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Hypothyroidism and fibromyalgia

from www.drlowe.com

Fibromyalgia & Thyroid Disease Dr. John C. Lowe Dr. Gina Honeyman-Lowe
Presented and discussed in Grenoble, France, May 6 (conference of the French Fibromyalgia Association of Région Rhône-Alpes) and in Toulon, France on May 11 (at the Centre Hospitalier Intercommunal), 2000.
Scheduled for publication in the French journal Myalgia.

The clinical features of fibromyalgia syndrome (FMS) and hypothyroidism are virtually the same (1,2,3,4,5,6,7,8,9,10). The most common symptoms of FMS are also common symptoms of hypothyroidism, and the objective abnormalities of FMS are also objective abnormalities of hypothyroidism. The symptoms and objective abnormalities of hypothyroidism are mediated by inadequate thyroid hormone regulation of cell function.
Inadequate thyroid hormone regulation also plausibly mediates the documented features of FMS (11).

Hypothyroidism in FMS

Primary Hypothyroidism.
The estimated incidence of hypothyroidism in FMS is higher than in the general public. The reported incidence of primary hypothyroidism in the general non-elderly USA population varies between 1% (12) and 5% (13). Laboratory thyroid function testing suggests that the incidence of primary hypothyroidism in FMS is 10% to 13% (14, 15, 16, 17, 18).

Anti-thyroid Antibodies

Aarflot and Bruusgaard measured thyroid microsomal antibodies in 737 men and 771 women who ranged in age from 40-to-42 (19). Subjects with chronic widespread musculoskeletal complaints had a significantly higher incidence of antibodies than did subjects without such complaints (16.0% versus 7.3%, p<0.01). The prevalence of antibodies was significantly higher in women than men (20.4% versus 11.6%, p = 0.02). It is noteworthy, however, that laboratory thyroid function test results did not differ significantly between the two groups. The investigators wrote that their results suggest that patients with microsomal thyroid antibodies may have symptoms due to subnormal thyroid hormone regulation of cell function before thyroid gland dysfunction is detectable by tests of thyroid hormone and TSH levels. The researchers implied that many patients diagnosed with FMS may in fact have chronic, widespread pain due to impaired thyroid gland function revealed only by increased titers of thyroid microsomal antibodies. If this is true, then the incidence of primary hypothyroidism among FMS patients may be higher than the 10% to 13% suggested by measures of TSH and thyroid hormone levels.

Central Hypothyroidism.

The incidence of central hypothyroidism, involving hypothalamic or pituitary dysfunction, in the USA population at large is about 0.00021% (12). My research group has found that of 92 sequential unselected FMS patients, 40 patients (43.5%) had laboratory test results consistent with central hypothyroidism (16, 18). Other researchers have also reported high incidences of test results consistent with central hypothyroidism (20,21).
Thus, the incidence of primary hypothyroidism among FMS patients may be 2 to 10 or more times higher than in the USA population at large. The incidence of possible central hypothyroidism, however, may be 250,000 times higher. If we trust in the reliability of thyroid function test results, we are compelled to reach a conclusion: If 10% of FMS patients have primary hypothyroidism, and 44% have central hypothyroidism, the total percentage of FMS patients with hypothyroidism is 54%.

Thyroid Hormone Resistance

Many researchers and clinicians consider the term "thyroid disease" to include only pathological processes that occur 1) within the thyroid gland itself, or 2) in other tissues, such as the pituitary gland, and indirectly result in subnormal function of the thyroid gland. However, this definition may be too narrow. In 1967, Refetoff et al. provided convincing evidence of partial cellular resistance to thyroid hormone in humans (22). Since then, a great volume of studies of human thyroid hormone resistance has accumulated. Also, mutations in the c-erbAß gene on chromosome 3 (which codes for the ß1 T3-receptor) have been shown to be the underlying mechanisms of general resistance to thyroid hormone (23). (The mechanisms of resistance in most afflicted patients remain unknown.) In some thyroidology textbooks, thyroid hormone resistance is grouped under "Special Topics in Thyroidology." However, it can be argued that thyroid hormone resistance should be classified as a subset of thyroid disease. As in central hypothyroidism, which is classed as a thyroid disease, thyroid gland function is indirectly altered in two classifications of thyroid hormone resistance. Also as in primary and central hypothyroidism, patients with symptoms and signs caused by thyroid hormone resistance can be effectively treated with thyroid hormone (albeit in higher than physiologic dosages, called "supraphysiologic" dosages). Thyroid Hormone Resistance and FMS. As far back as the late 1980s, I (JCL) was puzzled as to why euthyroid FMS patients (those with normal thyroid test results) had identically the same hypothyroid-like symptoms and signs as did hypothyroid FMS patients. In searching for an answer, I came into communication with thyroid hormone resistance researchers. One of these, Steve Usala, had established a link between the c-erbAß gene and thyroid hormone resistance (24). He was also first to discover a mutation in the gene (25). (More than 100 different mutations in the gene have now been discovered (11).) Based on communication with Usala and other thyroid hormone resistance researchers, in 1990, my colleagues and I treated 77 euthyroid female FMS patients with T3 (as part of more comprehensive metabolic treatment).
This treatment was based on our hypothesis that the patients had partial cellular resistance to thyroid hormone (26). Of the 77 patients, 19 (25%) did not feel that T3 had improved their status. They were withdrawn from the hormone. The remaining 58 patients (75%) reported that their symptoms were improved to varying degrees. For the group, the difference between pre- and post-treatment algometer scores (mean of the pressure/pain threshold of 18 tender points) was highly significant (p:< 0.0005). The mean pressure/pain threshold of the 18 tender point sites was significantly higher (improved) after T3 treatment. Effective dosages of T3 ranged from 75 µg. to 150 µg.
Most patients improved with dosages between 81.25 µg. and 100 µg. (Normal replacement dosages were reported to be from 25-to-75 µg.) Since that early open trial, my colleagues and I have continued to treat euthyroid FMS patients on the assumption that they have thyroid hormone resistance. We find that approximately 75% of euthyroid FMS patients markedly improve or completely recover when treated with what we term "metabolic rehabilitation." The treatment involves the use of T3, exercise to tolerance, wholesome diet, nutritional supplements, physical treatment, and cessation of the use of metabolism-impeding medications.
Most patients improve only with supraphysiologic dosages of T3. We are convinced that the patients who improve or recover with supraphysiologic dosages of T3 have cellular resistance to thyroid hormone. We conclude that a patient has thyroid hormone resistance when four criteria are met.
The patient:
(1) is euthyroid before beginning the use of T3, according to thyroid function test results, including a TRH stimulation test;
(2) markedly improves or completely recovers from hypothyroid-like FMS symptoms and signs with supraphysiologic dosages of T3;
(3) after beginning T3 therapy has an extremely high free T3 blood level;
(4) has no evidence of tissue thyrotoxicosis due to the high T3 level, according to the results of serial ECGs, serum and urine biochemical tests, and bone densitometry.
Most of our euthyroid patients who improve or recover with metabolic rehabilitation involving T3 therapy meet these four criteria. Clearly, this set of findings in many treated euthyroid FMS patients shows that they meet Refetoff's definition of thyroid hormone resistance: "reduced responsiveness of target tissues to concentrations of thyroid hormone that under normal conditions would be excessive" (23). According to the four criteria, we have documented the presence of thyroid hormone resistance in FMS patients in several double-blind, placebo-controlled, crossover studies (27, 28, 31). Also, in a case-control study, we found that the results of the treatment lasted long term (29). Throughout a 1-to-5 year follow-up period, 10 hypothyroid FMS patients maintained their improvement compared to untreated FMS matched control patients. Also, 10 euthyroid FMS patients treated with T3 maintained their improvement compared to control patients.

Criticisms

Eisinger (rheumatologist) and Fontaine and Rinaldi (thyroid specialists) have given several criticisms of the hypothesis we present here (30). We agree with most of the criticisms. For example, we know that a small amount of the available evidence contradicts the hypothesis. Despite this, the hypothesis is supported by far more of the available evidence than is any competing hypothesis of the etiology of FMS. Also, rigorous logical analyses show that the hypothesis is the most useful at this time for stimulating further fruitful exploration of FMS.
Eisinger, Fontaine, and Rinaldi also argued that the hypothesis applies only to a subgroup of FMS patients. We maintain that the subgroup is large - close to 90 percent. We agree with them, however, that patients should be treated with precaution. We also agree with an astute observation of theirs: that when the peripheral cellular effects of thyroid hormone can be normalized by agents such as selenium (which may increase the deiodination of T4), this therapy is preferable to the use of exogenous thyroid hormone. (The American FMS researcher Richard Garrison has made a similar argument.) We should rigorously study the treatment of FMS patients with agents such as thiol and selenium to learn whether some of them benefit more from these than from the use of T3. Even when patients do benefit from such agents, however, the benefits are mediated by an improvement in thyroid hormone regulation of cell function. This outcome further supports the hypothesis that in the involved patients, inadequate thyroid hormone regulation of cell function underlies their FMS.

Conclusions

If cellular resistance to thyroid hormone is accepted as a subset of thyroid disease not directly involving the thyroid gland, then our findings suggest that most FMS patients have thyroid disease. About 10% have laboratory test results consistent with primary hypothyroidism, and about 45% have results consistent with central hypothyroidism. This is a total of 55% of FMS patients who may have hypothyroidism.
Of the remaining 45% who have test results consistent with euthyroidism, 75% on average improve or recover when treated on the assumption that they have thyroid hormone resistance. This 75% is about 34% of our total sample of FMS patients. For a total percentage of FMS patients with possible thyroid disease, we can add this 34% of patients with thyroid hormone resistance (according to the four post-treatment criteria) to the 55% of hypothyroid patients (according to thyroid function test results). The result is 89% of FMS patients with possible thyroid disease. (See Table 1.) This estimate is consistent with previous findings such as glycolysis abnormalities and T3-induced improvement in FMS patients with the polymyalgia-hypothyroid intractability syndrome described by Eisinger (11,14). In fact, as I (JCL) recently argued (11), virtually every symptom and abnormal finding in FMS is plausibly explained by inadequate thyroid hormone regulation. This proposed mechanism is unique in this respect.
Table 1. Percentage of FMS patients with thyroid disease. Class of Thyroid Disease%
of Patients Primary hypothyroid10%
Central hypothyroid45%
Thyroid hormone resistant34%
Total % with thyroid disease89%
The remaining 11% of FMS patients also have symptoms and signs that resemble those of hypothyroidism. Our conjecture is that these patients’ symptoms and signs result from pathophysiological processes not related directly to thyroid hormone. However, we believe the pathophysiological processes in these patients impede metabolism in a set of tissues that generate symptoms and signs resembling those of hypothyroidism or thyroid hormone resistance.

References

1.Beetham, WP Jr. Diagnosis and management of fibrositis syndrome and psychogenic rheumatism. Med. Clin. North Am. 1979; 63:433-439.
2. Golding DN. Hypothyroidism presenting with musculoskeletal symptoms. Ann. Rheumatic. Dis. 1970; 29:10-41.
3. Bland JH, and Frymoyer JW. Rheumatic syndromes of myxedema. N. Eng. J. Med., 1970; 282:1171-1174.
4. Wilke SW, Sheeler LR, and Makarowski WS. Hypothyroidism with presenting symptoms of fibrositis. J. Rheumatol., 1981; 8:627-630.
5. Hochberg MC, Koppes GM, Edwards CQ, Barnes HV, and Arnett FC Jr. Hypothyroidism presenting as a polymyositis-like syndrome: report of two cases. Arthritis Rheum., 1976; 19:1363-1366.
6. Delamere JP, Scott DL, and Felix-Davies DD. Thyroid dysfunction and rheumatic diseases. J. Royal Soc. Med., 1982; 75:102.
7. Fessel W J. Myopathy of hypothyroidism. Ann. Rheumatic Dis., 1968; 27:590-596.
8. Wilson J, and Walton JN. Some muscular manifestations of hypothyroidism. J. Neurol. Neurosurg. Psychiat., 1959; 22:320-324.
9. Awad EA. Histopathological changes in fibrositis. In Advances in Pain Research and Therapy, vol. 17. Edited by J.R. Fricton and E.A. Awad, New York, Raven Press, 1990, pp.249-258.
10. Sonkin LS. Endocrine disorders and muscle dysfunction. In Clinical Management of Head, Neck, and TMJ Pain and Dysfunction. Edited by B. Gelb, Philadelphia, W.B. Saunders Co., 1985, pp.137170.
11. Lowe JC. The Metabolic Treatment of Fibromyalgia. Boulder, McDowell Publishing Co., 2000.
12. Hershman JM. Hypothalamic and pituitary hypothyroidism. In Progress in the Diagnosis and Treatment of Hypothyroid Conditions. Edited by P.A. Bastenie, M. Bonnyns, and L.VanHaelst, Amsterdam, Excerpta Medica, 1980, pp.40-50.
13. Tunbridge WMG, Evered DC, and Hall R. The spectrum of thyroid disease in a community survey. Clin. Endocrinol., 1977; 7:481-493.
14. Eisinger J. Hypothyroïdie et fibromyalgie: indications d’une double hormonothérapie thyroïdienne. Lyon Med. Med., 1999, 35 : 31-36.
15. Gerwin R. A study of 96 subjects examined both for fibromyalgia and myofascial pain. J. Musculoskel. Pain, 1995; 3:(Suppl.)1:121.
16. Lowe JC. Thyroid status of 38 fibromyalgia patients: implications for the etiology of fibromyalgia. Clin. Bull. Myofascial Ther., 1997; 2(1):36-41.
17. Shiroky JB, Cohen M, Ballachey M-L, and Neville C. Thyroid dysfunction in rheumatoid arthritis: a controlled prospective survey. Ann .Rheumat. Dis., 1993; 52:454-456.
18. Lowe JC, Reichman AJ, Honeyman GS, and Yellin J. Thyroid status of fibromyalgia patients (Abst.). Clin. Bull. Myofascial Ther., 1998; 3(1): 69-70.
19. Neeck G, and Riedel W. Thyroid function in patients with fibromyalgia syndrome. J. Rheumatol., 1992; 19:1120-1122.
20. Ferraccioli G, Cavalieri F, Salaffi F, et al. Neuroendocrinologic findings in primary fibromyalgia (soft tissue chronic pain syndrome) and in other chronic rheumatic conditions (rheumatoid arthritis, low back pain). J. Rheumatol., 1990; 17:869-873.
21. Aarflot T, and Bruusgaard D. Association between chronic widespread musculoskeletal complaints and thyroid autoimmunity: results from a community survey. Scand. J. Prim. Health Care, 1996; 14(2):111-115.
22. Refetoff S, Dewind LT, and DeGroot LJ. Familial syndrome combining deaf-mutism, stippled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J. Clin. Endocrinol. Metab., 1967; 27:279.
23. Refetoff S. Resistance to thyroid hormone: an historical overview. Thyroid, 1994; 4(3):345-349.
24. Usala SJ, Bale AE, Gesundheit N, et al. Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbAß gene. Mol. Endocrinol., 1988; 2:1217-1220.
25. Usala SJ, Tennyson GE, Bale AE, et al. A base mutation of the c-erbAß thyroid hormone receptor in a kindred with generalized thyroid hormone resistance: molecular heterogeneity in two other kindreds. J. Clin. Invest., 1990; 85:93-100.
26. Lowe JC. Results of an open trial of T3 therapy with 77 euthyroid female fibromyalgia patients. Clin. Bull. Myofascial Ther., 1997; 2 (1):35-37.
27. Lowe JC, Reichman A, Yellin J. The process of change with T3 therapy for euthyroid fibromyalgia: a double-blind placebo-controlled crossover study. Clin. Bull. Myofascial Ther., 1997; 2(2/3):91-124.
28. Lowe, J.C., Garrison, R.L., Reichman, A.J., and Yellin, J.: Triiodothyronine (T3) treatment of euthyroid fibromyalgia: a small-N replication of a double-blind placebo-controlled crossover study. Clin. Bull. Myofascial Ther., 2(4): 71-88, 1997.
29. Lowe JC, Reichman A, and Yellin J. A case-control study of metabolic therapy for fibromyalgia: long-term follow-up comparison of treated and untreated patients (abstract). Clin. Bull. Myofascial Ther., 1998; 3(1):23-24.
30. Eisinger, J, Fontaine, G, and Rinaldi JP (Toulon). Commentaires sur "Thyroid Disease and Fibromyalgia Syndrome" (J. Lowe and G. Honeyman-Lowe), April 20, 2000.
31. Lowe, J.C., Garrison, R., Reichman, A., Yellin, J., Thompson, M., and Kaufman, D.: Effectiveness and safety of T3 therapy for euthyroid fibromyalgia: a double-blind, placebo-controlled response-driven crossover study, Clin. Bull. Myofascial Ther., 2(2/3):31-57, 1997.
Acknowledgements: We would like to thank Prof. J.B. Eisinger, G. Fontaine, M.D., Richard L. Garrison, M.D., Don Michael, M.D., J.P. Rinaldi, M.D., and Devin Starlanyl, M.D. for reading and commenting on an early draft of this paper.
For a single copy of this article in booklet form, please send $1.00 and a self-addressed stamped envelop to Dr. John C. Lowe, P.O. Box 396, Tulsa, OK 74101. Please e-mail regarding bulk orders of the booklet. © J.C. Lowe ∓mp; G. Honeyman-Lowe 2000