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Porphyria, Heme, Hemoglobin, Low Iron/Ferritin, Mast Cells, CFS, Toxins, & the Metabolic Trap

Updated: May 28

This article is not medical or healthcare advice. Seek the care and guidance of a M.D. or healthcare practitioner before starting any health related regimen.

Thats kind of a mouthful for a title eh? This article will dive into heme dysregulation, and attempt to tie several things together across mutliple symptomologies. Before that, i will try and outline some things about the heme pathway, what it does, and the key bottlenecks and cofactors that are involved. This will be a long one, so hang in there. I will add more to this article as the days go on, and will add references as well.

Heme is created in the body to make hemoglobin (which is on any CBC panel). "Heme is an iron-containing molecule that is important for many biological processes. Heme combines with globin proteins to form hemoglobin, which carries oxygen in red blood cells from the lungs to the rest of the body". [2] To create heme the entry point uses Glycine, and Succinyl CoA from the Krebs Cycle. So you need Glycine, which can be converted from Serine (SCHMT1,2) or Threoneine, an essential amino acid (GCAT), and you will need B6 and or folate to do the conversion. The heme pathway goes through a dozen key steps (and genes) and each step requires a cofactor to work, and also can be upregulted (made to go faster) or inhibited by certain things (like metals, mycotoxins, etc). At each of these steps, different types of Porphyrins are created - and these end up in our bile, and can create little crystals that interfere with the galbladders exit tubes, the livers exit tubes, and the illeosacral valve between the large and small intestine. And of course, we see SIBO, mal digestion (poor bile delivery) with this crowd when there are too many Porphyrins, which are created when their is a block or buildup along one of a dozen or so steps to make heme. The final step after the last gene (FECH), heme goes on to be used as a cofactor in the body for many functions, some listed below, and to a gene called HMOX1 which then combines the heme with iron and stores it into Ferritin. Aha. Now we see why some people who are really compromised in ferritin levels, can simply be very compromised on HMOX1:). Below I will try and describe the symptomology, the heme pathway, considerations, and co mingling touble makers with heme pathway dysregulation.

Short Version Classic Symptomology (detailed list at end of article):

  • Fatigue

  • Mast cell activation

  • Mysterious intense abdominal pain (gall bladder issues/attacks),

  • Histamine issues

  • Neurological issues

  • Maldigestion (poor bile flow); SIBO (poor illeosacral valve functioning)

  • High porphyrins from a blocked heme pathway, block the Gaba receptors, anxiety.

  • Alcohol sensitivity - can cause gallbaldder attacks!NOS3

  • Reactions to herbs, medications, alcohol that tax CYP 450 Phase I detox pathway

  • Very reactive to foods, supplements, herbs, and medications.

Systemic/Co-Morbidities: Edema, Fatigue, Fibromyalgia, Autism, Autoimmunity, PMS, Low grade fever, Insomnia, Increased sweating, or inability to sweat, EMF Sensitivity, Immuno deficiency, Mast Cell disorders, Hypoxia; Environmental toxin exposure cormorbidity is very high.

Not Enough Heme - the easiest marker here is low hemoglobin on CBC panel, low red cells, and we would expect ferritin to also be low. Hemoglobin contains six trytpophan residues:).

A block somewhere in the heme pathway - we would would expect high porphyrins - which will cause all sorts of potential symptomology. The block can come from one or more of 6 main factors:

  1. Short on the input substrate to the pathway: Glycine or Succynl Co A

  2. Short on one of the many cofactors in the heme pathway: Cu, Zn, Iron, B6, B2, Tryptophan, Lipoic Acid, Oxygen (Hypoxia!), etc

  3. Inhibition of one of the genes by a toxin: Lead, Mercury, Mycotoxins have specific research related to some of the dozen genes in the heme pathway.

  4. Genetic mutations on one or more of the dozen genes in the pathway that compromise the genes function.

  5. Gut inflammation, IL-10 blocks one of the key genes in this pathway

  6. Inability to process sulfur - compromise in the sulfur pathway (genetically, cofactor deficiency - b2, molybdenum, selenium, iodine primarily, or excess oxidized glutathione): CBS, CTH, PAPSS1, PAPSS2, SUOX, SULT1A1, SULT2A1

  7. Artemesian and wormwood inhibit heme biosynthesis [24]

This study references: Dioxins, DDT,  polychlorinated phenols, benzylchlorophenol and sodium hypochlorite, vinyl chloride in a polyvinyl chloride,  polybrominated biphenyls (PBBs) , polychlorinated biphenyls (PCBs) in food oil, and diazinon. [17]. These toxins have less specificity where they inhibit the pathway, than the step by step analysis below.

Entry (Glycine) / Succinyl Co A From Krebs Cycle - combines with PLP (b6 form) and makes ALA

The krebs cycle is inhibited by Aluminum or a lack of glutathione at Aconitase (ACO2, ACO1). [20] The heme cycle shares these requirements, so i wanted to highlight the interconnected dependency and impact of these two things. On Organic Acids tests , this is the MOST common block i see, at Aconitase. Aconitase also has iron-sulfur clusters, and is also inhibited by Peroxynitrite. And the heme cycle has 3 genes that have iron sulfur clusters below, so also is inihibited by Peroxynitrite.

Step 1: ALAS1/ ALAS2 - ALAS2 is rate limiting factor, and uses tryptophan here; vegans take note, Plant-based sources of tryptophan include leafy greens, sunflower seeds, watercress, soybeans, pumpkin seeds, mushrooms, broccoli, and peas.

  • Modulated by circadium rythm[9]

  • Fasting up regulates ALAS1; feeding down regulates ALAS1[9]

  • Disturbed (down regulated) by Measles V Virus protein [6]

  • PPAR Gamma1Alpha co-activates (Berberine, Circumin)[9]

  • ALAS2 has gain of function mutations [7,8]

  • ALAS1 induced by the anti fungal griseofulvin

  • Tryptophan dependent (ALAS2)[9]

  • Blocked by Lead [9]

  • Inhibited by Cobalt [12,32]

  • Inhibited by Manganese [13,14]

  • ALAS2 indirectly relies on iron sulfur clusters and is thus inhibited by perxoynitrite [21,22,23]

  • Inhibited by Aluminum

  • Stimulated by excess Selenium [35]

  • Inhibited by glucose [26]

Step 2: SLC25A38 - Mitochondrial glycine transporter

Step 3: ABCB10 is one of the three ATP-binding cassette (ABC) transporters found in the inner membrane of mitochondria. ABCB10 is essential for erythropoiesis, and for protection of mitochondria against oxidative stress. ABCB10 is a potential therapeutic target for diseases in which increased mitochondrial reactive oxygen species production and oxidative stress play a major role.

  • If impaired hurts mitochondrial import of iron

Step 4: ALAD (Lead blocks, B3 and Zn Cofactor) - combines two molecules of delta-aminolevulinic acid (the product of the prior step) to form a compound called porphobilinogen. At least 10 mutations in the ALAD gene can cause a rare form of porphyria called ALAD deficiency porphyria. Most of these mutations change single protein building blocks ( amino acids) in delta-aminolevulinate dehydratase. These changes reduce the activity of the enzyme, allowing delta-aminolevulinic acid to build up to toxic levels in the body. This compound is formed during the normal process of heme production, but reduced activity of delta-aminolevulinate dehydratase allows it to accumulate to toxic levels. Very high levels of this compound can cause attacks of abdominal pain, vomiting, and other signs and symptoms of ALAD deficiency porphyria. A common variation (polymorphism) in the ALAD gene may affect the risk of developing lead poisoning in people exposed to environmental lead. Lead is a heavy metal that is toxic when inhaled or ingested. Lead poisoning can cause significant health problems involving the nervous system, blood, kidneys, and reproductive system. This variation may influence the amount of lead in a person's blood and bones. [19]

  • hereditary tyrosinemia type I, succinylacetone accumulates and potently inhibits ALAD[9]

  • ALAD can also be inhibited by styrene in animals and humans[9]

  • Arsenic inhibits ALAD [13]

  • Inhibited by Manganese [13,14]

  • Inhibited by VOC's (styrene, benzene, toluene) [16]

  • Contains iron sulfur clusters, which can be inhibited by peroxynitrite [21,22,23]

  • Inhibited by Aluminum [25]

  • Inhibited by high levels of selenium (toxicity - electronics mfg exposure) [33,35]

  • Inhibited by cadmium, 50% of this inhibition can be rescued with Vit C [34]

  • "Exposure of HepG2 and Hep3B cells to Cu2+ inhibited the enzymes PBGD and ALAD of the heme synthesis pathway and, in parallel, upregulated heme oxygenase-1 (HO-1)."[37]

Step 5: HMBS - combines four molecules of porphobilinogen (the product of the prior step) to form a compound called hydroxymethylbilane. Acute Intermittent Porphyria results from hydroxymethylbilane synthase (HMBS) mutations that markedly decrease HMBS enzymatic activity. This dominant disease is diagnosed when heterozygotes have life-threatening acute attacks, while most heterozygotes remain asymptomatic and undiagnosed.

Step 6: UROS (Cofactor, Lipoic Acid) - hydroxymethylbilane (the product of the prior step) is rearranged to form uroporphyrinogen III. Congenital erythropoietic porphyria (CEP) is an inborn error of heme biosynthesis characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in deleterious porphyrin accumulation in blood cells responsible for hemolytic anemia and cutaneous photosensitivity. We analyzed here the molecular basis of UROS impairment associated with twenty nine UROS missense mutations actually described in CEP patients. We show evidence that abnormal protein homeostasis is a prevalent mechanism responsible for UROS deficiency and that modulators of UROS proteolysis such as proteasome inhibitors or chemical chaperones may represent an attractive therapeutic option to reduce porphyrin accumulation and prevent skin photosensitivity in CEP patients when the genotype includes a missense variant.

Step 6B: UROD

Inhibited by : Polychlorinated biphenyls (PCBs) [27]

2,3,7,8-Tetrachorodibenzo-pdioxin (TCDD)[27]

Hexachlorobenzene (HCB)[27]

Step 7: CPOX (iron is cofactor) {IL-10 Regulates CPOX}- removal of carbon and oxygen atoms from coproporphyrinogen III. Hereditary coproporphyria is an acute hepatic porphyria characterized by the occurrence of neurovisceral manifestations. This rare metabolic disorder is due to deficient activity of the mitochondrial enzyme coproporphyrinogen oxidase (CPOX) and it's usually inherited in an autosomal dominant pattern. On one specific location of CPOX4, a single mutation can inhibit the gene significantly even with minor mercury exposure (think fish, fillings, and injections). A single copy of this mutation occurs in about 15-20% of the populations (african decent 40%), while a double copy of this mutation occurs in only 2% of the population. See my article, "The Sulfur People....". Some of the people who i have seen struggle the most, have this mutation. Il-10 (gut inflammation) blocks this gene! I wonder why people with high gut inflammation feel 'tired'.

  • The discovery that IL-10 can inhibit the production of CPOX, coproporphyrinogen oxidase may shed some lights on the mechanisms of anaemia induced by IL-10". [5]

  • CPOX inhibited by Arsenic and Lead [13]

Step 8: ABCB6 - This protein is a member of the heavy metal importer subfamily and plays a role in porphyrin transport. This gene is the molecular basis of the Langereis (Lan) blood group antigen and mutations in this gene underlie familial pseudohyperkalemia and dyschromatosis universalis hereditaria. Analysis of mutant yeast mitochondria suggested that ABCB6 may help maintain respiratory function and may also transport Fe/S clusters from mitochondria to the cytosol, thereby helping to prevent iron accumulation and DNA damage in the organelle.

Step 9: PPOX (Oxygen and FAD/B2 dependent)- hydrogen atoms are removed from protoporphyrinogen IX to form protoporphyrin IX. Variegate porphyria (VP) is a low-penetrance, autosomal dominant disorder characterized clinically by skin lesions and acute neurovisceral attacks that occur separately or together. It results from partial deficiency of protoporphyrinogen oxidase encoded by the PPOX gene. VP is relatively common in South Africa, where most patients have inherited the same mutation in the PPOX gene from a common ancestor, but few families from elsewhere have been studied.

  • Phenoxy acid herbicides are potent PPOX inhibitors[9]

  • These chemicals are also potent inducers of hepatic ALAS1, which further contributes to PPIX accumulation[9]

  • Fomesafen[27]

Step 10: FECH (Iron/zn, Copper [11] are cofactors, along with P5P/B6) - an iron atom is inserted into the center of protoporphyrin IX (the product of the prior step) to form heme. Erythropoietic protoporphyria (EPP), an autosomal dominant disease, is caused by partial deficiency of ferrochelatase (FECH), which catalyzes the terminal step of heme biosynthesis because of loss-of-function mutations in the FECH gene. To date, only a few cases have been described in Asia. "..these findings illustrate that FECH is responsible for salicylic acid-induced inhibition of heme synthesis..". [4]

  • Loss of function mutations (Thaper and Bonkovsky, 2008)[9]

  • Anti fungal Griseofulvin inhibits FECH[9]

  • Salicylic acid inhibits FECH[9]

  • Competitively Inhibited by Manganese [15]

  • Inhibited by VOC's (benzene, toluene, styrene) [16]

  • Has iron sulfur clusters [21]- and can be inhibited by peroxynitrite [22,23]

  • "Ferrous iron is then inserted by the inner membrane ferrochelatase to form heme."[29,30]

  • Inhibited by Silver

  • Inhibited by: Anti fungal Griseofulvin inhibits (eat organic) [27]

  • Competitively Inhibited by Manganese [27]

  • Inhibited by VOC's (benzene, toluene, styrene) [27]

  • Has iron sulfur clusters and can be inhibited by peroxynitrite and oxidative stress

  • Lead [27]

  • DDC/DDT - 3,5-Diethoxycarbonyl-1,4- dihydro-2,4,6-trimethylpyridine (DDC). [27]

  • Cobalt [27] (high serum b12, from low glutathione and or b2)

  • 3-[2-(2,4,6-Trimethylphenyl)- thioethyl]-4-methylsydnone (TTMS)[27]

  • Tralkoxydim[27]

Step 11: Output Path 1 - Heme is a Cofactor Used In the following Pathways/Genes/Systems:

a. Tryptophan Pyrrolase: Metabolism of Tryptophan through TDO, IDO1, IDO2 - yes these are the same genes studtied by Robert Phaire under his 'metabolic trap' theory for CFS.

b. GPX - Glutathione Peroxidase Enzymes 1-8; yes these are the same enzymes used to detoxify lipid peroxides from cell membrane oxidation. Especially important is GPX4, the only GPX, located inside the mitochondria.

c. Catalase and just like GPX, Cat neutralizes hydrogen peroxide!

d. NADPH - NAD - the single most common cofactor in the body, followed by magnesium, and b6:)

e. Cytochrome p450 (Phase 1 detox enzymes), enzymes are heme dependent! Low heme - inability to detox! These people are VERY sensitive to alcohol!

f. NOS3 mutations and inhibition is tied to NOS Uncoupling (massive oxidative stress), POTS - from poor blood flow, and poor circulation - cold hands and feet; and finally inhibits mast cell activation.

g. Finally SUOX - our sulfur friends. An un deniable link between heavy metal toxocity / exposure and our sulfur friends. For a few, even very minor mercury exposure causes issues:). Hmm. Maybe RFK is onto something:).

h. Electron Transport - Mitochondrial function in complexes 2,3,4 uses heme.

i. Hemoglobin, Myoglobin, Neuroglobin, Cytochrome C

Step 12 - Parallel To Step 11: Output directly to HMOX1 -

  • HMOX1 stores iron into ferritin, promotes billiverdin (which turns into billirubin) and blocks mast cell activation. Mast cell folks have low ferritin for a reason.

  • Heme oxygenase (HMOX1) is the primary antioxidant enzyme involved in heme group degradation. A variety of stimuli triggers the expression of the inducible HO-1 isoform, which is modulated by its substrate and cellular stressors. A major anti-inflammatory role has been assigned to the HO-1 activity. Therefore, in recent years HO-1 induction has been employed as an approach to treating several disorders displaying some immune alterations components, such as exacerbated inflammation or self-reactivity. Many natural compounds have shown to be effective inductors of HO-1 without cytotoxic effects; among them, most are chemicals present in plants used as food, flavoring, and medicine. This review opens a new outlook on the investigation of naturally derived HO-1 inducers, mainly concerning autoimmunity. Garlic, Quercetin, Circumin, Caeffeic Acid, ECGC, Capsacin, Hops.

  • Lee and Chau (2002) showed that IL10, but not IL6 (147620), induces expression of Hmox1 in mouse macrophages through the p38 MAP kinase

How to asssess - Where Is The Problem ?

One could imagine the power of a micronutrient panel that can assess the nutritional status for the required cofactors/substrates. The Porphyrins test by Doctors Data or Mosaic (ordered at, can help us pinpoint where in the heme pathway the block may be occurring, by showing us which Porphyrin is elevated. A heavy metals and mycotoxin panel can assess toxicity from metals and molds. Genetics can help us see reasons for blocks that are not obvious from a lack of cofactors, contaminants, etc. IL-10 can be measured by most hospitals and labs. The order in which this is explored is important, we need heme, but if we stimulate the cycle at the wrong point we will cause more of a back up, and symptoms become worse.

A few words about Glyphosate :

It is well known that glyphosate is molecularly similar to glycine - and is believed to substitute itself in glycine's place in various pathways. Even if we stop here, we see the potential issues with heme formation. But it goes on. We already spoke about the PON1 gene being responsible for deoxifying glyphosate, so we know its at least partially in play there too.

Glyphosate Inhibits CYP450 Enzymes - which - if we are short on heme - is already compromised

"Glyphosate's inhibition of cytochrome P450 (CYP) enzymes is an overlooked component of its toxicity to mammals. CYP enzymes play crucial roles in biology, one of which is to detoxify xenobiotics. Thus, glyphosate enhances the damaging effects of other food borne chemical residues and environmental toxins. Negative impact on the body is insidious and manifests slowly over time as inflammation damages cellular systems throughout the body. Here, we show how interference with CYP enzymes acts synergistically with disruption of the biosynthesis of aromatic amino acids by gut bacteria, as well as impairment in serum sulfate transport." [1]

Glyphosate inhibits ALA (delta aminolevulinic acid)!

"Thus, the site of action of glyphosate may involve two enzyme pathways:one controlling the conversion of α-ketoglutarate to ALA (a key cofactor in heme), and the other controlling the condensation of glycine with succinyl CoA to form ALA and carbon dioxide. Inhibition of ALA synthesis blocks synthesis of chlorophyll, as well as all other porphyrin ring compounds..."[3]

If you would like to explore this topic in detail and see how your labs and genetics may give us clues to what is going, send me a note to schedule an appointment. It shouldn't take long to explore this:).

Overview of  Protoporphyria:

Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic pathway. EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. Both disorders result in the accumulation of erythrocyte protoporphyrin, which is released in the plasma and taken up by the liver and vascular endothelium. The accumulated protoporphyrin is activated by sunlight exposure, generating singlet oxygen radical reactions leading to tissue damage and excruciating pain. About 2–5% of patients develop clinically significant liver dysfunction due to protoporphyrin deposition in bile and/or hepatocytes which can advance to cholestatic liver failure requiring transplantation.[10]

Clinically these patients present with acute, severe, non-blistering phototoxicity within minutes of sun-exposure. Anemia is seen in about 47% of patients and about 27% of patients will develop abnormal serum aminotransferases. The diagnosis of EPP and XLP is made by detection of markedly increased erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin. Genetic testing by sequencing the FECH or ALAS2 gene confirms the diagnosis. [10]

Treatment is limited to sun-protection and there are no currently available FDA-approved therapies for these disorders. Afamelanotide, a synthetic analogue of α-melanocyte stimulating hormone was found to increase pain-free sun exposure and improve quality of life in adults with EPP. It has been approved for use in the European Union since 2014 and is not available in the U.S. In addition to the development of effective therapeutics, future studies are needed to establish the role of iron and the risks related to the development of hepatopathy in these patients.[10]

Detailed Symptomology Below[2]

Gastro intestinal

  • Unexplain abdominal pain, nausea, vomitng, constipation, diarrhea, spastic colon, belching, bloating

  • Bowel symptoms caused by neurologic disturbance

  • Difficulty swallowing

  • Hiatal hernia, gastroparesis, paraltic ileus

Cardiovascular / Hematopoietic:

  • Rapid heart rate, hypertension, POTS

  • Blood disorders

  • Chest pain of inderterminant cause

Nervous System / Neurological

  • Anxiety, panic, restlessness, irratibility, poor concentration, tremors, OCD, hysteria, depression, paranoia, hallucinations, manic depression, hyper activity, psychosis

  • Dizziness

  • Nerve burning, itching, feeling of bugs crawling

  • Peripherla neurathy, tics, twitches

  • Pain: epigastric, stomach, generalized abdominal, musculoskeletal (back, head, neck)

  • Abdomnal, back, extremity pains

Endocrin Systems

  • Thyroid issues

  • Adrenal complications

Musculoskeletal and Respiratory

  • Muscle weakness

  • Respiratory weakness

  • Prolonged attacks impair sensory and motor function

  • Asthma

  • Foot drop and clumsiness


  • Frequent Hunger Pains

  • food addictions and cravings

  • Alcholism, Drug addiction

  • Obesity

  • Multiple Chemical Sensitivities

  • Sensitivity to chemicals, pesticides, alcohol, caeffeine, anesthetics, foods, supplements

  • Eating disorders

Organ Involvement

  • Kidney, bladder problems

  • Dark urine, red, brown

  • Dry eyes

  • Visual disturbances


  • Genetics

  • Fasting or rapdi weight loss

  • Keo diets

  • Stress

  • Infections

  • CYP 450 burdens - toxins, estrogen, medications, pesticides, VOC's, some herbs

  • Nutrient deficiencies

  • Hypoxia

  • UV Light

  • Alcohol

  • ROS - oxidative stress

  • Herbicides

  • Oxidized iron (too high of iron)

  • Sulfur foods


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