This website is dedicated to the millions of thyroid patients who are being ignored and left to suffer unnecessarily, and to healthcare practitioners, who want to better serve those patients.

Studies/Research: Doubts on the Usefulness of SerumTSH and Free T4 testing – which are being ignored.

‘On the Clinical Diagnosis and Treatment of Hypothyroidism’  Current professional guidelines for the diagnosis and treatment of hypothyroidism abandon clinical medicine for a laboratory exercise

‘More studies from The International Hormone Society’

‘Royal College of Physicians – The Great Thyroid Scandal’

Serum Thyroid Function Tests MUST NOT and CANNOT be relied on

____________________________________________

DISCUSSIONS ON THYROID DIAGNOSIS SERUM TSH: IS THE TSH SERUM MEASUREMENT ALONE SUFFICIENT FOR DIAGNOSIS AND FOLLOW-UP OF THYROID DEFICIENCY?

Claim: TSH is the first line test to do. It is sufficient to diagnose all forms of eu-, hypo- and hyperthyroidism. No other test is necessary for the diagnosis.

Facts: TSH is often insufficient on its own to diagnose between eu-, hypo- and hyperthyroidism, particularly to diagnose milder, borderline states of hypothyroidism. Other tests are necessary, as is a complete clinical evaluation (medical history, actual complaints, physical examination) of the patient.

Doubts on the usefulness of the serum TSH test alone for diagnosis

Overreliance on laboratory tests without clinical evaluation may lead to considerable diagnostic errors

  1. Nicoloff JT, Spencer CA. The use and misuse of the sensitive thyrotropin assay. J Clin Endocrinol Metab. 1990;71:553-8.
  2. De Los Santos ET, Mazzaferri EL. Sensitive thyroid-stimulating hormone assays: Clinical applications and limitations. Compr Ther. 1988; 14(9): 26-33.
  3. Becker DV, Bigos ST, Gaitan E, Morris JCrd, rallison ML, Spencer CA, Sugarawa M, Van Middlesworth L, Wartofsky L. Optimal use of blood tests for assessment of thyroid function. JAMA 1993 Jun 2; 269: 273 (“the decision to initiate therapy shoul be based on both clinical and laboratory findings and not solely on the results of a single laboratory test”)
  4. Rippere V. Biochemical victims: False negative diagnosis through overreliance on laboratory results—a personal report. Med Hypotheses. 1983; 10(2): 113.

Discussions and controversy in medical associations and journals on the TSH reference range

  1. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228–38 (conclusions of a consensus panel of the Endocrine Society, the American Thyroid Association,and American Association of Clinical Endocrinology. Although the panel concluded that there was good data that patients with slight elevations of TSH above 4.5 may progress to overt hypothyroidism, and that levothyroxine therapy would prevent symptoms, they did not agree that early treatment provided any benefit!)
  2. Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin level: normal ranges and reference intervals are not equivalent. Thyroid. 2005 Sep;15(9):1035-9
  3. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8 (remarkable article of which a lot of the following information is extracted)
  4. Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab. 2005;90:581–5
  5. Surks MI. Commentary: subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab. 2005;90:586–7
  6. Ringel MD, Mazzaferri EL. Editorial: subclinical thyroid dysfunction: can there be a consensus about the consensus? J Clin Endocrinol Metab. 2005;90:588–90
  7. Pinchera A. Subclinical thyroid disease: to treat or not to treat? Thyroid. 2005;15:1–2

Studies that show that the serum TSH reference range of 0.1-5.1 mU/liter for a POPULATION is too large

Studies indicating a population mean value of 1.5 mU/liter for an iodine-sufficient population

  1. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995;43:55–68
  2. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002; 87:489–99
  3. Andersen S, Petersen KM, Brunn NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87:1068–72
  4. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138–40
  5. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003 Jan;13(1):3-126

A longitudinal study in diabetics where a baseline TSH levels above the 1.53 mU/liter predicted subsequent thyroid dysfunction, whereas no thyroid dysfunction if TSH levels < 1.53 mU/liter, the reference range for diabetics should then be 0.4-1.52 mU/liter

  1. Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853–7

If the serum TSH reference range would be based upon a cohort of truly normal individuals with no personal or family history of thyroid dysfunction, no visible or palpable goiter, not taking any medication, who are seronegative for thyroid preoxidase antibodies, and whose blood samples are drawn fasting in the morning hours (06–10 h), the TSH reference range would become 0.4–2.5 mU/L (Demers & co, Baloch & co.)

  1. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138–40
  2. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002; 87:489–99
  3. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

When data for subjects with positive TPOAb or a family history of autoimmune thyroid disease are excluded, the normal reference interval becomes much tighter, i.e. 0.4–2.0 mU/liter. This tighter reference range may certainly be more applicable to African-Americans, who have a lower mean TSH

  1. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002; 87:489–99
  2. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138–40

Publications with data to support a more narrow reference range for serum TSH that would be obtained when persons with diffuse hypoechogenicity of the thyroid on ultrasound, a condition that precedes thyroid peroxidase antibody positivity in autoimmune thyroid disease, would be excluded

  1. Pedersen OM, Aardal NP, Larssen TB, Varhaug JE, Myking O, Vik-Mo H. The value of ultrasonography in predicting autoimmune thyroid disease. Thyroid. 2000;10:251–9

For the American Association of Clinical Endocrinologists the revised reference TSH range is 0.3–3.0 mU/L

  1. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8:457–69

Ethnic differences: the mean TSH level in African-Americans is 1.18 mU/liter, in contrast to a mean of 1.40 mU/liter in Caucasians, due to the greater frequency of autoimmune thyroid disease in whites (12.3%) than in blacks (4.3%), which may have unjustifiedly skewed the upper end of the TSH curve (NHANES data). ForAfrican-Americans, the TSH reference range should therefore be lower than in whites

  1. Hollowell JG, Staehling NW, Flanders WD, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489–9

A study, which suggests that the serum TSH cut-off point between hypo- and euthyroidism is 2, not 4 or 5.5

  1. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adampoulos P, Koutras DA. High serum cholesterol levels in persons with ‘high-normal’ TSH levels: Should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998 Feb;138(2):141-5(Treating TPO antibody-positive hypercholesterolemic patients with TSH levels between 2-4 mU/L with low dose levothyroxine normalizes TSH levels and improves the lipid profile)

In 2003, the National Academy of Clinical Biochemistry (NACB) has reduced the upper limit of the reference range from 5.5 to 4.1 mU/L, but stating also that “greater than 95% of healthy, euthyroid subjects have a serum TSH concentration between 0.4 – 2.5 mU/L”. “.. patients with a serum TSH >2.5 mU/L, when confirmed by repeat TSH measurement made after 3 to 4 weeks, may be in the early stages of thyroid failure, especially if thyroid peroxidise antibodies are detected”

  1. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

Supporters of the recommendations of the consensus panel (Endocrine Society, American Association of Clinical Endocrinologists, American Thyroid Association) promote a target TSH range of 1.0–1.5 mU/liter in patients already receiving T4 therapy

  1. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

The lower end of the normal or reference range for TSH lies between 0.2 and 0.4 mU/liter, as indicated by a number of clinical studies

  1. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126
  2. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991;34:77-83
  3. Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853–7
  4. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
  5. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM. Low serum thyrotropin (thyroid stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med. 1991;151:165–8
  6. Hershman JM, Pekary AE, Berg L, Solomon DH, Sawin CT Serum thyrotropin and thyroid hormone levels in elderly and middle-aged euthyroid persons. J Am Geriatr Soc. 1993;41:823–8
  7. Parle JV, Maisonneuve P, Sheppare MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358:861–5

The TSH reference range for an INDIVIDUAL is narrower than the reference range for a population

The value of a population-based reference range is limited when the individual patient-based reference range (i.e. his personal reference range) is narrow

  1. Fraser CG, Harris EK. Generation and application of data on biological variation in clinical chemistry. Crit Rev Clin Lab Sci. 1989;27:409–37
  2. Harris EK. Effects of intra- and interindividual variation on the appropriate use of normal ranges. Clin Chem. 1974;20:1535–42

The individual TSH reference ranges are remarkably narrow within a relatively small segment of the population reference range, i.e. confined to only 25% of a range of 0.3–5.0 mU/liter. A shift in the TSH value of the individual outside of his or her individual reference range, but still within the population reference range, would not be normal for that individual. For example, an individual (as in Anderson’s series) with a personal range of 0.5–1.0 mU/liter would be at subphysiological thyroid hormone levels at the population mean TSH of 1.5 mU/liter (as explained by Wartofsky 2005)

  1. Andersen S, Petersen KM, Brunn NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87:1068–72

Studies of twins have data to support that each of us has a genetically determined optimal free T4 (FT4)-TSH set point or relationship

  1. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003;58:138–40
  2. Meikle AW, Stringham JD, Woodward MG, Nelson JC. Hereditary and environmental influences on the variation of thyroid hormones in normal male twins. J Clin Endocrinol Metab. 1988 ; 66:588–92

A measured TSH difference of 0.75 mU/liter can already be significant in a patient. The NACB guideline 8 states that “the magnitude of difference in …TSH values that would be clinically significant when monitoring a patient’s response to therapy… is 0.75 mU/liter.” Greater TSH fluctuations in a specific patient may mean that s/he becomes hypothyroid or hyperthyroid.

  1. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

A serum TSH that rises in a given individual from a set point of 1.0 to 3.5 is likely to be abnormally elevated and imply early thyroid failure. A minor change in serum free T4 results in an amplified change in TSH to outside of the usual population-based reference range, although the free T4 is still within its own population-based reference range, because of the the log-linear relationship between TSH and free T4. In the case of subclinical hypothyroidism, for example, a slight drop in free T4 results in an amplified and inverse response in TSH secretion (as explained by Wartofsky 2005)

  1. Cooper DS. Subclinical hypothyroidism. N Engl J Med. 2001;345:260–5
  2. Ayala A, Wartofsky L. Minimally symptomatic (subclinical) hypothyroidism. Endocrinologist. 1997;7:44–50

There is a 3-fold difference between the average daily maximal TSH (3) and minimal TSH (1 mIU/ml)

  1. Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B,
  2. Feistner H, Hesch RD, von zur Muhlen A. Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab. 1990 Feb;70(2):403-9

Conclusion: TSH reference range is too large => need for narrower ranges

  1. Pain RW. Simple modifications of three routine in vitro tests of thyroid function. Clin Chem. 1976; 22(10): 1715-8.
  2. Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin level: normal ranges and reference intervals are not equivalent. Thyroid. 2005 Sep;15(9):1035-9
  3. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8

Other arguments that may explain why the TSH test alone is not the only test

The TSH test is insufficient to diagnose all forms of hypothyroidism, including the borderline forms. The frequency of abnormal TSH values

  1. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
  2. Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853–7

The pituitary 5’-deiodinase type 2 that converts thyroxine into triiodothyronine (T3), is different than the liver and kidney 5’-deiodinase type 1 that provides the T3 for the rest of the body. This difference may explain why TSH secretion and thus serum TSH secreted by the pituitary gland may be normal, while the rest of the body may be in a thyroid deficient state.

  1. Koenig RJ, Leonard JL, Senator D, Rappaport N, Watson A, Larsen PR. Regulation of thyroxine 5′-deiodinase activity by 3,5,3′-triiodothyronine in cultured anterior pituitary cells. Endocrinology. 1984 Jul;115(1):324-9.

In fasting, hypothyroidism or selenium deficiency for example, the 5‘-deiodinase of the pituitary gland increases or remains unchanged, while that of the liver decreases.

  1. Suda AK, Pittman CS, Shimizu T, Cambers JB. The production and metabolism of 3,5,3′-triiodothyronine and 3,3′,5′-triiodothyronine in normal and fasting subjects. J Clin Endocrinol Metab. 1978 Dec;47(6):1311-9
  2. Larsen PR, Silva JE, Kaplan MM. Relationships between circulating and intracellular thyroid hormones: Physiological and clinical implications. Endocr Rev. 1981 Winter;2(1):87-102.
  3. Chanoine JP, Safran M, Farwell AP, Tranter P, Ekenbarger DM, Dubord S, Arthur JR, Beckett GJ, Braverman LE Dubord S, Alex S, Arthur JR, Beckett GJ, Braverman LE, Leonard JLl. Selenium deficiency and type II 5′-deiodinase regulation in the euthyroid and hypothyroid rat: evidence of a direct effect of thyroxine. Endocrinology. 1992 Jul;131(1):479-84

A normal or low serum TSH may reflect in elderly persons hypothyroidism in peripheral tissues, and not anymore eu- or hyperthyroidism, because the pituitary gland has aged. Progressively with increasing age, the serum TSH test becomes less reliable as a diagnostic test.

  1. Urban RJ. Neuroendocrinology of aging in the male and female. Endocrinol Metab Clin North Am. 1992;21(4): 921-31.

Necessity for other tests than the TSH to diagnosis thyroid dysfunction, e.g. the serum free T4

  1. Ladenson PW. Diagnosis of hypothyroidism. In Werner and Ingbar’s The Thyroid, 7th edition, Braverman LE and Utiger RE, Lippincott-Raven Publishers, Philadelphia. 1996; 878-82
  2. Pacchiarotti A, Martino E, Bartalena L, Aghini Lombardi F, Grasso L, Buratti L, Falcone M, Pinchera A. Serum free thyroid hormones in subclinical hypothyroidism. J Endocrinol Invest. 1986 Aug;9(4):315-9
  3. Surks MI, Chopra IJ, Mariosh CN, Nicoloff JT, Salomon DH. American Thyroid Association guidelines for use of laboratory tests in thyroid disorders. JAMA. 1990 Mar 16;263(11):1529-32
  4. Davis JR, Black EG, Sheppard MC. Evaluation of a sensitive chemiluminescent assay for TSH in the follow-up of treated thyrotoxicosis. Clin Endocrinol Oxf. 1987; 27(5): 563-70

Necessity for other tests than the TSH to diagnosis thyroid dysfunction, e.g. the serum free T4

  1. Escobar del Rey F, Ruiz de Ona C, Bernal J, Obregon MJ, Morreale de Escobar G. Generalized deficiency of 3, 5, 3′-triiodothyronine in tissues from rats on a low iodine intake, despite normal circulating T3 levels. Acta Endocrinol (Copenh) 1989; 120: 490-8

Need to analyse valuable indicators of peripheral activity such as the serum levels of plasma binding proteins SHBG, TBG, CBG, or of thyroid-dependent enzymes such as alkaline phosphatase, osteocalcin

  1. Smallridge RC. Metabolic, physiologic, and clinical indexes of thyroid function. In Werner and Ingbar’s The Thyroid, 7th edition, Braverman LE and Utiger RP, Lippincott-Raven Publishers, Philadelphia, 1996
  2. Foldes J, Tarjan G, Banos C, Nemeth J, Varga F, Buki B. Biologic markers in blood reflecting thyroid hormone effect at peripheral tissue level in patients receiving levothyroxine replacement for hypothyroidism. Exp Clin Endocrinol. 1992; 99(3): 129-3

Conditions or factors that DEPRESS the serum TSH

Aging

  1. Urban RJ. Neuroendocrinology of aging in the male and female. Endocrinol Metab Clin North Am. 1992;21(4): 921-31
  2. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM. Low serum thyrotropin (thyroid-stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med. 1991; 151(1): 165-8

Fasting

  1. Croxson MS, Hall TD, Kletzky OA, Jaramillo JE, Nicoloff OA. Decreased serum thyrotropin induced by fasting. J Clin Endocrinol Metab. 1977; 45: 560
  2. Borst GC, Osburne RC, O’Brian JT, Georges LP, Burman KD. Fasting decreases thyrotropin responsiveness to thyrotropin-releasing hormone: A potential cause of misinterpretation of thyroid function tests in the critically ill. J Clin Endocrinol Metab. 1983 Aug;57(2):380-3
  3. Campbell GA, Kurcz M, Marshall S, Meites J. Effects of starvation in rats on serum levels of follicle stimulating hormone, luteinizing hormone, thyrotropin, growth hormone and prolactin; response to LH-releasing hormone and thyrotropin-releasing hormone. Endocrinology. 1977; 100(2): 580-7
  4. Opstad PK. The thyroid function in young men during prolonged physical stress and the effect of energy and sleep deprivation. Clin Endocrinol. 1984; 20: 657-69.

Strenuous physical exercise

  1. Scanlon MF, Toft AD. Regulation of thyrotropin secretion. In Werner and Ingbar’s The Thyroid, 7th edition

Pregnancy (first trimester)

  1. Braverman LE and Utiger RE, Lippincott-Raven Publisers, Philadelphia. 1996; 220-40.

Depression and anxiety disorders

  1. Bartalena L, Placidi GF, Martino E, Falcone M, Pellegrini L, Dell’Osso L, Pacchiarotti A, Pinchera A. Nocturnal serum thyrotropin (TSH) surge and the TSH response to TSH-releasing hormone: dissociated behavior in untreated depressives. Clin Endocrinol Metab. 1990 Sep;71(3):650-5.
  2. Rupprecht R, Rupprecht C, Rupprecht M, Noder M, Mahlstedt J. Triiodothyronine, thyroxine, and TSH response to dexamethasone in depressed patients and normal controls. Biol Psychiatry. 1989;25(1): 22-32.
  3. Maeda K, Yoshimoto Y, Yamadori A. Blunted TSH and unaltered PRL responses to TRH following repeated administration of TRH in neurological patients: A replication of neuroendocrine features of major depression. Biol Psychiatry. 1993; 33(4): 277-83.
  4. Duval F, Macher JP, Mokrani MC. Difference between evening and morning thyrotropin responses to protirelin in major depressive episode. Arch Gen Psychiatry. 1990; 47(5): 443-8.
  5. Loosen PT, Prange AJ Jr. erum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: A review. Am J Psychiatry 1982; 139(4): 405-16.

Non-thyroidal diseases: diabetes mellitus, Cushing’s syndrome, renal failure, cancer, myocardial infarction, AIDS, post-traumatic syndromes, chronic alcoholic liver disease, other illnesses

  1. Devos P. Rationele keuze van schildklierfunctie tests. Tijdschr Geneesk. 1990; 46(8): 591-9
  2. Alexander CM, Kaptein EM, Lum SMC, Spencer CA, Kumar K, Nicoloff JT. Pattern of recovery of thyroid hormone indices associated with treatment of diabetes mellitus. J Clin Endocrinol Metab. 1982; 54: 362-366
  3. Andrade SF, Kanitz-Ml, Povoa H Jr. Study of thyrotropic reserve in diabetics of adult type. Acta-Biol Mod Ger 1977; 36(10): 1479-81
  4. Gonzalez C, Montoya-E, Jolin T. Effect of streptozotocin diabetes on the hypothalamic pituitary thyroid axis in the rat. Endocrinology 1980; 107(6): 2099-103
  5. Rossi GL, Bestetti GE, Tontis DK, Varini M. Reverse hemolytic plaque assay study of luteinizing and follicle-stimulating hormone and thyrotropin secretion in diabetic rat pituitary glands. Diabetes 1989; 38(10): 1301-6
  6. Adriaanse R, Brabant G, Endert E, Wiersinga W. Pulsatile thyrotropin secretion in patients with Cushing’s syndrome. Metabolism. 1994 Jun;43(6):782-6
  7. Beyer HK-, Schuster P, Pressler H. Studies on hypothalamic pituitary thyroid regulation in hemodialysis patients. Nuklearmedizin 1981;20(1):19-24
  8. Kokei S, Inoue T, lino S. Serum free thyroid hormones and response of TSH to TRH in nonthyroidal illnesses. Nippon Naibunpi Gakkai Zasshi. 1986; 62(11): 1231-43
  9. De Marinis L, Mancini A, Masala R, Torlontano M, Sandric S, Barbarino A. Evaluation of pituitary-thyroid axis response to acute myocardial infarct. J Endocrinol Invest. 1985; 8(6): 519-22
  10. Rondanelli M, Solerte SG, Fioravanti M, Scevola K, et al. Circadian secretory pattern of growth hormone, insulin-like growth factor type I, cortisol, adrenocorticotropic hormone, thyroid-stimulating hormone, and prolactin during HIV infection. AIDS Res Hum Retroviruses. 1997; 13(14): 1243-9.
  11. Wintemitz WW, Dzur JA. Pituitary failure secondary to head trauma. Case report. J Neurosurg. 1976; 44(4): 504-5
  12. Dzur JA, Wintemitz WW. Posttraumatic hypopituitarism: Anterior pituitary insufficiency secondary to head trauma. South Med J. 1976; 69(10): 1377-9
  13. Modigliani E, Periac P, Perret G, Hugues JN, Coste T. TRH response in 53 patients with chronic alcoholism. Ann Med Interne Paris. 1979; 130(5):297-302
  14. Ekman AC, Vakkuri 0, Ekman M, Leppalusto J, Ruckonen A, Knip M. Ethanol decreases nocturnal plasma levels of thyrotropin and growth hormone but not those of thyroid hormones or protection in man. J Clin Endocrinol Metab. 1996; 81(7):2627-32
  15. Bacci V, Schussler GC, Kaplan TB. The relationschip between serum triidothyronine and thyrotropin during systemic illness. J Clin Endocrinol Metab. 1982; 54:1229-35
  16. Hamblin PS, Dyer SA, Mohr VS, Le Grand BA, Lim CF, Tuxen DV, Topliss DJ, Stockigt JR. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness. J Clin Endocrinol Metab. 1986 Apr;62(4):717-22
  17. Bermudez F, Sucks MI, Opperheimer JH. High incidence of decreased serum triiodothyronine concentration in patients with nonthyroidal disease. J Clin Endocrinol Metab. 1975; 41: 27-40.

Medications: thyroid therapy, estroprogestative birth control pills, progestogens, anti-infammatory agents (incl. glucocorticoids and aspirin), antidepressants, L-Dopa, bromocriptine, neuroleptica, anti-hypertensives, antiarrhythmics (amiodarone), hypolipemic agents, IGF-1, somatostatin, etc.

  1. Franklyn JA, Black EG, Betteridge J, Sheppard MC. Comparison of second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy, and those with nonthyroidal illness. J Clin Endocrinol Metab. 1994;78(6):1368-71
  2. Gow SM, Caldwell G, Toft AD, Seth J, Hussey AJ, Sweeting VM, Beckett GJ. Relationship between pituitary and other target organ responsiveness in hypothyroid patients receiving thyroxine replacement. J Clin Endocrinol Metab. 1987;64(2):364-70
  3. Custro N, Scafidi V Costanzo G, Corsello FP. Variations in the serum levels of thyroid hormones and TSH after intake of a dose of L-thyroxine in euthyroid subjects and in adequately treated hypothyroid patients. Bull Soc Ital Biol Sper. l989; 65(11):1045-52
  4. England ML, Hershman JM. Serum TSH concentration as an aid to monitoring compliance with thyroid hormone therapy in hypothyroidism. Am J Med Sci. 1986 Nov;292(5):264-6
  5. Chopra U, Carlson HE, Solomon DH. Comparison of inhibitory effects of 3,5,3′-triiodothyronine (T3), thyroxine (T4), 3,3,’,5′-triiodothyronine (rT3,), and 3,3′-diiodothyronine (T2) on thyrotropin-releasing hormone-induced release of thyrotropin in the rat in vitro. Endocrinology. 1978; 103(2): 393-402
  6. Fraser WD, Biggart EM, O’Reilly DS, Gray HW, McKillop JH, Thomson JA. Are biochemical tests of thyroid function of any value in monitoring patients receiving thyroxine replacement? Br Med J (Clin Res Ed). 1986 Sep 27;293(6550): 293-808
  7. Cooper DS, Walker H, Rodbard D, Maloof F. Peripheral responses to thyroid hormone before and after L-thyroxine therapy in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1981 Dec;53(6):1238-42
  8. Saberi M, Utiger RD. Serum thyroid hormone and thyrotropin concentrations during thyroxine and triiodothyronine therapy. J Clin Endocrinol Metabol. 1974;39:923-7
  9. Rey Stocker I, Zufferey MM, Lemarchand MT, Rais M. The sensibility of the hypophysis, the gonads and the thyroid before and after the administration of oral contraceptives. A resume. Pediatr Ann. 1981;10(12):15-20.
  10. Lemarchand-Beraud T. Influence of estrogens on pituitary responsiveness to LHRH and TRH in human. Reymond M, Berthier C. Ann Endocrinol Paris. 1977; 38(6): 379-82.
  11. El-Etreby MF, Graf KJ, Gunzel P, Neumann F. Evaluation of effects of sexual steroids on the hypothalamic-pituitary system of animals and man. Arch Toxicol Suppl. 1979;2:11-39
  12. Prank K, Ranft U, Bergmann P, Schuermeyer T, Hesch RD, von Zur Muhlen A. Circadian and pulsatile TSH secretion under physiological and pathological conditions. Horm Metab Res Suppl. 1990; 23:12-7
  13. Re RN, Kourides IA, Ridgeway EC, Weintraub BD, Maloof F. The effect of glucocorticoid administation on human pituitary secretion of thyrotropin and prolactin. J Clin Endocrinol Metab. 1976; 43:338-46.
  14. Atterwill CK, Catto LC, Heal DJ, Holland CW, Dickens TA, Jones CA. The effects of desipramine (DMI) and electroconvulsive shock (ECS) on the function of the hypothalamo-pituitary-thyroid axis in the rat. Psychoneuroendocrinology. 1989;14(5):339-46
  15. Kaptein EM, Kletzsky OA, Spencer CA, NicoloffJT. Effects of prolonged dopamine infusion on anterior pituitary function in normal males. J Clin Endocrinol Metab 1980; 51:488-91
  16. Samuels MH, Kramer P, Wilson D, Sexton F. Effect ofnaloxone infusions on pulsatile thyrotropin secretion. J Clin Endocrinol Metab. 1994;78(5):129-32.
  17. Burger A, Nicod DP, Lemarchaud-Beraud T, Vallotton MB. Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxine and thyrotropin. J Clin Invest 1976; 58: 255-9
  18. Davis PJ, Davis FB, Utiger RD, Kulaga SF Jr. Changes in serum thyrotropin (TSH) in man during halofenate administration. J Clin Endocrinol Metab 1976; 43(4): 873-81
  19. Trainer PI, Holly 1, Medbak S, Rais LH, Besser GM. The effect of recombinant IGF-1 on anterior pituitary function in healthy volunteers. Clin Endocrinol (Chef) 1994; 41(6): 801-7.

Toxic foods: MSG, alcohol

  1. Bakke JL, Lawrence N, Bennett J, Robinson S, Bowers CY. Late endocrine effects of administering monosodium glutamate to neonatal rats. Neuroendocrinology 1978; 26(4): 220-8.
  2. Greeley GH Jr, Nicholson GF, Kizer JS. A delayed LH/FSH rise after gonadectomy and a delayed serum TSH rise after thyroidectomy in monosodium-L-glutamate (MSG)-treated rats. Brain Res 1980; 195(1):111-22
  3. Modigliani E, Periac P, Perret G, Hugues JN, Coste T. TRH response in 53 patients with chronic alcoholism. Ann Med Interne Paris. 1979; 130(5): 297-302

Thyroid diseases: hyperthyroidism, Graves-Basedow disease, nodular goiter, thyroiditis, secondary or tertiary hypothyroidism, congenital hypothyroidism

  1. Spencer CA, Lai-Rosenfeld AO, Guttler RB, LoPresti J, Marcus AO, Nimalasuriya A, Eigen A, Doss RC, Green BJ, Nicoloff JT. Thyrotropin secretion in thyrotoxic and thyroxine-treated patients: assessment by a sensitive immunoenzymometric assay. J Clin Endocrinol Metab. 1986 Aug;63(2):349-55
  2. Yeo PP, Loh KC. Subclinical thyrotoxicosis. Adv Intern Med. 1998; 43: 501-32
  3. Chanson P. Insuffisance thyrotropic. Rev Prat. 1998 15; 48(18): 2023-6
  4. Petersen PH, RosleffF, Rasmussen J, Hobolth N. Studies on the required analytical quality of TSH measurements in screening for congenital hypothyroidism. Scand J Clin Lab Invest Suppl. 1980;155: 5-93.
  5. Fofanova 0V, Takamura N, Kinoshita E, Yoshimoto M, Tsuji Y, Peterkova VA, Evgrafov 0V, Dedov II, Goncharov NP, Yamashita S. Rarity of PIT1 involvement in children from Russia with combined pituitary hormone deficiency. Am J Med Genet 1998; 77(5): 360-5.

FACTORS that ELEVATE the serum TSH Neonatus, stress – emotional arousal, cold exposure, sleep deprivation, adrenal insufficiency, recovery from severe illness, congenital malformations

  1. Hashimoto H, Sato F, Kubo M, Ohki T. Maturation of the pituitary-thyroid axis during the perinatal period. Endocrinol Jpn 1991;38(2):151-7
  2. Gendrel D, Feinstein MC, Grenier J, Roger M, Ingrand J, Chaussain JL, Canlorbe P, Job JC. Falsely elevated serum thyrotropin (TSH) in newborn infants: Transfer from mothers to infants of a factor interfering in the TSH radioimmunoassay. J Clin Endocrinol Metab 1981;52(1):62-5.
  3. Armario A, Lopez Calderon A, Jolin T, Castellanos JM. Sensitivity of anterior pituitary hormones to graded levels of psychological stress. Life Sci 1986; 39(5): 471-5
  4. Reed HL, Silverman ED, Shakir KM, Dons R, Burman KD, O’Brian JT. Changes in serum triiodothyronine (TQ kinetics after prolonged Antarctic residence: The polar T3 syndrome. J Clin Endocrinol Metab. 1990; 70(4): 965-74
  5. Sadamatsu M, Kato N, Iida H, Takahashi S, Sakaue K, Takahashi K, Hashida S, Ishikawa E. The 24-hour rhythms in plasma growth hormone, prolactin and thyroid stimulating hormone: effect of sleep deprivation. J Neuroendocrinol. 1995 Aug;7(8):597-606
  6. Sjoberg S, Wemer S. Increased level of TSH can be a sign of adrenal cortex failures: Not necessarily of thyroid gland disease. Lakartidningen 1999; 96(5):464-5
  7. De Nayer P, Dozin B, Vandeput Y, Bottazzo FC, Crabbe J. Altered interaction between triiodothyronine and its nuclear receptors in absence of cortisol: A proposed mechanism for increased thyrotropin secretion in corticoid deficiency states. Eur J Clin Invest. 1987 Apr;17(2):106-8
  8. Oakley GA, Muir T, Ray M, Girdwood RW, Kennedy R, Donaldson MD. Increased incidence of congenital malformations in children with transient thyroid-stimulating hormonal elevation on neonatal screening. J Pediatr. 1998; 132(4): 573-4

Medications: iodine, antithyroidea, , lithium, neuroleptica (haloperidol, chlorpromazine), cimetidine, sulfapyridine, clomifen, antidepressants (sertraline), antihistaminic agents, cholestograhic agents, etc.

  1. Devos P. Rationele keuze van schildklierfunctie tests. Tijdschr Geneesk. 1990;46(8):591-9
  2. Kleinmann RE, Vagenakis AG, Braverman LE. The effect of iopanoic acid on the regulation of thyrotropin secretion in euthyroid subjects. J Clin Endocrinol Metab. 1980;51(2): 399-403
  3. Mc Caven KC, Garber JR, Spark R. Elevated serum thyrotropin in thyroxine-treated patients with hypothyroidism given sertraline. N Engl J Med. 1997; 337(14):1010-1
  4. Brown CG, Harland RE, Major IR, Atterwill CK. Effects of toxic doses of a novel histamine (H2) antagonist on the rat thyroid gland. Food Chem Toxicol. 1987; 25(10):787-94

Auto-immune thyroiditis and hypothyroidism: primary, iodine-deficient, thyroid hormone resistance

  1. Devos P. Rationele keuze van schildklierfunctie tests. Tijdschr Geneesk. 1990;46(8): 591-9
  2. Missler U, Gutekunst R, Wood WG. Thyroglobulin is a more sensitive indicator of iodine deficiency than thyrotropin: Development and evaluation of dry blood spot assays for thyrotropin and thyroglobulin in iodine- deficient geographical areas. Eur J Clin Chem Clin Biochem 1994; 32(3): 137-43
  3. Volpe R. Subacute (de Quervain’s) thyroiditis. J Clin Endocrinol Metab. 1979 Mar;8(1):81-95
  4. Massoudi MS, Meilahn EN, Orchard TJ, Foley TP Jr, Kuller LH, Costantino JP, Buhari AM. Thyroid function and perimenopausal lipid and weight changes: the Thyroid Study in Healthy Women (TSH-W). J Womens Health. 1997 Oct;6(5):553-8
  5. Smallridge RC, Parker RA, Wiggs EA, Rajagopal KR, Fein HG. Thyroid hormone resistance in a large kindred: physiologic, biochemical, pharmacologic, and neuropsychologic studies. Am J Med. 1989 Mar;86(3):289-96

TSH-secreting tumors (rare)

  1. Smallridge RC. Thyrotropin-secreting pituitary tumors, Endocrinol Metab Clin North Am 1987 Sep;16(3):765-92

FACTORS that ELEVATE or DEPRESS serum TSH Physiological serum TSH fluctuations

  1. Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B, Feistner H, Hesch RD, von zur Muhlen A. Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab. 1990 Feb;70(2):403-9
  2. Brabant G, Prank K, Ranft U, Bergmann P, Schuermeyer T, Hesch RD, von zur Muhlen A. Circadian and pulsatile TSH secretion under physiological and pathophysiological conditions. Horm Metab Res Suppl. 1990;23:12-7
  3. Goichot B, Brandenberger G, Schlienger JL. Secretion of thyrotropin during states of wakefulness and sleep. Physiological data and clinical applications. Presse Med. 1996;25(21):980-4
  4. Rao ML, Gross G, Strebel B, Halaris A, Huber G, Braunig P, Marler M. Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia. Biol Psychiatry. 1994;1:35(3): 151-63
  5. Rose SR, Nisula BC. Circadian variation of thyrotropin in childhood. J Clin Endocrinol Metab. 1989; 68(6):1086-90
  6. Scanlon MF, Weetman AP, Lewis M, Pourmand M, Rodriguez Arnao MD, Weightman DR, Hall R. Dopaminergic modulation of circadian thyrotropin rhythms and thyroid hormone levels in euthyroid subjects. J Clin Endocrinol Metab. 1980 Dec;51(6):1251-6
  7. Rom Bugoslavskaia ES, Shcherbakova VS. Seasonal characteristics of the effect of melatonin on thyroid function. Bull Eksp Biol Med. 1986;101(3):268-9

Variations in the biological activity of TSH

  1. Beck-Peccoz P, Persani L. Variable biological activity of thyroid stimulating hormone. Eur J Endocrinol. 1994 Oct;131(4):331-40
  2. Maes M, Mommen K, Hendrickx D, Peeters D, D’Hondt P, Ranjan R, De Meyer F, Scharpe S. Components of biological variation of TSH, TT3, FT4, PRL, cortisol and testosterone in healthy volunteers. Clin Endocrinol (Oxf). 1997 May;46(5):587-98
  3. Hiromoto M, Nishikawa M, Ishihara T, Yoshikawa N, Yoshimura M, Inada M. Bioactivity of thyrotropin (TSH) in patients with central hypothyroidism: Comparison between the in vivo 3,5,3′- triiodo-thyronine response to TSH and in vitro bioactivity of TSH. J Clin Endocrinol Metab. 1995 Apr;80(4):1124-8

TSH test kit imperfections

  1. Rasmussen AK, Hilsted L, Perrild H, Christiansen E, Siersbaek-Nielsen K, Feldt-Rasmussen U. Discrepancies between thyrotropin (TSH) meaasurement by four sensitive immunometric assays. Clin Chim Acta. 1997 Mar 18;259(1-2):117-28
  2. Libeer JC, Simonet L, Gillet R. Analytical evaluation of twenty assays for determination of thyrotropin (TSH). Ann Biol Clin Paris. 1989; 47(1): 1-11
  3. Spencer CA, Takeuchi M, Kazarosyan M, MacKenzie F, Beckett GJ, Wilkinson E. Interlaboratory/intermethod differences in functional sensitivity of immunometric assays of thyrotropin (TSH) and impact on reliability of measurement of subnormal concentrations of TSH. Clin Chem. 1995 Mar;41(3):367-74
  4. Faber J, Gam A, Siersbaek Nielsen K. Improved sensitivity of serum thyrotropin measurements: Studies on serum sex hormone-binding globulin in patients with reduced serum thyrotropin. Acta Endocrinol Copenh 1990; 123(5): 535-40
  5. Laurberg P. Persistent problems with the specificity of immunometric TSH assays. Thyroid. 1993 Winter;3(4):279-83
  6. Schlienger JL, Sapin R, Grunenberger F, Gasser F, Pradignac A. Thyrotropin assay by chemiluminescence in the diagnosis of dysthyroidism with low thyrotropin and normal thyroid hormones levels. Pathol Biol Paris. 1993; 41(5): 463-8
  7. Spencer C, Eigen A, Shen D, Duda M, Qualls S, Weiss S, Nicoloff J. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem. 1987 Aug;33(8):1391-6
  8. Spencer CA, Challand GS. Interference in a radioimmunoassay for human thyrotropin. Clin Chem 1977;23(3): 584-8
  9. Kahn BB, Weintraub BD, Csako G, Zweig MH. Factitious elevation of thyrotropin in a new ultra-sensitive assay: Implications for the use of monoclonal antibodies in ‘sandwich’ immuno-assay. J Clin Endocrinol Metab. 1988 Mar;66(3):526-33
  10. Kourides IA, Weintraub BD, Martorana MAL, Maloof F. Alpha subunit contamination of human albumin preparations: Interference in radioimmunoassay. J Clin Endocrinol Metab. 1976; 43(4): 919-23
  11. Bartlett WA, Browning MC, Jung RT. Artefactual increase in serum thyrotropin concentration caused by heterophilic antibodies with specificity for IgG of the family Bouidea. Clin Chem. 1986; 32(12): 22(4-9)
  12. Csako G, Weintraub BD, Zweig MH. The potency of immunoglobulin antibodies in a monoclonal immunoradiometric assay for thyrotropin. Clin Chem. 1988 Jul;34(7):1481-3
  13. Seghers J, Schruers F, De Nayer P, Beckers C. Interference in thyrotropin (TSH) determination: Falsely elevated TSH values in a transplanted patient. Eur J Nucl Med. 1989; 15(4): 194-6
  14. Spencer C, Eigen A, Shen D, Duda M, Quails S, Weiss S, Nicoloff J. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem. 1987;33(8):1391-6
  15. Ealey PA, Marshall NJ, Ekins RP. Time-related thyroid stimulation by thyrotropin and thyroid-stimulating antibodies, as measured by the cytochemical section bioassay. J Clin Endocrinol Metab. 1981;52(3): 483-7

Doubts on the adequateness of measuring the serum TSH as a help to monitor a thyroid treatment ( follow-up) The serum TSH test for follow-up: The risk of misinterpretation increases when monitoring the treatment of hyper- or hypothyroidism

  1. Talbot JN, Duron F, Feron R. Aubert P, Milhaud G. Thyroglobulin, thyrotropin and thyrotropin binding inhibiting immunoglobulins assayed at the withdrawal of antithyroid drug therapy as predictors of relapse of Graves’ disease within one year. J Endocrinol Invest. 1989; 12(9): 589-95

In 36-47 % of cinically euthyroid patients receiving adequate long-term thyroid therapy for hypothyroidism, an undetectable serum TSH is found.

  1. Franklyn JA, Black EG, Betteridge J, Sheppard MC. Comparison of second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy, and those with nonthyroidal illness. J Clin Endocrinol Metab 1994; 78(6): 1368-71
  2. Gow SM, Caldwell G, Toft AD, Seth J, Hussey AJ, Sweeting VM, Beckett GJ. Relationship between pituitary and other target organ responsiveness in hypothyroid patients receiving thyroxine replacement. J Clin Endocrinol Metab. 1987; 64(2): 364-70

After intake of thyroidhormones, the serum TSH is transitorily depressed within 60 minutes and remains low for up to 9 hours after intake

  1. Chopra U, Carlson HE, Solomon DH. Comparison of inhibitory effects of 3,5,3′-triiodothyronine (T3), thyroxine (T4), 3,3,’,5′-triiodothyronine (rT3,), and 3,3′-diiodothyronine (T2) on thyrotropin-releasing hormone-induced release of thyrotropin in the rat in vitro. Endocrinology. 1978;103(2):393-402

Some patients who exhibit reversion of an initially high TSH level back into the reference range, are found to subsequently develop mild thyroid failure

  1. Calaciura F, Motta RM, Miscio G, Fichera G, Leonardi D, Carta A, Trichitta V, Tassi V, Sava L, Vigneri R. Subclinical hypothyroidism in early childhood: a frequent outcome of transient neonatal hyperthyrotropinemia. J Clin Endocrinol Metab. 2002;87:3209–14

Supporters of the recommendations of the consensus panel promote a target TSH range of 1.0–1.5 mU/liter in patients already receiving T4 therapy, whereas they refuse to accept TSH levels of 3–10 mU/liter as abnormal in patients not receiving T4 therapy

  1. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126

The lower end of the normal or reference range for TSH lies between 0.2 and 0.4 mU/liter, as indicated by a number of clinical studies

  1. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruj J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry 2003 Laboratory medicine practice guidelines. Thyroid. 2003 Jan;13(1):3-126
  2. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991;34:77-83
  3. Warren RE, Perros P, Nyirenda MJ, Frier BM. Serum thyrotropin is a better predictor of future thyroid dysfunction than thyroid autoantibody status in biochemically euthyroid patients with diabetes: implications for screening. Thyroid. 2004;14:853–7
  4. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
  5. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM. Low serum thyrotropin (thyroid stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med. 1991;151:165–8
  6. Hershman JM, Pekary AE, Berg L, Solomon DH, Sawin CT Serum thyrotropin and thyroid hormone levels in elderly and middle-aged euthyroid persons. J Am Geriatr Soc. 1993;41:823–8
  7. Parle JV, Maisonneuve P, Sheppare MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358:861–5

Other tests : urinary T3 as a complementary test

  1. Baisier W, Hertoghe J, Eeckhaut W. Thyroid insufficiency Is TSH measurement the only diagnostic tool? J Nutr Environm Med. 2000; 10(3): 109-113

DISCUSSIONS ON THYROID TREATMENT DOES THYROID TREATMENT DEFINITELY SUPPRESS THE THYROID GLAND?

NO! – after stopping thyroid medications, the thyroid axis recovers its initial condition in 2 to 3 weeks on the average

  1. Krugman LG, Hershman JM, Chopra IJ, Levine GA, Pekary E, Geffner DL, Chua Teco GN. Patterns off recovery of the hypothalamic-pituitary-thyroid axis in patients taken of chronic thyroid therapy. J Clin Endocrinol Metab. 1975 Jul;41(1):70-80 (full recoveryback to initial serum T3, T4, TSH levels is obtained after a mean of 16 to 22 days, even after 28 years of treatment)
  2. Vagenakis AG, Braverman LE, Azizi F, Portinay GI, Ingbar SH. Recovery of pituitary thyrotropic function after withdrawal of prolonged thyroid-suppression therapy. N Engl J Med. 1975 Oct 2;293(14):681-4 (“During exogenous hormone administration, 131l uptake was suppressed, and serum thyrotropin concentrations before and after administration of thyrotropin-releasing hormone were undetectable. …. After withdrawal of long-term thyroid hormone, decreased thyrotropin reserve persisted for two to five weeks. Detectable values of serum thyrotropin (less than 1.2 muU per milliliter) and a normal 131l uptake usually occurred concurrently in two to three weeks. Serum thyroxine concentration returned to normal at least four weeks after hormone withdrawal.”)
  3. Greer MA. The effect on endogenous thyroid activity of feeding desiccated thyroid to normal human subjects. N Engl J Med. 1951 Mar 15;244(11):385-90 (“After withdrawal of thyroid therapy, thyroid function returned to normal in most subjects within 2 weeks, although a few were depressed ofr 6-11 weeks. Thyroid function returned as rapidly in those whose glands had been depressed by several years of thyroid medication as it did for those whose glands had been depressed for only a few days.”)
  4. Mosier HD, DeGolia RC. Effect of prolonged administration of thyroid hormone on thyroid gland function of euthyroid children. J Clin Endocrinol Metab. 1960 Sep;20:1296-301. (“In all of the echildren and adolescents included in this study, thyroid function returned to normal (as judged by clinical signs ans by laboratory measurements) within four months after discontinuing thyroid hormone,in spite of previous administration of suppressive doses for periods of 20 too 125 months during years of somatic growth”).
  5. Farquharson RF, Squires AH. Inhibition of the secretion of the thyroid gland by continued ingestion of thyroid substance. Tr A Am Physicians. 1941;56:87
  6. Johnston MW, Squires AH, Farquharson RF. The effect of prolonged administration of thyroid. Ann Intern Med. 1951 Nov;35(5):1008-22
  7. Riggs DS, Man EB, Winkler AW. Serum iodine of euthyroid subjects treated with desiccated thyroid. J Clin Invest. 1945;24:722-31
  8. Stein RB, Nicoloff JT. Triiodothyronine withdrawal test -a test of thyroid-pituitary adequacy. J Clin Endocrinol Metab. 1971 Feb;32(2):127-9

If the thyroid treatment is stopped because it is judged not necessary, recovery takes place

  1. Rubinoff H, Fireman BH. Testing for recovery of thyroid function after withdrawal of long-term suppression therapy. J Clin Epidemiol. 1989;42(5):417-20 (At 8 weeks, 30 of the 45 patients whose chart reviews did not demonstrate a clear need for thyroid replacement., were normal)

MILD THYROID FAILURE: TO TREAT OR NOT TO TREAT? Arguments pro thyroid treatment of mild thyroid failure Longitudinal studies indicating a rate of progression of mild thyroid failure into overt hypothyroidism of about 5% per year (50% or more in 10 years!): they have to be treated

  1. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995; 43:55–68
  2. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991;34:77–83
  3. Huber G, Staub J-J, Meier C, Mitrache C, Guglielmetti M, Huber P, Braverman LE. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87:3221–6
  4. Kabadi UM. ‘Subclinical hypothyroidism:’ natural course of the syndrome during a prolonged follow-up study. Arch Intern Med. 1993;153:957-61

MILD THYROID FAILURE: TO TREAT OR NOT TO TREAT Arguments pro thyroid treatment of mild thyroid failure Longitudinal studies indicating a rate of progression of mild thyroid failure into overt hypothyroidism of about 5% per year (50% or more in 10 years!): they have to be treated

  1. Meier C, Staub J-J, Roth C-B, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism. Am J Med. 2001;112:348–54
  2. Meier C, Staub J-J, Roth C-B, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab. 2001; 86:4860–6
  3. Cooper DS 2001 Subclinical hypothyroidism. N Engl J Med 345:260–5
  4. Ayala A, Wartofsky L. Minimally symptomatic (subclinical) hypothyroidism. Endocrinologist. 1997;7:44–50
  5. McDermott MT, Ridgway EC. Clinical perspective: subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab. 2001; 86:4585–90 (shows benefit with minimal TSH reductions down to only the range of 3–3.5 mU/liter)

Studies with appropriate dosage titration to TSH levels under 3.0 are more often associated with improvement in symptoms, lipid abnormalities, and cardiovascular function

  1. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adampoulos P, Koutras DA. High serum cholesterol levels in persons with ‘high-normal’ TSH levels: should one extend the definition of subclinical hypothyroidism. Eur J Endocrinol. 1998;138:141–5
  2. Ayala A, Wartofsky L 2002 The case for more aggressive screening and treatment of mild thyroid failure (“subclinical” hypothyroidism). Cleveland Clin J Med. 69:313–20
  3. Faber J, Petersen L, Wiinberg N, Schifter S, Mehisen J. Hemodynamic changes after levothyroxine treatment in subclinical hypothyroidism. Thyroid. 2002; 12:319–24
  4. Monzani F, DiBello V, Caraccio N, Bertini A, Giorgi D, Guisti C, Ferranni E. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab. 2001; 86:1110–5
  5. Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A, Bone F, Lombardi G, Sacca L. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1999; 84:2064–7
  6. Di Bello V, Monzani F, Giorgi D, Bertini A, Caraccio N, Valenti G, Talini E, Paterni M, Ferrannini E, Giusti C. Ultrasonic myocardial textural analysis in subclinical hypothyroidism. J Am Soc Echocardiogr. 2000;13:832–40
  7. Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P, Mantzos J, Stametelopoulos S, Koutras DA. Flow-mediated, endothelium-dependent vasodilatation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin values. Thyroid. 1997; 7:411-4
  8. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, Salvetti A, Ferrannini E, Monzani F. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003;88:3731–7
  9. Bakker SJ, ter Maaten JC, Popp-Snijders C, Slaets JPJ, Heine RJ, Gans ROB. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab. 86:1206–11
  10. Krausz Y, Freedman N, Lester H, Newman JP, Barkai G, Bocher M, Chisin R, Bonne O. Regional cerebral blood flow in patients with mild hypothyroidism. J Nucl Med. 2004; 45:1712–5
  11. Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M, Usa T, Ashizawa K, Yokayama N, Maeda R, Nagataki S, Eguchi K. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004;89:3365–70
  12. Monzani F, Caraccio N, Kozakowa M, Dardano A, Vittone F, Virdis A, Taddei S, Palombo C, Ferrannini C. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2004;89:2099–106

Other studies in defence of treatment of mild thyroid failure: it is important to treat mild thyroid failure to avoid adverse physical and psychological consequences

  1. Monzani F, Del Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, Baschieri L. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin Investig. 1993 May;71(5):367-71
  2. Tappy L, Randin JP, Schwed P, Wertheimer J, Lemarchand-Beraud T. Prevalence of thyroid disorders in psychogeriatric inpatients. A possible relationship of hypothyroidism with neurotic depression but not dementia. J Am Geriatr Soc. 1987;35:526–31
  3. Joffe RT, Levitt AJ 1992 Major depression and subclinical (grade 2) hypothyroidism. Psychoneuroendocrinology. 17:215–21
  4. Haggerty Jr JJ, Stern RA, Mason GA, Beckwith J, Morey CE, Prange Jr AJ. Subclinical hypothyroidism: A modifiable risk factor for depression? Am J Psychiatry. 1993;150:508–10
  5. Manciet G, Dartigues JF, Decamps A, et al. 1995 The PAQUID survey and correlates of subclinical hypothyroidism in elderly community residents in the southwest of France. Age Aging. 24:235-41
  6. Baldini IM, Vita A, Maura MC, Amodei V, Carrisi M, Bravin S, Cantalamessa L. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):925-35
  7. Ganguli M, Burmeister LA, Seaberg EC, Belle S, DeKosky ST. Association between dementia and elevated TSH: a community-based study. Biol Psychiatry. 1996;40:714–25
  8. Monzani F, Caraccio N, Siciliano G, Manca L, Murri L, Ferrannini E. Clinical and biochemical features of muscle dysfunction in subclinical hypothyroidism. J Clin Endocrinol Metab. 1997;82:3315–8
  9. Monzani F, Caraccio N, Del Guerra P, Casolaro A, Ferrannini E. Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficial effect of L-T4 replacement therapy. Clin Endocrinol. 1999;51:237–42
  10. Misiunas A, Ravera HN, Faraj G, Faure E. Peripheral neuropathy in subclinical hypothyroidism. Thyroid 1995;5:283–6
  11. Goulis DG, Tsimpiris N, Delaroudis S, Maltas B, Tzoiti M, Dagilas A, Avramides A. Stapedial reflex: a biological index found to be abnormal in clinical and subclinical hypothyroidism. Thyroid. 1998 Jul;8(7):583-7
  12. Beyer IW, Karmali R, DeMeester-Mirkine N, Cogan E, Fuss MJ. Serum creatine kinase levels in overt and subclinical hypothyroidism. Thyroid 1998;8:1029–31
  13. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999 Aug 19;341(8):549-55
  14. Foundation for Blood Research, Scarborough, ME 04074, USA
  15. Ridgway EC, Cooper DS, Walker H, Rodbard D, Maloof F. Peripheral responses to thyroid hormone before and after L-thyroxine therapy in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1981 Dec;53(6):1238-42
  16. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med. 1984;101:18–24
  17. Nystrom E, Caidahl K, Fager G, Wikkelso C, Lundberg P-A, Lindstedt G. A double-blind cross-over 12-month study of L-thyroxine treatment of women with ’subclinical’ hypothyroidism. Clin Endocrinol. 1988;29:63–76 (Approximately one woman in four with this ‘subclinical’ condition will benefit from L-thyroxine treatment)
  18. Bell GM, Todd WT, Forfar JC, Martyn C, Wathen CG, Gow S, Riemersma R, Toft AD. End-organ responses to thyroxine therapy in subclinical hypothyroidism. Clin Endocrinol (Oxf). 1985 Jan;22(1):83-9
  19. Forfar JC, Wathen CG, Todd WT, Bell GM, Hannan WJ, Muir AL, Toft AD. Left ventricular performance in subclinical hypothyroidism. Q J Med. 1985 Dec;57(224):857-65 Foldes J, Istvanfy M, Halmagyi M, Varadi A, Gara A, Partos O. Hypothyroidism and the heart. Examination of left ventricular function in subclinical hypothyroidism. Acta Med Hung. 1987;44:337–47
  20. Kahaly GJ 2000 Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid 10:665–79
  21. Arem R, Rokey R, Kiefe C, Escalante DA, Rodriquez A. Cardiac systolic and diastolic function at rest and exercise in subclinical hypothyroidism: Effect of thyroid hormone therapy. Thyroid. 1996 ;6:397-402
  22. Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, Ferrannini E. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab. 2001 Mar;86(3):1110-5
  23. Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A, Bone F, Lombardi G, Sacca L. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1999 Jun;84(6):2064-7
  24. Tanis BC, Westendorp RGJ, Smelt AHM. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol. 1996;44:643–9
  25. Danese MD, Ladenson PW, Meinert CL, Powe NR; Effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab. 2000;85:2993–3001
  26. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P, Koutras DA. High serum cholesterol levels in persons with ‘high-normal’ TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998 Feb;138(2):141-5
  27. Bindels AJ, Westendorp RG, Frolich M, Seidell JC, Blokstra A, Smelt AH. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding? Clin Endocrinol. 1999;50:217–20
  28. Bakker SJL, Ter Matten JC, Popp-Snijders C, Slaets JPJ, Heine RJ, Gans ROB. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab. 2001;86:1206–11
  29. Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P. Flow-mediated, endothelium-dependent vasodilatation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values. Thyroid. 1997;7:411–4
  30. Powell J, Zadeh JA, Carter G, Greenhalgh RM, Fowler PB. Raised serum thyrotrophin in women with peripheral arterial disease. Br J Surg. 1987;74:1139–41
  31. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Rodgers H, Tunbridge F, Young ET. The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Thyroid 1996 Jun;6(3):155-60
  32. Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, Harper S, Griffith L, Carbotte R. Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med. 1996 Dec;11(12):744-9
  33. Diekman T, Lansberg PJ, Kastelein JJ, Wiersinga WM. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med. 1995;155:1490–5
  34. Perk M, O’Neill BJ. The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol. 1997;13:273–
  35. Stockigt J. Serum thyrotropin and thyroid hormone measurements and assessment of thyroid hormone transport. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the thyroid. 2000, ed 8. Philadelphia: Lippencott Williams and Wilkins; 376–92
  36. Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild thyroid failure at the periodic health examination. JAMA. 1996;276:285–92
  37. McDermott MT, Haugen BR, Lezotte DC, Seggelke S, Ridgway EC. Management practices among primary care physicians and thyroid specialists in the care of hypothyroid patients. Thyroid. 2001;11:757–76
  38. Zoncu S, Pigliaru F, Putzu C, Pisano L, Vargiu S, Deidda M, Mariotti S, Mercuro G. Cardiac function in borderline hypothyroidism: a study by pulsed wave tissue Doppler imaging. Eur J Endocrinol. 2005 Apr;152(4):527-33 (“impairment of systolic ejection, a delay in diastolic relaxation and a decrease in the compliance to the ventricular filling… Several significant correlations were found between the parameters and serum-free T(3) and T(4) and TSH concentrations. Data strongly support the concept of a continuum spectrum of a slight thyroid failure in autoimmune thyroiditis.”)

Subclinical thyroid dysfunction is an abnormal serum thyroid-stimulating hormone level (reference range: 0.45 to 4.50 µU/mL) and free thyroxine and triiodothyronine levels within their reference ranges

  1. Wilson GR, Curry RW Jr. Subclinical thyroid disease. Am Fam Physician. 2005 Oct 15;72(8):1517-24

Important frequency of subclinical hypothyroidism:

  1. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG,
  2. Young E, Bird T, Smith PA. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977 Dec;7(6):481-93
  3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34
  4. Hollowell J, Braverman LE, Spencer CA, Staehling N, Flanders D, Hannon H Serum TSH, T4, and thyroid antibodies in the United States population: NHANES III. 72nd Annual Meeting of the American Thyroid Association, Palm Beach, FL, 1999; Abstract 213
  5. Guel KW, van Sluisveld IL, Grobbee DE, Docter R, de Bruyn AM, Hooykaas H, van der Merwe JP, van Hemert AM, Krenning EP, Hennemann G, et al. The importance of thyroid microsomal antibodies in the development of elevated serum TSH in middle-aged women: associations with serum lipids. Clin Endocrinol (Oxf). 1993 Sep;39(3):275-80
  6. Rivolta G, Cerutti R, Colombo R, Miano G, Dionisio P, Grossi E. Prevalence of subclinical hypothyroidism in a population living in the Milan metropolitan area. J Endocrinol. Invest. 1999;22:693–7
  7. Bagchi N, Brown TR, Parish RF. Thyroid dysfunction in adults over age 55 years. A study in an urban U.S. community. Arch Intern Med. 1990;150:785–7
  8. Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach P. The aging thyroid. Increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA. 1979;242:247–50
  9. Lindeman RD, Schade DS, LaRue A, Romero LJ, Liang HC, Baumgartner RN, Koehler KM, Garry PJ. Subclinical hypothyroidism in a biethnic, urban community. J Am Geriatr Soc. 1999 Jun;47(6):703-9
  10. Hak AE, Pols HAP, Visser TJ, Drexhage HA, Hofman A, Witteman JCM. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam study. Ann Intern Med. 2000;132:270–8
  11. Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly: microsomal antibodies as discriminant for therapy. JAMA. 1987 ;258:209–13
  12. Wilson GR, Curry RW Jr. Subclinical thyroid disease. Am Fam Physician. 2005 Oct 15;72(8):1517-24 (“The prevalence of subclinical hypothyroidism is about 4 to 8.5 percent, and may be as high as 20 percent in women older than 60 years”)

Important risk of progression into overt hypothyrodism

  1. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 1991;34:77–83
  2. Bastenie PA, Bonnyns M, Vanhaelst L. Natural history of primary myxedema. Am J Med. 1985;79:91–100
  3. Kabadi UM. Subclinical hypothyroidism. Natural course of the syndrome during a prolonged follow-up study. Arch Intern Med. 1993;153:957–61
  4. Tunbridge WMG, Brewis M, French JM, Appleton D, Bird T, Clark F, Evered DC, Evans JG, Hall R, Smith P, Stephenson J, Young E. Natural history of autoimmune thyroiditis. Br Med J (Clin Res Ed). 1981 Jan 24;282(6260):258-62
  5. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F,Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995 Jul;43(1):55-68
  6. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am. 1997;26:189–218
  7. Huber G, Mitrache C, Guglielmetti M, Huber P, Staub JJ. Predictors of overt hypothyroidism and natural course: a long-term follow-up study in impending thyroid failure. 71st Annual Meeting of the American Thyroid Association, Portland, OR, 1998; Abstract 109

Importance of clinical evaluation of subclinical hypothyroidism

  1. Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997;82:771–6

Studies showing that it is important to treat mild glandular failure that causes other diseases such as diabetes and hypertension

  1. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1C with cardiovascular disease and mortality in adults: the European Prospective Investigation into Cancer in Norfolk. Ann Intern Med. 2004;141:413–20
  2. Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, Benjamin EJ, Levy D. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004 351:33–41
  3. Dluhy RG, Williams GH. Aldosterone: villain or bystander? N Engl J Med. 2004;351:8–10

Arguments contra thyroid treatment of mild thyroid failure

  1. Chu JW, Crapo LM. Should mild hypothyroidism be treated? Am J Med. 2002;112:422–3
  2. Chu JW, Crapo LM. The treatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Metab. 2001;86:4591–9

Initiation of levothyroxine therapy for mild thyroid failure would be inappropriate because it results in overtreatment with attendant risks of subclinical hyperthyroidism. (citic: this risk applies to a very small fraction of the population to be treated. An equivalent risk of undertreatment of such individuals applies as well. Both results could be minimized by education of our primary care physicians about the desirable TSH target in their patients)

  1. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228–38
  2. Surks MI. Commentary: subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society. J Clin Endocrinol Metab. 2005;90:586–7

T4 treatment does not improve clinically hypothyroid patients who have normal tests (critic: but possibly T3-T4 does)

  1. Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, McLaren EH. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ. 2001 Oct;323(7318):891-5

T4 treatment in subclinically hypothyroid patients but normal tests does not improve the patient (explanation: The absence of clinically relevant benefits of thyroid therapy for mild thyroid failure may be due to (1) a TSH normalization that was typically described as lowering of TSH to < 5 mU/liter, whereas levels between 3 – 5 mU are probably still elevated and request higher dosage; (2) the use of thyroxine without any addition of triiodothyronine)

  1. Kong WM, Sheikh MH, Lumb PJ, Naoumova RP, Freedman DB, Crook M, Dore CJ, Finer N. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med. 2002;112:348–54

Thyroxine treatment does improve cholesterol levels and clinical symptoms in subclinical hypothyroidism

  1. Meier C, Staub J-J, Roth C-B, Gugliemetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog M, Muller B. TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab. 2001 Oct;86:4860–6 (An important risk reduction of cardiovascular mortality of 9-31% can be estimated from the observed improvement in LDL cholesterol)

Studies that show the importance of treating mild thyroid excess: Subclinical hyperthyroidism

  1. There is an equal concern about correct diagnosis and treatment of patients with TSH levels that are slightly below the reference interval because of risks to both heart and bone
  2. Parle JV, Maisonneuve P, Sheppare MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358:861–5
  3. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW, Benjamin EJ, D’Agostino RB. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;331:1249–52
  4. Stathatos N, Wartofsky L. Effects of thyroid hormone on bone. Clin Rev Bone Miner Metab. 2004;2:135–50

See also – http://www.intlhormonesociety.org/r…hyroid_biochemically_hypothyroid_patients.pdf

 

Tags:

You must be logged in to post a comment.

Previous comments