Concept:Iron and TrPs

Iron is an essential mineral whose deficiency is estimated to be present in 9–11% of adolescent girls and women of childbearing age in the United States — making it the most prevalent micronutrient deficiency in the developed world. Iron deficiency increases the irritability of myofascial trigger points (TrPs) through multiple mechanisms: it impairs oxygen transport to muscle, disrupts oxidative phosphorylation in mitochondria, impairs thermoregulation, disturbs catecholamine metabolism, and reduces work capacity — each of which directly converges on the energy crisis at the TrP endplate.

The symptom of coldness that is often seen in persons with chronic myofascial pain has iron deficiency as one of its causes — a fact confirmed when impaired thermoregulation was present in 57% of patients with myofascial pain syndrome, with tissue iron depletion found in 65%.

Biochemical Functions

Iron serves essential roles throughout human metabolism:

Oxygen Transport and Storage

Iron is the central atom of haem, the prosthetic group of:

• Haemoglobin — the oxygen-carrying protein of red blood cells; transports oxygen from lungs to all tissues
• Myoglobin — the oxygen-storage protein of muscle fibres; provides the immediate oxygen reserve for aerobic metabolism in muscle

The relation of iron to muscle pain has several facets. One is the essential role of iron in energy production and oxygenation that affects the ability of muscle to meet its energy demands. This energy factor relates strongly to the TrP mechanism (see Chapter 2, Section D of the source volume).

Mitochondrial Oxidative Phosphorylation

Iron is required for enzymatic reactions that have to do with tissue respiration and oxidative phosphorylation:

• Cytochrome oxidase reactions — iron is the essential redox-active atom in the cytochromes of the electron transport chain
• Porphyrin metabolism
• Collagen synthesis (iron-dependent hydroxylases)
• Neurotransmitter synthesis and catabolism

Iron-deficient animals accumulate lactic acid as a result of impaired glycolysis, and this is also postulated to be the cause of reduced physical activity. The effect of iron on energy metabolism is of special interest because of the hypothesis that the myofascial TrP is a localised region of "energy crisis" that reflects the metabolic distress of the muscle stress.

Thyroid Hormone and Thermoregulation

Another role of iron in myofascial pain is its regulation of hormonal functions like thyroid hormone — which itself plays a critical role in energy metabolism and is clinically important in chronic myofascial pain syndromes. Iron deficiency anaemia is associated with:

• Impaired thermoregulation — the ability to maintain body temperature is compromised
• Impaired triiodothyronine (T₃) response to a cold stressor
• Impaired catecholamine response to environmental cold
• Increase in catecholamine levels may represent the body's attempt to raise core temperature

Iron deficiency anaemia in young women impaired the ability to maintain body temperature when exposed to a moderately cold environment. Plasma triiodothyronine and thyroxine levels were both decreased in women with iron-deficiency anaemia.

Catecholamine Metabolism

Iron is required for the synthesis and catabolism of catecholamines. Impaired catecholamine metabolism in iron deficiency produces additional autonomic dysregulation that compounds TrP irritability.

Immune Function

Iron-dependent enzymes are essential for the respiratory burst of neutrophils and for lymphocyte proliferation. Chronically iron-deficient patients have impaired immune surveillance, which contributes to susceptibility to the chronic infections that themselves perpetuate TrPs.

Stages of Iron Deficiency

Iron deficiency occurs in three distinct stages:

1. Stage 1 — Depletion of tissue iron stores: detected by serum ferritin levels; the patient may be entirely asymptomatic
2. Stage 2 — Depletion of essential iron stores associated with metabolic and enzymatic activity: iron-dependent enzyme activities decline; the patient may experience reduced work capacity, impaired thermoregulation, and increased TrP irritability before anaemia develops
3. Stage 3 — Deficient erythropoiesis leading to iron deficiency anaemia: haemoglobin and haematocrit fall; full clinical anaemia; the TrP-relevant metabolic effects of stages 1 and 2 are now compounded by tissue hypoxia

Detection of iron insufficiency before anaemia develops is most important, because decreased work capacity and impaired energy metabolism are present in stages 1 and 2, before the haematological markers of anaemia appear.

Iron deficiency anaemia is associated with impaired thermoregulation or ability to maintain body temperature, with impaired triiodothyronine response to a cold stressor, and with impaired catecholamine response to environmental cold. The symptom of coldness was present in 57% of patients with myofascial pain syndrome in one study, and of these, tissue iron depletion was found in 65%. Work capacity is reduced in iron-deficient women.

Laboratory Assessment

Serum Ferritin — The Key Test

Measurement of serum ferritin is an accurate way of assessing tissue iron stores. Normal serum ferritin levels have a two-fold diurnal variation and are less sensitive to the state of tissue iron stores than ferritin.

Ferritin level	Clinical significance
< 20 ng/mL	Signifies iron loss without adequate replacement
20–30 ng/mL	May signify iron loss without adequate replacement
30–50 ng/mL	May indicate need for replacement of iron stores
> 50 ng/mL (up to 300 ng/mL)	Normal tissue iron stores

Depletion of tissue iron is reflected in the lowering of serum ferritin levels, as non-essential iron stores are depleted first. Essential iron stores are depleted when serum ferritin levels reach 20 ng/ml.

Iron Requirements and Daily Losses

Iron requirements are determined by daily iron losses, which are about 0.8–1.0 mg daily, except in menstruating women whose losses are 1.4–2.4 mg/day. About 10% of dietary iron is absorbed, with a ceiling of 4–5 mg/day in anaemic individuals.

Complete Blood Count Limitations

The CBC provides important secondary information:

• Low erythrocyte count, low haemoglobin, and low/or microcytosis indicates anaemia — which tends to make muscles hypoxic and to increase TrP irritability
• An increased mean corpuscular volume (MCV) > 92 fl is suspicious as it rises from 95 to 100 fl — the likelihood of a folate or cobalamin deficiency increases
• Eosinophilia may be due to an active allergy or to infestation with an intestinal parasite such as a tapeworm
• An increased proportion of mononuclear cells (> 50%) may occur because of low thyroid function or due to active infectious mononucleosis or an acute viral infection

However, absence of anaemia does not exclude clinically significant iron deficiency — stages 1 and 2 are pre-anaemic but already metabolically consequential.

Dietary Sources

Iron is present in food as easily absorbed haem iron or as poorly absorbed non-haem iron:

Haem Iron (from animal products)

• Directly absorbed into intestinal cells as the intact haem molecule
• Absorption rate: approximately 20–30% regardless of the iron status of the individual
• Sources: red meat, organ meats, dark poultry meat, shellfish

Non-Haem Iron (from plant products and supplements)

• Absorption rate: highly variable, 1–15%, depending on numerous factors
• Sources: legumes (lentils, beans), dark leafy greens, fortified cereals, nuts and seeds, dried fruit, iron cooking vessels

Enhancers and Inhibitors of Non-Haem Iron Absorption

Major absorption promoter:

• Ascorbic acid (vitamin C) — the most potent absorption promoter; the strong iron absorption promoter ascorbic acid can overcome the effect of dietary inhibitors to a significant degree. This is why taking iron supplements with vitamin C significantly improves absorption

Major inhibitors:

• Calcium — calcium in milk, cheese, or as a supplement can decrease non-haem iron absorption by 50%, and can also significantly reduce absorption of haem iron. Calcium supplements should NOT be taken together with iron supplements
• Phytic acids — components of cereal grains, constituting 1–2% of many cereals, nuts, and legumes; chelate heavy metals and are potent inhibitors of iron absorption; however, the presence of phytic acids in nuts and soy is offset by the high iron content of these foods
• Polyphenols (in tea, coffee, red wine)
• Antacids and proton pump inhibitors

Causes of Insufficiency and Deficiency

• Insufficient dietary intake — to replace menstrual blood loss places menstruating women at risk of iron insufficiency or deficiency
• Iron deficiency in men usually indicates a specific illness — such as carcinoma — that must be identified
• Gastric irritation with microscopic blood loss in both men and women who take non-steroidal anti-inflammatory drugs (NSAIDs)
• Also associated with pernicious anaemia, occurring in 43% of persons diagnosed with this condition
• Moderate exercise has been shown to reduce iron stores — but on the other hand, moderate exercise increases iron absorption

Treatment: A Practical Guide

Suspect iron inadequacy when:

• Myofascial TrPs persist despite appropriate therapy
• Fatigue or coldness are prominent symptoms
• NSAIDs have been taken regularly for pain relief
• Menstruating women, particularly those whose menstrual flow is heavy
• Low erythrocyte volume or low mean cell haemoglobin concentration

Measurement

Measure iron stores by the serum ferritin test:

• Levels of 20 ng/mL or less signify iron store depletion
• Levels of 30–50 ng/mL may indicate need for replacement of iron stores

Treatment Protocol

Treat iron depletion at ferritin levels of 30 ng/ml or lower, and even levels up to 40 ng/ml, to prevent depletion. At ferritin levels of 30 ng/ml or less, iron supplements containing 150 mg of iron (equivalent to 50 mg of elemental iron) are taken twice daily if tolerated, or once daily if necessitated by constipation or gastric irritation.

• Do not take with calcium supplements or with meals of dairy foods
• Taking them with vitamin C helps absorption
• Folic acid 1 mg taken with iron lessens the symptom of gastric irritation
• Supplements are available with stool softeners and in different formulations — finding one that is tolerable is usually possible
• Once the serum ferritin level reaches 30–40 ng/mL, a small daily supplement of 12–15 mg, commonly found in most multivitamin mineral preparations, is enough to maintain tissue iron stores

Warning

Iron supplementation should always be monitored to avoid excessive iron storage and haemochromatosis. Serum ferritin levels every 3 months are adequate to monitor supplementation at higher doses, and every 6 months until stable for lower dose maintenance.

Iron supplements should not be given unless iron insufficiency is established through the measurement of serum ferritin levels, because iron overload can lead to haemochromatosis — ischaemic heart disease and a poorer outcome after stroke.

The Biology of Starvation: Iron

Iron occupies a paradoxical position in starvation biology. Unlike the water-soluble vitamins, iron is not lost rapidly during starvation — the body is exquisitely conservative with iron, having no dedicated excretory pathway. Instead, in starvation, iron deficiency emerges through the collapse of the absorptive infrastructure:

The starvation cascade:

1. Reduction of dietary intake removes the primary iron source
2. Atrophy of the gastrointestinal mucosa (driven by protein and folate deficiency) impairs the absorptive epithelium that would concentrate ingested iron
3. Protein deficiency reduces the synthesis of transferrin (the iron transport protein) and ferritin (the iron storage protein) — tissue stores cannot be maintained even when some iron is present
4. Progressive haemoglobin synthesis failure occurs as protein and iron simultaneously become limiting; anaemia develops
5. The anaemia of starvation is therefore a combined deficiency anaemia — iron, protein, folate, B₁₂, and B₆ all contributing simultaneously

The muscle energy cascade in iron-deficient starvation: In iron-deficient starvation, the mitochondrial electron transport chain is progressively impaired as iron-containing cytochromes are not replaced. The muscle cell shifts from efficient oxidative phosphorylation toward anaerobic glycolysis, with lactate accumulation even at rest or minimal activity. This is the same metabolic state hypothesised at the active locus of a TrP — a localised energy crisis with lactate accumulation, ATP depletion, and consequent failure of the calcium pump.

The evolutionary context is that in ancestral environments, dietary iron was predominantly haem iron from fresh animal products, absorbed at 20–30%. The dominance of plant-based iron with low bioavailability in many modern and traditional diets — combined with the inhibitory effect of phytic acids, calcium, and cooking losses — means that dietary iron adequacy is structurally precarious for large populations, particularly women of reproductive age.

In the chronic pain patient, this means that even patients who eat adequate calories may be iron-insufficient — particularly menstruating women, regular NSAID users, and patients with GI pathology. The symptom cluster of fatigue, coldness, reduced exercise tolerance, and treatment-resistant TrPs should always prompt ferritin measurement.

Related Pages

• Perpetuating Factors — Overview
• Vitamin C (Ascorbic Acid) and Trigger Points — primary enhancer of non-haem iron absorption
• Calcium and Trigger Points — major inhibitor of iron absorption; do not combine supplements
• Vitamin B₁₂ and Trigger Points — pernicious anaemia co-occurs with iron deficiency in 43%
• Hypometabolism and Trigger Points — iron deficiency impairs thyroid hormone metabolism
• Iron deficiency — Wikipedia
• Iron deficiency anaemia — Wikipedia
• Ferritin — Wikipedia
• Haemoglobin — Wikipedia
• Myoglobin — Wikipedia
• Haem — Wikipedia
• Transferrin — Wikipedia

References

• Travell JG, Simons DG. Myofascial Pain and Dysfunction: The Trigger Point Manual, Volume 1. 2nd ed. Baltimore: Williams & Wilkins; 1999. Chapter 4, Section C.