron. Multivitamins containing iron are readily available. Many are brightly colored and sugarcoated, making them attractive to animals and small children. In addition, several iron supplements are available over the counter. Another frequent source of iron overdose in pets is prenatal vitamins. Many prescription prenatal vitamins contain more than 60 mg of elemental iron in each pill, so animals can develop severe iron toxicosis even if only a few tablets are ingested.

    Numerous other products contain iron, including one-time-use heating pads. Iron can also be found in fertilizers and pesticides and in the soil.1,2,4

    Iron is also used in injectable products and is bound to proteins in supplements (chelated iron) to treat iron deficiencies in animals. There are several forms of injectable iron (iron dextran, iron dextrin, iron sorbitol, ferric ammonium citrate) and several chelated forms of iron. Chelated iron is almost as effective in treating iron deficiencies as other salts are but is about a fourth as toxic.1,2,4 Product labels do not always indicate if the iron is chelated. Most products that contain iron have it in a salt form. Table 1 lists several iron salts and the percentage of elemental iron in each.

    Iron absorption

    Iron absorption is a two-step process. First, iron ions are absorbed from the intestinal lumen into mucosal cells. Ferrous iron is better absorbed than ferric iron because ferric iron precipitates out of solution at around pH 7 or under normal physiologic conditions.7 However, both forms can be absorbed if they are ionized.1,2,5Because iron must be ionized to be absorbed, metallic iron and iron oxide (rust) are not generally of concern when they are ingested.1,2 Most iron absorption occurs in the duodenum and upper jejunum, but in animals with iron toxicosis, the iron seems to be well-absorbed along all parts of the intestinal tract.1,2,5,6 A diet high in sugar and vitamin C increases iron absorption, while a high-phosphate diet reduces iron absorption.1,2,4,5 But in acute overdoses, the iron seems to be absorbed in a passive, concentration-dependent fashion, similar to how most other metals are absorbed.

    Second, iron is transferred to ferritin or into circulation bound to transferrin proteins. Transferrin is an alpha1-globulin produced in the liver.1,2,7 Complexed with transferrin, iron is distributed to other iron storage locations in the body. A unique feature of iron metabolism is the almost complete absence of iron excretion. Any iron lost from hemoglobin degradation is rapidly bound to transferrin and transported to the bone marrow for the resynthesis of hemoglobin.2,7 Consequently, little iron is lost in the urine and feces. In addition, iron loss is not notably increased even after iron overdoses.2,4 Most iron loss is through the exfoliation of gastrointestinal mucosal cells in all mammals and through menstrual blood loss.5While anywhere from 2% to 15% of the iron ingested is absorbed, only about 0.01% of the iron body burden is eliminated every day.1,5

    Mechanism of action

    When the absorbed iron is not bound to protein, it produces a variety of harmful free radicals. Consequently, the concentration of iron is rigorously controlled in mammalian cells and biological fluids. Acute iron toxicosis causes both a direct corrosive effect on the gastrointestinal tract and cellular damage due to circulating unbound iron.2 Large doses of iron may overcome the rate-limiting absorption step and allow excessive iron to enter the body. When iron-binding proteins become saturated, free iron ions are allowed into the general circulation.2,4-6 Free iron penetrates the cells of the liver, heart, and brain. At the cellular level, free iron increases lipid peroxidation with resulting membrane damage to mitochondria, microsomes, and other cellular organelles.1

    Iron exerts its most profound effects on the cardiovascular system. Excessive iron can cause fatty necrosis of the myocardium, postarteriolar dilatation, increased capillary permeability, and reduced cardiac output.2 Free iron stimulates serotonin and histamine release as well as systemic metabolic acidosis caused by lactic acid accumulation. All these mechanisms lead to shock. Excessive iron also interferes with clotting mechanisms, augmenting hemorrhagic processes.1,2,4 Excessive iron also has been reported to cause thrombocytopenia.5

    Excessive iron causes metabolic acidosis through several mechanisms. First, lactic acidosis occurs because of hypovolemia and hypotension. Iron disrupts oxidative phosphorylation by interfering in the electron transport chain. Thus, anaerobic metabolism is promoted. As ferrous iron is converted to ferric iron, hydrogen ions are released, adding to the metabolic acidosis. Free iron ions also inhibit the Krebs cycle, and organic acids accumulate.5

    The liver accumulates free iron in Kupffer cells and the hepatocytes. The iron localizes in mitochondria of these cells and damages several cell organelles.5Eventually, hypoglycemia, hyperammonemia, coagulation defects, and hepatic encephalopathy occur.2,5 Free iron inhibits the thrombin-induced conversion of fibrinogen to fibrin. Histopathologic evidence of iron-induced hepatic damage includes cloudy and swollen hepatocytes, portal iron deposition, fatty metamorphosis, and massive periportal necrosis.2,4,5


    Since no mechanism exists for excreting iron, toxicity depends on the amount of iron already in the body. Consequently, some animals develop clinical signs of toxicosis even when they receive doses that cause no problems in other animals. Iron is most toxic when given intravenously. Intramuscular injections are less toxic, and iron given orally is the least toxic, probably because the amount of iron absorbed orally is not 100% of the dose ingested.4 When assessing the potential toxicity of an iron overdose, the amount of elemental iron in the products ingested must be determined (Table 1).4 For example, if a 500-mg tablet of ferrous gluconate was ingested, only 60 mg of elemental iron would have been ingested (500 mg X 0.12).

    No clinical signs of toxicosis are expected in dogs ingesting less than 20 mg/kg of elemental iron. Dogs ingesting between 20 and 60 mg/kg of elemental iron can develop mild clinical signs. When the amount of elemental iron ingested is greater than 60 mg/kg, serious clinical signs can develop.2 In all animals, oral doses between 100 and 200 mg/kg are potentially lethal.2,4

    Clinical signs

    Iron toxicosis manifests clinically in four stages. The first stage occurs in the six hours after an iron overdose. It is marked primarily by gastrointestinal effects, such as vomiting, diarrhea, and gastrointestinal bleeding.2,4-6 The greatest mucosal damage occurs on an empty stomach. Most animals with mild to moderate iron toxicosis do not progress beyond this stage.5

    The second stage occurs six to 24 hours after the overdose. This is referred to as a latent period, a period of apparent clinical recovery. In animals with severe iron toxicosis, this recovery period is transient and soon progresses to the third stage.2

    The third stage of iron toxicosis occurs about 12 to 96 hours after the initial clinical signs develop. This stage is marked by lethargy, a recurrence of gastrointestinal signs, metabolic acidosis, shock, hypotension, tachycardia, cardiovascular collapse, coagulation deficits, hepatic necrosis, and possibly death.2,5,6

    The fourth stage, which may occur two to six weeks after the iron overdose,2,5 is when animals that had gastrointestinal ulcerations and survived are healing. As these ulcerations heal, scarring occurs and strictures may develop. Even animals that had only gastrointestinal irritation in the first stage of iron toxicosis are at risk of developing strictures.2

    Other abnormalities noted when iron overdoses occur are dehydration, hypovolemia, anemia, evidence of hepatic necrosis (elevated alanine transaminase and aspartate transaminase activities), and liver failure (hypoglycemia, hyperammonemia).2,5 In addition, iron toxicosis causes coagulation disturbances that are related to thrombocytopenia, hypoprothrombinemia, and impaired clotting factor synthesis.5In people, the presence of hyperglycemia and leukocytosis often indicates a serum iron concentration of greater than 30 ug/dl.2 Finally, iron toxicosis results in several central nervous system signs. Often these signs result from effects on other cellular processes. For example, metabolic acidosis and hepatotoxicity can lead to other signs such as lethargy and hepatic encephalopathy.5 Other central nervous system signs that occur are comas, seizures, and tremors.1,2,5


    Testing an animal's serum iron concentration is the best method to confirm iron poisoning. It is also beneficial to measure total iron-binding capacity, although neither test alone is sufficient to determine whether treatment is needed. Most human hospitals offer serum iron concentration and total iron-binding capacity testing, but not all veterinary clinical pathology laboratories do.

    Since the normal serum iron concentration and normal total iron-binding capacity can vary from animal to animal, it is best to measure both and correlate the test results with clinical observations. Serum iron concentrations can change dramatically during the first few hours after ingestion, so repeat the serum iron test four to six hours after initial measurement. When the serum iron concentration exceeds the total iron-binding capacity or the serum iron concentration is greater than 500 ug/dl, severe systemic effects can be expected. Normal serum iron-binding capacity is usually about 25% to 30% saturated.2 Every laboratory is different, but an example of how the serum iron concentration and total iron-binding capacity results are reported is Fe = 134 ug/dl and total iron-binding capacity = 436 ug/dl, or 134/436 X 100 = 30.7% saturated.

    Obtaining multiple blood samples to test serum iron concentrations may be indicated, especially when the total iron dose is unknown or the animal is symptomatic. An abdominal radiographic examination can be useful to identify metallic objects since iron tablets are radiopaque.2,5


    Figure 1. Management of Iron Toxicosis A protocol for treating iron toxicosis is described in Figure 1. Animals that have recently ingested large doses of iron will benefit from gastrointestinal decontamination. In animals that can vomit, induce emesis with 3% hydrogen peroxide (1 to 5 ml/kg orally), apomorphine hydrochloride (0.03 mg/kg intravenously, 0.04 mg/kg intramuscularly), or other appropriate emetics.8 Gastric lavage can be performed on anesthetized animals, although it may not be effective if large pills are involved or if the pills adhere to gastric mucosa. Place a cuffed endotracheal tube to prevent aspiration of lavage material.2 In a recent study, activated charcoal adsorbed ferrous sulfate solution at a pH environment consistent with that of the duodenum.9 It has been suggested that iron can be precipitated to a nonabsorbable form in the digestive tract by using sodium phosphate, sodium bicarbonate, or magnesium hydroxide; however, the clinical significance of this therapy is questionable.2,4,6

    Restoring fluids, electrolytes, and acid-base balance is essential to successfully treating iron toxicosis. Fluids are also needed to prevent hypovolemic shock. Administer fluids based on the animal's maintenance and replacement needs.2Monitor electrolytes, and correct any abnormalities. Administering gastrointestinal protectants such as sucralfate, cimetidine, misoprostol, or other inhibitors of gastric acid secretion may also be helpful.2,10

    Chelation therapy is indicated in animals at risk of or showing clinical signs of severe iron toxicosis. This includes animals that ingest more than 60 mg/kg of elemental iron, animals that have a total iron-binding capacity that is greater than the serum iron concentration, or animals that have a serum iron concentration greater than 500 ug/dl. Deferoxamine mesylate (Desferal—Novartis Pharmaceuticals), the chelator of choice for excessive iron in the body, is the only chelator available that seems to be effective at reducing serum iron concentrations. The recommended dosage of deferoxamine is 40 mg/kg given intramuscularly every four to eight hours. Alternatively, give deferoxamine as a continuous infusion at the rate of 15 mg/kg/hr. Continue chelation therapy until the serum iron concentrations decrease below 300 ug/dl and the clinical signs resolve. Often, iron toxicosis requires two or three days of chelation therapy.2,4,5 Deferoxamine causes reddish-colored urine, which indicates free iron is being excreted. In people, deferoxamine therapy is continued until the urine color returns to normal.6 Deferoxamine has not been reported to cause iron deficiency.

    Calcium EDTA has also been used to reduce serum iron concentrations but has not been shown to reduce mortality in cases of acute iron poisoning. An experimental iron chelator, N, N'-bis(2-hydroxybenzyl) ethylenediamine-N, N'-diacetic acid monosodium salt (NaHBED), has been used to successfully treat iron overdoses in dogs and monkeys and was shown to be about twice as effective as deferoxamine and with fewer side effects.11 If NaHBED is approved for use in people, it may also become an alternative iron chelator for animals.

    Monitoring and prognosis

    Monitor all treated animals for four to six weeks for evidence of gastrointestinal obstruction.2 Once signs of iron toxicosis have developed, the prognosis is guarded.

    Severe iron poisoning requires a lot of time and effort to treat effectively. Thus, treatment can become costly. In addition, it is often difficult to obtain deferoxamine. If the serum iron concentration exceeds 500 ug/dl and a chelator is unavailable, the prognosis is poor.

    Prevention is the best treatment for iron toxicosis. Teaching owners about the dangers of iron toxicosis and the importance of keeping all medications, multivitamins, and iron supplements out of reach of animals will help avoid serious injury.


    1. Goyer RA. Toxic effects of metals. In: Klaassen CD, ed. Casarett & Doull's toxicology: the basic science of poisons. 5th ed. New York City, NY: McGraw-Hill, 1996;715-716.

    2. Greentree WF, Hall JO. Iron toxicosis. In: Bonagura JD, ed. Kirk's current therapy XII small animal practice. Philadelphia, Pa: WB Saunders Co, 1995;240-242.

    3. Williams RJ. Biomineralization: iron and the origins of life. Nature 1990;343:213-214.
    4. Osweiler GD, Carson TL, Buck WB, et al. Iron. In: Clinical and diagnostic veterinary toxicology. 3rd ed. Dubuque, Iowa: Kendall/Hunt Publishing Co, 1985;104-106.

    5. Hillman RS. Hematopoietic agents: growth factors, minerals, and vitamins. In: Hardman JG, Limbird LE, Molinoff PB, et al, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 9th ed. New York City, NY: McGraw-Hill, 1995;1311-1340.

    6. Liebelt EL. Iron. In: Haddad LM, Shannon MW, Winchester JF, eds. Clinical management of poisoning and drug overdose. 3rd ed. Philadelphia, Pa: WB Saunders Co, 1998;757-766.

    7. Ponka P, Schulman HM, Woodworth RC. Iron transport and storage. Boca Raton, Fla: CRC Press, 1990.

    8. Dorman DC. Emergency treatment of toxicoses. In: Bongura JD, ed. Kirk's current veterinary therapy XII small animal practice. Philadelphia, Pa: WB Saunders Co, 1995;211-217.

    9. Chyka PA, Butler AY, Herman MI. Ferrous sulfate adsorption by activated charcoal. Vet Hum Toxicol 2001;43:11-13.

    10. Plumb DC. Veterinary Drug Handbook. 3rd ed. Ames: Iowa State University Press, 1999.

    11. Bergeron RJ, Wiegand J, Brittenham, GM. HBED ligand: preclinical studies of a potential alternative to deferoxamine for treatment of chronic iron overload and acute iron poisoning. Blood 2002;99:3019-3026.

    "Toxicology Brief" was contributed by Jay Albretsen, DVM, PhD, DABT, DABVT, Covance Laboratories, 3301 Kinsman Blvd., Madison, WI 53704. The department editor is Petra A. Volmer, DVM, MS, DABVT, DABT, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

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  2. alethea


    Interesting questions in my inbox & I figured I might as well post the answers here, too:

    I started with 3 BenfoMax daily (Pure Encapsulations), per Izabella Wentz. That was astonishing at first, but the effects diminished until I added manganese (still tweaking the Mn; I use BodyBio drops and take them throughout the day). You can overdo Mn; keep an eye on it. I have double mutations @MnSOD, so I tend to need more. See Eric over at "How I Recovered" for more on the relationship bet CFS and MnSOD.

    After several weeks I dropped down to only 1 or 2 of Benfo and started also occasionally taking Lipothiamine (Cardiovascular Research) bc Lonsdale feels this is the only form of B1 that crosses the BBB. But there's a lot of sulfur in it (it has some ALA, too), and too much sulfur can give me problems @CBS. I already have severe hyperammonemia on my OAT (was very interested to read in the above article that hyperammonemia can be caused by iron), so ... don't need any more ammonia.

    For active B1, I take liquid drops of thiamine pyrophosphate made by Metabolics (UK). These are especially good in coffee or tea or other things that are useful for increasing manganese and lowering iron but not as good for thiamine status. (All diuretics will lower thiamine and both tea & coffee contain anti-thiamine compounds.) Heat kills thiamine so this will only work in room-temp beverages (how I always drink my tea, I'm an oddball).

    I don't try to maintain alkalinity through diet. Such diets, even juicing, always proved too high ox for me. Plus excess alkalinity can be damaging to thiamine, so ... another balancing act. I'm using electrolytes (BioPure Matrix) and Miracle Salt. I have many symptoms of low potassium, but at the same time, "active" thiamine transport (when stores are low) is sodium-dependent, so ... electrolytes have been problematic for me, and I've struggled with edema, including swollen face/eyelids.

    I also take "megadoses" of zinc (50 mg picolinate) and B6 (100 mg B6, 75 mg P5P), and quite a bit of vitamin A (5000 IU), and L-5-MTHF (800 mcg), in addition to many other things (over 30 pills/day). I don't mind the "reliance" on vitamins, or the number of them. I'm just happy to feel so much better.

    For a while, I thought the "answer" was Pyroluria. (I even wrote a short story that ends with a nod to Pyroluria -- a term that stumped a lot of editors -- free to read here: But I could never really get a satisfactory answer regarding the core etiology of Pyroluria. The closest I got was a shrug and vague explanations of "excess oxidative stress." So even though the therapies largely worked for me, on some level, I kept looking.

    I now think Pyroluria and its oxidative stress are actually caused by iron toxicity. (Any time I hear "oxidative," I find myself thinking "iron.") I even think the degree to which it's a "defect in heme synthesis" (another semi wonky explanation I was given) could be due to the activity of hemoglobin under conditions of iron dysregulation. I read the following sentence (from above) with some interest: "Any iron lost from hemoglobin degradation is rapidly bound to transferrin and transported to the bone marrow for the resynthesis of hemoglobin." I wonder if this forced recycling could ever get a little wobbly or inefficient.

    I should have mentioned autism, with its characteristic oxalates problems and disrupted sulfation, when I mentioned the myriad diseases that might fall under the aegis of iron dysregulation. I suspect iron hoarding is a defense mechanism that takes place when the body is under (real or perceived) attack. Could a vaccine be perceived by the immune system as an attack? Hm.

    I'm going on at some length, at the risk of boring and/or annoying, because my initial response to thiamine was so profound. It was akin to being born anew; there is no other way to describe it. In fact, I would venture to say I probably felt *better* than when I was born. I was an extremely unhappy baby with severe intolerance (projectile vomiting) to every baby formula they gave me -- all of which, even back in 1969, were "fortified" with iron. I suspect I already had some degree of iron toxicity at birth. In the earliest pictures of me, I appear vaguely cross-eyed, but this resolved after the first few days. Lateral eye muscle weakness or a "lazy eye" (which my left-handed sister has, and my father developed post-chemotherapy, and my mother has now developed post-Alzheimer's) can be an indication of thiamine deficiency. As mentioned, IMHO, high iron = low thiamine. I think some babies may be born iron-toxic. Lonsdale has found thiamine deficiency in sudden infant death syndrome.

    In fact, I wonder if there's some sort of "iron transfer" that takes place in the final weeks of pregnancy, or during birth, that's intended to help the infant transition to breathing oxygen through the lungs. (Hear "oxygen,"think "iron." ;)) Apparently after she gave birth to me, my mother my so severely constipated that she still remembers it (in spite of Alzheimer's!) 48 years later. Another possibility is that the drugs they give to induce labor muck with iron; I was induced, and was a very difficult forceps delivery. Or they could have been pumping my mom full of too much iron while she was pregnant. She certainly has deranged iron metabolism now (Alzheimer's), so she may have had aberrant absorption even then.

    That's probably enough for now. Happy Halloween, everyone! :eek:
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  3. duncan

    duncan Senior Member

    Interesting idea @alethea , but without some abnormal testing somewhere, it's not unlike the 800 lb invisible gorilla - but that is not to say you are not correct for at least a subset.

    I'm curious: How might you interpret high serum iron (out of range high), and low ferritin (borderline out of range low), with patches of skin bronzing? I realize of course you are not a medical doctor, but these labs and signs stump me, except for a kid overdosing on his parents' iron supplements - which does not apply (no iron supplements or kids involved:) )

    My understanding is that iron and ferritin levels typically mirror one another, except when iron overdosing - usually from iron supplements - is involved.
  4. Mary

    Mary Forum Support Assistant

    Southern California
    @alethea - there do seem to be some overlaps in symptoms or expression of iron toxicity and ME/CFS but I don't see any mention of PEM with iron toxicity. I take almost all the supplements you mention, several have helped my energy and functioning, but none of them have touched my PEM. The only thing which has really helped with PEM are BCCAs, which cut my recovery time in half. If iron toxicity were implicated in ME/CFS, I think it would have been uncovered by now. At the very least bronzing of the skin would have been noted as a symptom of ME/CFS. And iron toxicity has nothing to do with the sudden onset of ME/CFS after a severe viral infection. So the overlaps are interesting, maybe similar processes are occurring in some respects, but I just don't think your theory holds up.
  5. rodgergrummidge

    rodgergrummidge Senior Member

    Iron overload is very toxic and can produce symptoms resembling CFS. Iron overload was something I looked into as a potential underlying cause (long story). However, it is very difficult to explain how you might have iron toxicity if i) your ferritin levels ii) your total iron binding capacity (TIBC) and iii) iron-saturated transferrin (TSF-sat) are all normal. In iron overload situations, patients usually have reduced TIBC together with high TSF-sat and elevated free iron. In other words, there are insufficient levels of total transferrin (low TIBC) and even when it is maximally saturated with iron (measured as high TSF-sat), there is still unbound iron (measured as increased free iron) in the blood leading to iron overload and iron toxicity. The table below is helpful in diagnostic use of iron studies

    Yes but while free iron is very toxic, your path results make it very unlikely that you have 'iron overload' or toxicity due to excessive free iron. Perhaps I am missing something?

    Iron and infections: True, abnormal iron pathology can be due to infections. Because bacteria use iron for their growth, the body tries to sequester iron in order to block bacterial growth. But in such cases patients usually have low TIBC, low TSF-sat but increased ferritin. In other words, transferrin levels are reduced in an effort to prevent bacteria from getting access to iron while ferritin levels increase in order to sequester iron away from bacteria. The table below is also a helpful guide in diagnosing iron-related pathologies due to infections.


    Thiamine is a different issue. In some cases, defects in mitochondrial metabolism have been shown to respond to high-dose thiamine supplements. Vit B1 is required for a number of critical in mitochondrial energy production including 3 key enzymes:
    • Pyruvate dehydrogenase
    • alpha-ketoglutarate dehydrogenase
    • branched-chain keto acid dehydrogenases (BCKDHs)
    Did you test positive for elevated pyruvate or lactate before taking thiamine? What were your readings? Did you ever test positive for lactic acidosis? What were your readings? Did you test positive to high levels of ketones or branched chain amino acids in your blood?

    Its great that you have found this treatment. Your thiamine-responsive CFS may not have anything to to with iron, but it works and thats wonderful! Great outcome!

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  6. Sidereal

    Sidereal Senior Member

    You might wanna check out the many thiamine threads here on PR where Lonsdale's work has been discussed in detail. Some people here have reported a clinical response to high-dose thiamine therapy. Given your normal iron labs and your dramatic response to thiamine, and given the Fluge/Mella findings of pyruvate dehydrogenase inhibition in ME/CFS, it seems more likely that your CFS happens to be thiamine-responsive since thiamine is a known treatment for PDH dysfunction. I will say that of the people who've written to me not everyone who has tried allithiamine has experienced results. I've personally had the sorts of miraculous benefits you describe (and similar symptoms from birth onward, in hindsight) but no longer need to take it because an alkalising diet produces cleaner energy for me now without all the electrolyte derangements, the refeeding syndrome and the need to constantly troubleshoot out of the next emerging deficiency. It is possible to create a low oxalate version of such a diet. I cannot really eat any green vegetables and such due to ox issues.
    dannybex, alethea, echobravo and 2 others like this.
  7. alethea


    Thank you all for such insightful and informative responses!

    @Sidereal - I'd especially love to hear more about your alkalizing (yet low greens) diet. Managing acidity has really bedeviled me.

    I think you are right, and I must have the thiamine-responsive PDH dysfunction.

    However, I still think iron is part of this. It may not be the whole picture, and it may not be present for everyone. But for some people, I think addressing iron could produce benefits.

    I know it's strange. But it's not a derangement that shows up in serum. It's in tissues. Specifically, the mucosa of the intestines. At least -- that's where I feel it most. (And maybe, correspondingly, in the brain?)

    Here's an experiment you can try: Take high-dose thiamine. (I've used Benfotiamine and also Lipothiamine; I wouldn't "mega dose" with the lipo.) Take a little ALA with it. If you're really ambitious, throw in some lactoferrin, colostrum, or EGCG. OR (in addition to the thiamine), drink mild green tea (made with room-temp water, never boiled) instead of water all day.

    See what happens in your intestines.

    In me, the effect is very unusual and very specific. I would expect B1 (helps with peristalsis) and green tea (contains caffeine, stimulates bowels) to help with bowel movement. But whoa, that is not what happens. Yet nor is it constipation. It is a very intense churning, grinding feeling -- it leaves me breathless -- almost like trying to move molten metal with a hand crank, like the gears of my intestines are trying to move the heaviest thing they've ever tried to move. It's as if something is stimulating peristalsis, yet resisting it at the same time.

    I think it's iron. I think the green tea (colostrum, lactoferrin, EGCG, curcumin) is binding to iron; I think the B1, through supporting Krebs/Glycine Cleavage, is helping the body to finally process or "move" iron. Whatever is going on (ideas?), I think it's addressing a dysfunction that is part of this disease.

    This is speculative, I realize; I hope this is a forum that welcomes speculation? (Probably should have asked that earlier LOL! :nervous: ) I'm not at all ego-invested in this theory. I'm only interested in sharing thoughts and brainstorming so we can maybe collectively slay this thing.

    I'm with @echobravo : "Keep searching, the answer is out there." I believe it. I know it is. I know we will find it, and I think we might even find it soon.

    One final thought: While I'm very curious if others will have a similar response to this experiment, I'm not sure it's for the weakest among us. The effect can be quite intense and it actually leaves me exhausted. Additional ALA can sometimes mitigate it, if you really get into a crisis, but ... I would hate to suggest something that would make anyone worse. :)
    echobravo and ukxmrv like this.
  8. Ravn

    Ravn Senior Member

    If iron was a major factor wouldn't we expect a higher than usual proportion of PwME here to have haemochromatosis? Or, alternatively, a lot of people in the haemochromatosis forums to complain about PEM, rather than just plain fatigue? My impression is that that's not the case but haven't really looked at this systematically. Maybe somebody else has? Would be interesting.

    I have genetic haemochromatosis and my doctors struggle to control it, especially the transferrin saturation %. It drops down to about 20% for about a month after a venesection (taking 500ml of blood off to reduce iron levels) and then shoots up to 80-90% in the second month. I've never noticed my ME symptoms to be any better when low iron, nor worse when high iron.
    alethea, Sidereal and Isaiah 58:11 like this.
  9. Sidereal

    Sidereal Senior Member

    I get this only from sulbutiamine but not other forms of thiamine. IMO this is a vagal reaction, a thiamine-driven surge of acetylcholine / parasympathetic nervous system activity. If I take too much, I get very lightheaded and my heart rate drops and I feel like I'm verging on syncope. At high doses it abolishes orthostatic tachycardia altogether (an ongoing nightmare and probably my most disabling symptom) but the side effects are intolerable.

    Regarding diet, feel free to search my old posts for 'diet'. I've written a fair amount about it previously. It's by no means a cure, or even a remission, but it has helped me function at a substantially higher level. In short, as much vegetable matter of the tolerable varieties as possible, sprouted grains + legumes, no oils, as little animal food as possible, no processed foods of any kind.
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  10. Maile


    Wow, that is all really interesting. Thank you for sharing @alethea. Its a really interesting theory and makes me wonder also about metals besides iron. Could there be a cumulative effect? Its great you have figured so much out about what keeps your system running well. I think that you are sensitive to the changes over time is especially interesting as it seems like the trick is not only finding the right treatment, but also matching treatments to the stage a person is in. Very tricky.

    In speculating on mechanisms and what lab tests are and aren't elevated, I think it is important to keep in mind that these are only the tests we have so far. As lab tests get more refined, we have more information to work with, but we are still completely limited by what we are testing for. It almost seems like the science in this area has been driven by trying to figure out why helpful things work for different diseases as much as anything. If this turns out to be like most other diseases, then even the most gold standard for tests will be falsely negative some of the time. So, I am just cautious to dogmatically limit my thinking. Seems like over confidence in what we know leads to some of the bigger blind spots.

    Like you, I have found meditation and essential oils to be overwhelmingly useful. My diet is also very un-alkalizing. I would love to eat plant based, and did for many years, but alas, now my body has other ideas. A combination of the ketogenic diets, low histamine and fodmap has made some sense of this for me.

    Finally, vaccines are certainly designed to be perceived as a threat to our immune systems. That is how they work- by getting us to mount a response (which is believed to be therapeutic.)
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  11. aquariusgirl

    aquariusgirl Senior Member

    Yep. I think copper & iron dysregulation is the core of my CFS.

    I think we will need an iron chelator, & I understand new & better ones are in the pipeline.

    Here's one for your files Alethea. Iron can interfere with the SOD2.

    I think a flow diagram might read:

    Heavy copper & iron.....oxidative stress,.... oxolates...which switch off sulfation.. which switches off methylation....viruses, intracellular bacterial pathogens....etc...

    Reversing secondary hyperoxoluria looks a lot like Naviaux's refeeding program.
    Last edited: Nov 1, 2017
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  12. alethea


    So interesting.

    Thank you @Maile :)

    @aquariusgirl Iron interferes with SOD2! I've often thought it could contribute to ALS. In people who are homozygous for the form of hereditary hemochromatosis for which I carry a gene -- H63D -- it's been shown that if they get ALS, it will progress more quickly.

    @Sidereal Do you happen to know where you stand with SLC19A1 (thiamine/folate transport)? The next time I get the unbearable grinding/churning, I'm going to see if I can help things with a liter of salt water. I've been borderline hyponatremic in the past, and when I do a salt flush, I often don't flush. I think my body might be using salt (active thiamine transport = sodium-dependent) to make up for double mutations at SLC19A1.
    Maddie likes this.
  13. Sidereal

    Sidereal Senior Member

    No idea. Is the SNP in question tested by 23andme?
  14. aquariusgirl

    aquariusgirl Senior Member

    @alethea... I'lll be interested to hear if you hear back from Ron Davis. I suspect those of us with really bad oxolate problems might be a subset on our own, we get the syndrome... but we get in a deeper hole.. because we have the genes that handle oxolate poorly...

    I'm glad you reached out because otherwise I wonder if our subset, if indeed it is a subset, might get overlooked.

    I've been dumping oxolate for 8 months...and its coming out of the brain as well as the bones.. Dumping from the brain is painful, but you really want it out of there. It's neurotoxic.

    In fact, if I understand correctly, oxolate is what causes chemo brain in some folks.
    Susan Owens posted a paper on this... about how some people become an oxolate making machiine when they are prescribed the chemo drug Oxiplatin.

    I have labs that show how severe my case is .. serum B6 20x higher than it should be. Let me know if they could be helpful.

  15. aquariusgirl

    aquariusgirl Senior Member

    Hmm. Your comment on iron & ALS:

    So I guess anyone with those Snps associated with poor iron handling, or iron overload, is going to have bigger issues with this syndrome, once it gets going, because they are going to accumulate more iron, arent' they?

    I've always thought the Irish were overrepresented in the autism (CFS) community..I wonder if this is why?
  16. debored13

    debored13 Senior Member

    Vermont, school in Western MA
    wait, is it

    are you saying that it is possible to have iron overload and not have it show up on any tests? How, then, would one know if they had iron overload? regardless the science looks sort of solid as an idea, so I'll get my levels checked
  17. mariovitali

    mariovitali Senior Member


    Your investigative work resembles in many points with my Research (especially about Thiamine Deficiency) which was also communicated to @Janet Dafoe (Rose49).

    According to [1]

    I would strongly suggest you to have a Fibroscan test to check for Liver fibrosis. There is also the possibility that you have a compensated form of Liver Disease (the possibility that compensated Liver Disease can be higly associated to ME/CFS was also communicated to @Janet Dafoe (Rose49). See also [2]



    [2] :
  18. mariovitali

    mariovitali Senior Member

    @Janet Dafoe (Rose49) @Jesse2233

    See below the snapshot where i check some hemochromatosis SNPs in 63 DNA files with people having CFS/PFS/Post-Accutane Syndrome :

    Screen Shot 2017-11-03 at 11.08.36.png

    It appears that :

    rs1800562 pathogenic allele with a MAF of 0.01 was found in 10.34% of these patients (heterozygous)

    rs1799945 pathogenic allele with MAF 0.07% was found in 29.31% of these patients (heterozygous)

    for rs235756 allele, 48,28% were found heterozygous, 10.34% homozygous

    Could someone with knowledge in SNPs investigate this further?

    Janet : I also believe that we could add "Hemochromatosis" to the list of Liver Stressors responsible for ME/CFS and several other syndromes (Hypothesis)
    Last edited: Nov 3, 2017
  19. aquariusgirl

    aquariusgirl Senior Member

  20. rodgergrummidge

    rodgergrummidge Senior Member

    Hi @alethea , I just wanted follow up my previous post where I pasted a table that detailed how iron studies can be used to diagnose a number of conditions including inflammation. In your case iron values were in the normal range making it difficult to attribute your symptoms to iron abnormalities.

    But, is an imbalance in iron a common feature of CFS?
    The answer is probably no. The table below shows that there was no significant difference in either ferritin, sol-Fe, TIBC or %TSF-sat when CFS patients were compared to controls (Redox Report, 5:1, 35-41). Note that even free iron is in the normal range so the evidence that iron may be 'hiding' somewhere is difficult to support given the data.

    Hopefully this helps

    GreenBlanket and debored13 like this.

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