Concept:Hypometabolism and TrPs

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Hypometabolism (thyroid inadequacy) describes the condition of someone whose serum levels of thyroid hormones are in the low euthyroid range, or just below the "normal" two standard deviation limit. It is covered in depth as a perpetuating factor for myofascial trigger points (TrPs) because, when present, the results of specific therapy for myofascial pain syndrome (MPS) can be utterly frustrating until the hypometabolism is corrected — patients obtain only temporary relief with specific myofascial therapy, yet recover promptly once thyroid function is adequately supported.

The importance of this perpetuating factor is illustrated by Dr. Gerwin's clinical observation: achieving a TSH of 0.5–2.0 mIU/L in hypothyroid myofascial pain patients can produce spontaneous resolution of TrPs and full recovery from MPS within 4–6 weeks — a result that corresponds to spontaneous recovery in patients without any perpetuating factors.

This page covers the full clinical, molecular, and diagnostic landscape of hypometabolism as a TrP perpetuator. For the related metabolic conditions of hypoglycaemia and hyperuricaemia, see Perpetuating Factors — Overview.

Thyroid Hormone Biology

The Thyroid Hormones

  • Thyroxine (T₄) — the primary product of the thyroid gland; the dominant form of circulating thyroid hormone; physiologically relatively inactive
  • Triiodothyronine (T₃) — the biologically active form; over 80% of circulating T₃ is derived by deiodination of extrathyroidal T₄ by the enzyme thyroxine 5'-deiodinase

T₄ is converted to T₃ at rates determined by the state of the individual. The most physiological means of providing T₃, therefore, is to give thyroxine and to let the body needs regulate the rate of conversion of T₄ to T₃.

Molecular Basis of Thyroid Hormone Action

Brent has reviewed the molecular basis of thyroid function in detail. Inactive thyroxine (T₄) is the primary product of the thyroid gland and the dominant form of circulating thyroid hormone. It is converted to the active form triiodothyronine (T₃) by thyroxine 5'-deiodinase. The functions of thyroid hormone are primarily mediated through the action of T₃ receptors of the cell nucleus.

The receptors are hormone-responsive nuclear transcription factors determining which genes are stimulated or suppressed by T₃. Interaction of the T₃-receptor complex with DNA regulatory regions modifies gene expression. Transport of T₃ from outside the cell to the cell nucleus is a complex chain of events beyond the reach of current clinical laboratory testing.

The effects of T₃ include:

  • T₄ affects growth by increasing the rate of microsomal protein synthesis through a direct effect on translation that does not require synthesis of RNA
  • T₃ increases both ribosomal RNA and protein synthesis through an increase in RNA polymerase activity
  • Thyroxine selectively increases the activity of some enzymes 5–10 times — this helps to explain why adequate thyroid hormone is critical for the replication of many kinds of cells

Thyroid Hormones and Energy Metabolism

The chief product of oxidative phosphorylation is adenosine triphosphate (ATP), the primary source of energy for muscular contraction. The production of ATP by mitochondria is significantly increased when the concentration of T₃ increases. The hormone acts at the inner membrane of the mitochondrion, which is the site of oxidative phosphorylation.

A major mechanism by which T₃ causes increased energy expenditure is the increase of adenosine triphosphatase (ATPase) activity in cell membrane. ATP supplies the energy for muscle contraction and drives the sodium-potassium pump that maintains gradients of these ions across cell membranes. These gradients are essential to the excitability of muscle and nerve fibres and apparently have a "vent" system so that, although overactivity of the pump expends additional energy, it does not produce serious hyperpolarisation of the membrane.

Muscle Changes in Hypothyroidism

Muscle changes occur in hypothyroidism that may be reflected in the clinical signs of weakness and fatigue:

  • Myosin develops the characteristics of slow fibres
  • Certain mitochondrial enzymes show reduced activity
  • Studies using phosphorus-31 nuclear magnetic resonance spectroscopy showed that the ratio of phosphocreatine to inorganic phosphate (PCr/Pi) was low at rest in patients with hypothyroidism; PCr depletion during exercise was increased; and postexercise recovery of PCr/Pi was delayed — consistent with impaired oxidative phosphorylation in hypothyroid muscle
  • These changes may be the result of impaired mitochondrial function resulting in abnormal oxidative metabolism of chiefly type I fibres and impaired glycolytic metabolism affecting type 2 fast-twitch muscle fibres

Muscle relaxation is controlled by the balance between fast and slow forms of calcium ATPase in the sarcoplasmic membrane of skeletal muscle. The genes for transcription of these two forms of ATPase are controlled by T₃. Likewise, lipogenesis, lipolysis, and levels of total serum cholesterol and low-density lipoprotein cholesterol are controlled by T₃ receptor-regulated genes.

Thermogenesis and T₃

Thermogenesis is regulated in part by T₃ and adrenergic receptors on brown-fat-specific genes found in rodents and recently found in humans. Growth hormone synthesis in the pituitary gland is T₃-regulated, including nocturnal secretion of growth hormone and secretion of insulin-like growth factor 1 — both are decreased in patients with FMS.

Cold Intolerance — The Clinical Hallmark

Hypometabolism patients nearly always experience cold intolerance; occasionally they are intolerant of both heat and cold. They tend to wear additional clothing (a sweater, jacket, or pullover) when others do not, rarely sweat, and frequently complain of cold hands and, especially, cold feet. These patients are "weather conscious," and muscular pain increases with the onset of cold, rainy weather.

Cold intolerance directly overlaps with the symptom of coldness seen in iron deficiency (see Iron and TrPs) — the two conditions can coexist and compound each other. Both should be screened simultaneously.

Hypometabolism and Myofascial Pain =

Clinical Evidence

Gerwin identified hypothyroidism in 10% of a cohort of chronic myofascial pain patients, using clinical symptomatology and determinations of T₃, T₄, FT₄, TSH, or TRH stimulation test. A striking feature of these patients was the widespread distribution of myofascial TrPs.

In FMS patients, TrPs were found, and the semispinalis capitis was the next most likely muscle to have TrPs (6 patients). TrP palpation clearly reproduced the headache in 8 of 11 patients. TrPs were predominantly on the most symptomatic side.

The relationship of hypothyroidism to widespread muscle pain, whether fibromyalgia or myofascial pain, remains a controversial issue and is not widely accepted by endocrinologists. This may be true largely because, until very recently, the causes of those two pain diagnoses were not convincingly identified.

The TrP Response

As many FMS patients have persistent or recurrent TrPs, and as none of the studies excluded myofascial TrPs as a cause of tender points, FMS findings are likely to be relevant to chronic myofascial pain as well. Despite these reports, the relationship of hypothyroidism to widespread muscle pain, whether fibromyalgia or myofascial pain, remains controversial.

  • Patients referred to us with MPS often arrive untreated for their slightly low thyroid function because they have only mild symptoms of hypothyroidism and borderline low, or low normal, thyroid tests
  • Experience has shown that these patients are more susceptible to myofascial TrPs and they obtain only temporary pain relief with specific myofascial therapy
  • Their poor response to therapy is greatly improved by supplemental thyroid, if they have no other major perpetuating factor
  • In hyperthyroidism, active TrPs are uncommon, but respond well to therapy — Dr. Travell could not remember seeing a hyperthyroid patient with TrPs unresponsive to specific myofascial therapy

The Thiamine-Thyroid Interaction

Thyroid hormone therapy alone may not clear the TrPs in hypothyroid patients any more than these patients might recover spontaneously if they were euthyroid patients. However, one author (RDG) has repeatedly seen considerable reduction in TrPs and even full recovery from MPS within 4–6 weeks of achieving a TSH of 0.5–2.0 mIU/L in hypothyroid myofascial pain patients.

A critical interaction: before starting treatment with thyroid hormone it is important that the patient have an adequate vitamin B₁ level. Since thiamine increases metabolism and thiamine requirements are metabolism-dependent, thyroid therapy can convert a vitamin B₁ inadequacy to a severe vitamin B₁ deficiency. If there is any doubt, the patient should first be given a sufficient supplement of vitamin B₁ to establish a safe level (25–100 mg, three times daily, for at least 2 weeks before starting thyroid medication). Thiamine in a reduced dosage should be continued during thyroid therapy.

Smoking impairs the action of thyroid hormone and will accentuate the clinical features of hypothyroidism, including raising thyrotropin levels, total and LDL cholesterol levels, and CK levels, and prolonging the ankle reflex duration. Every effort should be made to help the patient stop smoking.

Forms of Hypothyroidism

Mild (Subclinical) Hypothyroidism

The issues relating to hypometabolism in patients with chronic myofascial pain more often concern mild hypothyroidism rather than overt, clinically advanced disease. Mild hypothyroid failure is often called subclinical hypothyroidism. Danese et al. defined this condition as an elevated serum TSH in the presence of a normal serum free T₄, and noted that it may or may not be symptomatic. The condition is more common in women than men, and increases in frequency with age. Some studies report the prevalence to be as high as 17% in women and 7% in men.

Identification and treatment of individuals with subclinical hypothyroidism can reverse subtle clinical symptoms of thyroid hormone deficiency, including multiple muscles with myofascial TrPs that may not be thought of as a manifestation of thyroid disease.

Hashimoto's Thyroiditis

Chronic autoimmune (Hashimoto's) thyroiditis is a common disorder, causing the majority of cases of hypothyroidism. Autopsy prevalence rates of significant thyroiditis are as high as 15% in women and 5% in men. When iodine deficiency is not an issue, 50% of individuals with serum TSH levels > 5 mIU/L and 80% of those with TSH levels > 10 mIU/L had thyroid antibodies characteristic of thyroiditis. The presence of antithyroid microsomal antibodies indicates autoimmune thyroiditis.

Causes of Hypothyroidism

Hypothyroidism can be produced by:

  • Inorganic iodine in excess of that normally provided in the diet
  • Organic iodine in pharmacological preparations such as the antiarrhythmic agent amiodarone, the asthma drug combination elixophyllin-KI, and intravenous contrast agents — especially true in patients with autoimmune thyroiditis or otherwise impaired damaged thyroid
  • Lithium inhibits the secretion of thyroid hormone; subclinical hypothyroidism (abnormalities of thyroid function tests) and clinically overt hypothyroidism each occur in 20% of patients taking lithium on a long-term basis
  • Anticonvulsant drugs (phenytoin and carbamazepine) displace thyroid hormone from its binding to serum proteins, resulting in lower serum T₄ and T₃ levels; however, this results in increased free hormone fractions, resulting in normal free T₃ and T₄ concentrations
  • Glucocorticoids in large doses decrease the activity of T₄ 5'-deiodinase, inhibiting the conversion of T₄ to T₃, resulting in significant decreases of serum T₃
  • Chronic opiate use (methadone, slow release morphine, oxycodone) increases serum TBG concentrations, raising the serum T₄ concentration but not necessarily increasing the active, free fraction of the hormone

Confusing Symptoms of Hypometabolism

Inadequate metabolism may cause additional symptoms that are suggestive of myxoedema or, in some patients, just the opposite:

  • The latter group of patients are thin, nervous, and hyperactive — confusingly, just as if they were hyperthyroid
  • Constipation is much more likely than diarrhoea
  • Disturbed menses may be evidenced by menorrhagia, amenorrhoea, or irregular menses
  • Patients are likely to suffer from dry, rough, sallow skin — they often mask this with an emollient skin cream
  • Some individuals have difficulty losing weight
  • Patients are intolerant to low-dose thyroid therapy repeatedly — this has been due to this dose aggravating symptoms of vitamin B₁ deficiency

Rosen has reported the occurrence of myoedema in response to TrP injections, which he attributes to histamine sensitivity. However, myoedema is a well-described phenomenon in hypothyroidism, and such patients should be evaluated for hypothyroidism.

Sonkin notes that diffuse muscle tenderness may be the major physical finding in mild hypothyroidism. Sonkin points out that 73% of the patients treated with thyroid supplementation had symptomatic improvement; responsiveness was correlated with the degree of change in the basal metabolic rate and in cholesterol levels.

Thyroid Function Measurement

The Testing Cascade

The measurement of thyroid function has undergone great changes in the past two or three decades. The basal metabolic rate test gave way to thyroxine-based testing that in turn has been replaced by the newer sensitive thyrotropin (sTSH) assays.

Klee and Hay recommend a scheme for evaluating thyroid function employing a second generation sTSH test that can measure to 0.1 mIU/L. If that is normal, no further testing need be done.

  1. Perform second generation sTSH test
  2. If sTSH is elevated: obtain FT₄ and microsomal antibody tests
  3. If sTSH is low (less than 0.3 mIU/L): obtain FT₄
  4. If FT₄ is normal: obtain FT₃
  5. If the second generation sTSH is below 0.1 mIU/l: perform a third generation sTSH test

This "thyroid cascade" can be performed on the initial sample of blood, providing a rapid turnaround time and minimising patient discomfort and inconvenience.

Key Tests and Their Interpretation

sTSH (sensitive thyrotropin):

  • The preferred initial test for stable ambulatory patients with normal pituitary function — the pituitary gland is a sensitive monitor of the body's requirement for thyroid hormone
  • Elevated sTSH indicates primary hypothyroidism or inadequate thyroid hormone replacement therapy
  • A very low sTSH level (less than 0.1 mIU/L) indicates hyperthyroidism, either exogenous or primary

Free thyroxine (FT₄):

  • Gives an indication of the severity of the thyroid dysfunction
  • FT₄ is elevated in hyperthyroidism and is low in hypothyroidism
  • Almost all T₄ and T₃ is bound to one of the three major transport proteins, primarily thyroxine-binding-globulin (TBG) — only the 0.1% free hormone concentration is active
  • Drugs that alter the binding of thyroxine to these proteins will alter total serum levels of T₄ and T₃, but do not affect the serum concentrations of free T₄ and T₃

Free triiodothyronine (FT₃):

  • Useful in the assessment of hyperthyroidism, and is appropriately assessed when sTSH is low and FT₄ is normal

sTSH determinations are not affected by renal or hepatic disease, or by oestrogen therapy.

Drug Effects on Thyroid Function Tests

  • Estrogen raises TBG concentrations — resulting in elevations of serum T₄ concentrations of 20–35% at usual doses of estradiol. TrPs are more common in women with a chronic deficiency of oestrogen, and oestrogen supplement decreases TrP activity
  • Salicylates in high doses (>2.0 g/day) inhibit the binding of T₃ and T₄ to TBG, but do not affect the serum free T₄ concentration
  • Androgens and glucocorticoid steroids decrease TBG concentrations, although free T₃ and T₄ concentrations remain unchanged
  • Lithium inhibits the secretion of thyroid hormone; subclinical and overt hypothyroidism each occur in 20% of patients taking lithium long-term
  • Amiodarone — especially true in patients with autoimmune thyroiditis

Thyroid Tests in Clinical Practice

Practical clinical indicators suggesting thyroid evaluation in MPS patients:

  • TSH should be obtained if it is clearly elevated, then treatment with levothyroxine (T₄) should be started
  • If the TSH is between 4.0 and 6.0 mIU/L, the sTSH and FT₄ should be evaluated
  • If these levels are borderline, the CK and serum cholesterol can help reach a determination of thyroid status
  • If either are elevated, thyroid supplementation can be started
  • Once supplementation is started, sTSH is used to monitor the result; the target range is being 0.5–2.5 mIU/L

Clinical tip-offs for hypothyroidism screening:

  • Symptoms of widespread chronic fatigue, coldness or cold intolerance, constipation, dry skin, dry hair, husky voice, or mild periorbital oedema
  • Slowed ankle reflex return
  • Multiple treatment-resistant TrPs

Treatment of Hypothyroidism

Levothyroxine (T₄)

Levothyroxine (T₄) is the treatment of choice for hypothyroidism. Adults require about 1.7 μg/kg of body weight for complete replacement of thyroid hormone. In younger individuals, treatment can be initiated at the full dose. In persons over the age of 50, the replacement dose needed may be less, and the starting dose should be 0.025–0.05 mg of levothyroxine daily.

In persons with peripheral resistance to thyroid hormone, the eventual dose of T₄ needed to normalise function can be quite high. The maintenance dose is monitored by measuring serum TSH, which should be in the lower normal range. Thyroxine has a half-life of about one week — therefore the steady state of serum T₄ is not reached for about 4 weeks after initiation of therapy. Tests of serum TSH levels to monitor the dose of thyroxine should be done no sooner than every 4–5 weeks.

T₄ is physiologically converted to T₃ at rates that are determined by the state of the individual. Over 80% of circulating T₃ is derived by deiodination of extrathyroidal T₄. The most physiological means of providing T₃, therefore, is to give thyroxine and to let the body needs regulate the rate of conversion of T₄ to T₃.

Several generic and brand name levothyroxine products have been compared and found to be bioequivalent — an important factor in a drug that is being used for long periods of time and in many persons.

The B₁ Prerequisite

Before starting treatment with thyroid hormone it is important that the patient have an adequate vitamin B₁ level.

Since thiamine increases metabolism and thiamine requirements are metabolism-dependent, thyroid therapy can convert a vitamin B₁ inadequacy to a severe vitamin B₁ deficiency. Suggested protocol:

  • Give vitamin B₁, 25–100 mg three times daily, for at least 2 weeks before starting thyroid medication
  • Continue thiamine in a reduced dosage during thyroid therapy
  • "Intolerance" to low-dose thyroid therapy that has repeatedly occurred should be recognised as a sign of thiamine deficiency being unmasked, not as true intolerance to the thyroid hormone

Smoking and Thyroid Therapy

Smoking impairs the action of thyroid hormone and will accentuate the clinical features of hypothyroidism, including raising thyrotropin levels, total and LDL cholesterol levels, and CK levels, and prolonging the ankle reflex duration. Every effort should be made to help the patient stop smoking and to prevent others from becoming addicted. See Smoking cessation — Wikipedia.

Thyroid Hormone and Pregnancy

Thyroid supplementation in hypothyroid patients must be increased during pregnancy, with the additional dose determined by the serum TSH level. TrPs are more common in women with a chronic deficiency of oestrogen.

The Biology of Starvation: Thyroid Function

The relationship between starvation and thyroid function illustrates how the body prioritises survival over metabolic efficiency in conditions of acute caloric deprivation:

The euthyroid sick syndrome (non-thyroidal illness syndrome): In any significant illness, injury, or starvation, serum T₃ falls while reverse T₃ (rT₃) rises — this is not hypothyroidism but an adaptive response that reduces basal metabolic rate to conserve energy. The conversion of T₄ to the active T₃ is reduced, and the conversion to the inactive rT₃ is increased.

In the context of chronic pain and myofascial pain specifically:

  • Chronic stress, pain, and inflammatory cytokines all suppress T₃ conversion — creating a functional hypometabolic state that perpetuates TrPs even when thyroid gland function is structurally normal
  • Severe caloric restriction (crash dieting, restrictive eating) reduces T₃ levels within days — the body responds to reduced caloric intake as if to starvation, reducing its basal metabolic rate
  • Refeeding after starvation must therefore be accompanied by normalisation of thyroid function monitoring, as thyroid requirements may shift rapidly

The chromatin remodelling cascade: T₃ receptors are nuclear transcription factors — meaning that thyroid hormones directly regulate gene expression across virtually every cell type. In starvation, the fall in T₃ reduces the transcription of genes encoding:

  • Mitochondrial ATP synthase subunits — reducing maximal ATP production capacity
  • SERCA (sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase) — impairing the calcium pump that relaxes muscle and normally prevents the sustained sarcomere shortening of TrPs
  • Fast myosin heavy chain isoforms — shifting muscle toward slow, energy-inefficient fibres

This means that in starvation, the muscle becomes structurally less capable of efficient contraction and complete relaxation — setting the stage for the sustained shortened sarcomeres and energy depletion that define TrP formation.

References

  • Travell JG, Simons DG. Myofascial Pain and Dysfunction: The Trigger Point Manual, Volume 1. 2nd ed. Baltimore: Williams & Wilkins; 1999. Chapter 4, Section D. With contributions by Robert D. Gerwin, MD.
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