HYPOTHYROIDISM – DETECTION, DIAGNOSIS & TREATMENT

Dr. Neville Wilson

15 January 2015

 

Multitudes of people wake up every day experiencing a wide range of chronic and debilitating systems without the realization that their unrelenting complaints may be the direct cause of an undetected and untreated underactive thyroid gland.

The thyroid gland is a small “shield shaped” gland, resembling a butterfly with 2 spread wings, located in the lower part of the neck, and situated in front of the trachea (windpipe) just beneath the larynx (voice-box).

 Anatomy of the Thyroid and Parathyroid Glands

This important gland has often been described as the “mother of all glands” because of the vast range of vital body functions orchestrated by the hormones it secretes.

Classified as an endocrine gland, like the parathyroid glands, adrenals, pancreatic and pituitry glands, it produces, stores and secretes specialized hormones into the blood stream, which in turn play a positive role in the support of life sustaining functions of several organs within the human body.

The key thyroid hormones produced and released into the blood stream are triiodothyronine (T3) and thyroxine (T4),  with T3 being the biologically active hormone, following its conversion from T4 in the peripheral tissues by a process called deiodination of thyroxine. ( 1 )

The healthy active thyroid will produce 4 times more T4 than T3 (Roughly 80% T4 and 20% T3, ) and then convert the T4 into T3 for uptake in the various organ cells for energy production. Further transformations to T1 and T2 may occur in the peripheral tissues.

In an average sized adult (body surface of 1.79m2) the thyroid gland may produce 100mcg of T4 and 29mcg of T3 each day, with the half life of T4 being 1 week, and the half life of T3 being 1 day.

This has implications for thyroid replacement therapy in patients with underactive thyroid glands, since  T3 replacement needs to be done in several doses throughout the day. (2) (Excessive and rapid absorption of T3 may cause palpitations and anxiety in some patients).

Thyroid cells depend on many factors for their normal function.

While adequate nutritional intake of iodine is required for combination with the amino acid, tyrosine, in order to form T4 and T3, it appears that emotional stress, infections, a faulty immune system, and environmental toxins can interfere with the normal production of thyroid hormones, giving rise to a situation where thyroid hormone therapy is required.

In some cases an excess of dietary iodine can cause hypothyroidism, as can certain drugs such as lithium and amioderone.

Radiotherapy treatment for cancer can also damage the thyroid gland resulting in hypothyroidism..

Any damage to the Pituitry gland can also disrupt the release of the hormone TSH that stimulates the thyroid gland, resulting in hypothyroidism.

In some cases, cancer of the thyroid may require removal of the gland, partially or totally, also necessitating the introduction of thyroid hormonal support therapy.

Inadequate T3 conversion from T4 may occur in some cases, and  express itself in inefficient energy production in some organs, resulting  in symptoms that may not be attributed to an underactive thyroid in the clinical setting.

It appears that some people may not be able to convert their T4 into T3 efficiently, resulting in poor cellular energy production, followed by a range of debilitating mental and physical conditions.

Medical doctors should be alerted to the likelihood that common physical ailments, presented by patients, in the presence of “normal thyroid tests”, may well be an expression of an undiagnosed underactive thyroid that has not been detected or adequately treated.

 

Thyroid Hormones:

The Thyroid hormones control the functions of every human cell, whereby oxygen and calories are converted into the energy required by those cells for their normal life-giving and life-sustaining functions.

As such, these hormones play a vital role in sustaining the functions of the brain, heart, lungs, the gut, bones, joints muscles and skin.

It is not surprising, therefore, that a poorly or under-functioning thyroid gland may present with a variety of symptoms and physical signs related to the malfunctioning of any of these organ systems.

Since the heart is the main target for thyroid hormone activity, hypothyroidism may precipitate or aggravate heart failure, affecting heart rate and blood pressure, while increasing cardiovascular stiffness and cardiomegaly (heart enlargement).

Patient complaints of fatigue, weight gain, muscle and joint pains, dry skin, hair loss, digestive complaints, depressive moods, brain fog and poor concentration, breathing difficulties, headaches, sleep disturbances, dry eyes and hearing loss may all be related to an underactive thyroid gland, without either the patient or the doctor, suspecting the connection.

Many patients will report that they have presented with these complaints to their doctors, even while laboratory blood levels have been interpreted as being  normal, and have been told that there is nothing physically wrong, and that they may be required to take anti-depressive medication !

Some patients report that their doctors have attributed  their symptoms to the  inevitable consequences of aging, or to the onset of the menopause,  and that nothing further can be done for them.

It is not uncommon for these patients to have an undetected underactive thyroid gland, which does not present itself with abnormal blood levels of thyroid hormones, and which drastically improves with symptomatic relief when given thyroid hormone replacement.

Added to this group of patients are those who have been correctly diagnosed by blood tests as having an underactive thyroid, but who continue to experience debilitating symptoms, despite taking the standard thyroid medication (L-Thyroxine / Eltroxin) that has been prescribed by their doctor.

There is evidence that a large body of patients who are taking their regularly prescribed medication, ( Eltroxin) continue to complain of weight gain, chronic fatigue, muscles pains, brain fog and dry skin, despite the lab report that their thyroid hormones are “normal”.

In a UK community based study of 1922 patients, many reported feelings of lethargy and related symptoms, even while on Thyroxine (T4) and with normal TSH levels. (3)

In my clinical experience many of these patients, report feelings of mood swings and even depression, with some requesting anti-depressant therapy in the hope of finding relief.

Many of these patients will have been prescribed standard thyroxine (Eltroxin) medication by their doctors, and continue to feel overwhelmed by chronic fatigue, muscle pain and mental lethargy.

The possibility, and likelihood, exists that these groups of patients have an undetected underactive thyroid, despite the perception that their blood tests are “normal”, or that their medication is “appropriate”.

 

THYROID HORMONE TESTS:

 

Blood tests conducted by investigating doctors would be a Thyroid Stimulating Hormone (TSH),  a Thyroxine  (T4) level, a Triiodothyronine (T3) level and, and Thyroid Antibody Tests, which may be antithyroid microsomal antibodies, or anti-TPO (thyroperoxidase) antibodies, which test for antibodies to a Thyroid enzyme.

The more commonly requested laboratory tests would be the TSH and T4, with which most doctors are likely to be familiar.

The T3 and free T3 blood level reports may not be readily supplied by conventional labs, leaving most practicing physicians unaware of their importance, and also unfamiliar with their usage in managing patients with underactive thyroid glands.

 

Thyroid Stimulating Hormone (TSH):

 

The hypothalamus in the brain acts as a vital monitoring and controlling centre for human body metabolism, and detects, not only changes in the requirements and functions of many organs, but also regulates those functions, by releasing a hormone called thyrotropin releasing hormone (TRH), which is sent to the pituitary gland, where it regulates the release of a specialized hormone called thyrotropin.

The Pituitry gland in the brain  produces thyrotropin, also known as Thyroid Stimulating Hormone (TSH) , which in turn prompts the Thyroid gland to produce its hormones, T4 and T3, which are then carried into the bloodstream by a protein called thyroxine-binding globulin (TBG).

Receptors on the cells of body tissues receive these hormones for their normal cellular function.  If they have sufficient hormone for their function they communicate their sufficiency to the hypothalamus, through a feed-back system, whereby the hormones TRH and TSH are adjusted to maintain the required secretion of T4 and T3 by the thyroid gland.

If the hypothalamus senses that the body is suffering because of poor T4 or T3 supply, it will increase its supply of TRH and cause the pituitary to produce more TSH, until the thyroid gland is able to produce more hormone.

If the body is healthy and the supply of thyroid hormones is adequate, the hypothalamus will reduce its supply of TRH causing the pituitary to reduce its supply of TSH, resulting in a “normal”, or low level, of TSH, as reflected in the laboratory blood report.

Traditionally, medical doctors and endocrinologists have used the lab report of TSH as a marker of thyroid function.

The British Thyroid Association (BTA) states that “the aim of treatment should be to restore and maintain the TSH within the normal range” (4) but fails to add that a “normal range” has never been agreed upon by researchers who frequently offer varying opinions on the subject of “normal range”, and, that  the normal range may vary across population groups and age groups, being narrowed in some and widened in others. (5) (6)

Conventionally, TSH and T4 will be reported by most labs when a Doctor requests thyroid studies for a patient, but the range of “normal values” is likely to vary from lab to lab, with most labs currently reflecting a wider range than the narrower range recommended by the American Association for Clinical Chemistry (AACC) in 2002.

During the 1980s and 1990s the “normal” TSH range was considered to be between 0.3 – 0.5 mIU/L to an upper level of 4.7-5.5 mIU/L, beyond which the patient was diagnosed as having an underactive (hypothyroid) thyroid gland, and requiring thyroid hormone replacement.

In 2002, the National Academy of Clinical Biochemistry (NACB) and the Academy of the American Association for Clinical Chemistry (AACC) revised these figures, and issued new laboratory guidelines which were a significant departure from the previously accepted range.

 

REVISED TSH LEVELS 2002:

 

The revised AACC Guidelines stated : “ It is likely that the current upper limit of the population reference range is skewed by the inclusion of persons with occult thyroid function……In the future, it is likely that the upper limit of the serum TSH euthyroid reference range will be reduced to 2.5 mIU/L because >95% of rigorously screened normal euthyroid volunteers have serum TSH values between 0.4 and 2.5 mIU/L….

A serum TSH results between 0.5 and 2.0 mIU/L is generally considered the therapeutic target for a standard L-T4 replacement dose for primary hypothyroidism”.  (7)

In Jan 2003 the AACC made the announcement :

“Until November 2002, doctors had relied on a normal TSH level ranging from 0.5 to 5.0 to diagnose and treat patients with a thyroid disorder who tested outside the boundaries of that range.

Now AACC encourages doctors to consider treatment for patients who test outside  the boundaries of a narrow margin based on a target TSH of 0.3 to 3.0.

AACC believes the new range will result in proper diagnosis for millions of Americans who suffer from a mild thyroid disorder, but have gone untreated until now.” ( 8 )

 

 2012 -TSH REVISED AGAIN !

 

In 2012 the AACC once again revised the range for normal TSH levels, this time reversing their earlier narrow margin of 0.3-3.0 mIU/L , and favouring the broader range recommended by the NHANES 111 reference population range as between 2.5 and 4.5mIU/L (9)

The 2012Clinical Practice Guidelines (CPG) do however acknowledge that variations in TSH levels are acceptable as being “normal” for different population groups, age groups and under different clinical circumstances, and base their recommendations on findings from a NHANES 111 study.

These recommendations were further supported by findings from the Hanford Thyroid Disease Study.

The wider range of purported “normal” levels for TSH may inadvertently lead to a failure by physicians to identify a large number of patients who have symptoms of an underactive thyroid but have “normal” lab results. These individuals are not likely to receive replacement therapy from which they may have derived a therapeutic health benefit.

The National Academy of Clinical Biochemists, however, found that 95% of individuals without evidence of thyroid disease have TSH concentrations below 2.5mIU/L, thus recommending that the upper limit of the TSH reference range be lowered to 2.5m IU/L.  (10) (11)

 

BRITISH THYROID ASSOCIATION (BTA) GUIDELINES:

 

According to the British Thyroid Association (BTA) the goal of treatment for thyroid disorders is to “normalize the TSH level” regardless of other hormone levels or clinical symptoms.

It states “ the aim of treatment should be to restore and maintain the TSH level within the reference range”, (4)  but this recommendation fails to account for variations within different population and age groups.

The difficulty with this recommendation is that not all patients who have mild TSH elevations are hypothyroid, requiring thyroid hormone replacement, and some patients who appear to have a “normal” TSH level may be hypothyroid and in need of thyroid hormone replacement !

Any clinician who works closely with hypothyroid patients knows that such a goal is unrealistic, and that the goal of treatment is to normalize thyroid function and restore the patient to full health with symptomatic relief, regardless of the TSH level !

In some cases, the TSH may be suppressed below the “normal” range during hormone replacement therapy, and patients may feel better when T3 and T4 levels have been restored to a favourable level, despite a low TSH level.

 

TSH VARIATIONS :

 

The new AACC guidelines suggest that slightly  higher levels of TSH in the elderly may not necessarily reflect an underactive thyroid. ( 8) and that critically ill hospitalized patients may have a suppressed TSH, while increased levels may be seen during the recovery phase for non thyroid illness. (12)

 During the first trimester of pregnancy TSH levels may fall to below 0.1 mIU/L because of the stimulating effect of human chorionic gonadotropin (HCG), and may return to normal during the second trimester.

TSH levels may also reflect Adrenal gland insufficiency, and may be reversed with glucocorticoid replacement. (13) (14)

TSH goals may therefore vary, according to clinical circumstances, and the definition of a “normal range” continues to be a matter of controversy and debate..

The NHANNES 111 recommendation of an upper limit of 4.12 mIU/L has not been universally accepted, with proposals from some sources that the upper normal  should be either 2.5 or 3.0 mIU/L (10)

 

OTHER BLOOD HORMONE TESTS :

 

  1. 1.     Total serum Thyroxine T4:  T4 levels may vary, and if low, with an elevated TSH, suggest a Thyroid gland cause for hypothyroidism.
  2. 2.     A low T4 with a normal or low TSH may suggest a Pituitry cause for hypothyroidism.
  3. 3.     An artificially elevated T4 may occur during pregnancy, or during oestrogen replacement therapy or oral contraception, in a normally functioning thyroid gland.
  4. 4.     Free T4 measures unbound T4 and low levels suggest an underactive thyroid, while higher than normal levels suggest an overactive thyroid gland.
  5. 5.     Total T3 (Serum Triiodothyronine) in the blood is indicative of thyroid function. If low it suggests hypothyroidism. If higher than normal it suggests hyperthyroidism.
  6. 6.     Free T3 measures the amount of free unbound T3 in the blood. Low levels are suggestive of an underactive thyroid gland.
  7. 7.     Reverse T3 Test. It is not commonly available, while specialized labs will provide this test on request. Under conditions of stress the normal mechanism of converting T4 to T3, the active form of thyroid hormone, is suspended and the body makes an inactive form of T3, known as Reverse T3 (RT3) in order to conserve energy.

 

ANTIBODIES TESTS :

Thyroid antibodies can be detected in the blood in the presence of an auto-immune disease, where the body’s own immune system mounts an attack on the thyroid tissue, causing it to become either underactive (Hashimoto’s Hypothyroidism), or overactive (Graves’ disease/hyperthyroidism).

Antithyroid microsomal antibodies (TgAb1) are usually elevated in Hashimoto’s thyroiditis, indicative of an autoimmune cause for the hypothyroidism.

Anti-TPO (thyroperoxidase) antibodies measures antibodies to a thyroid enzyme and are often raised in Hashimoto’s disease.  They may however be absent in Hashimoto’s disease.

TSH receptor antibodies (TSHRAb) measurements  may be offered by some labs.

On a worldwide basis environmental iodine is the most common cause of hypothyroidism (15), but in areas of iodine sufficiency, such as the USA, the most common cause of hypothyroidism is chronic auto immune thyroiditis (Hashimoto’s Disease).

IMAGING THYROID TESTS:

 

  1. Nuclear Scans / Radioactive Iodine Uptake measures iodine uptake in the thyroid gland and can be used to detect an overactive or underactive thyroid gland.
  2. Thyroid Ultrasound is commonly used to evaluate thyroid nodules or cystic lesions.
  3. CT Scan of the Thyroid may detect larger  nodules, but is less effective in detecting smaller nodules.
  4. MRI (Magnetic Resonance Imaging) can evaluate size and shape of the thyroid gland, but does not provide information regarding thyroid function.
  5. Needle Biopsy and Fine Needle Aspiration (FNA) is commonly used for withdrawing fluid from a thyroid cyst and may be used, under guided ultrasound, to evaluate the presence of cancerous cells within the thyroid gland.

 

 OTHER DIAGNOSTIC TESTS FOR HYPOTHYROIDISM:

 

  1. Basal Metabolic Rate: A morning axillary (under armpit) temperature before eating or drinking, and immediately after waking, with an oral glass/ mercury thermometer is a useful method for evaluating thyroid status in symptomatic persons with normal TSH and T4 levels.

Temperature is taken over a 10 minute period for 5 consecutive days, and low body temperatures of 35C or even 36C are highly indicative of hypothyroidism. (16)

Menstruating women should wait until after day 5 to perform this test.

I have found this test to be useful when all blood tests appear to be “normal”, with a low BBT correlating well with symptoms and signs of an under active thyroid gland and reverting back to normal following hormone replacement therapy.

  1. A decrease in sleeping heart rate may indicate an under active thyroid.
  2. Elevated serum total cholesterol and LDL, and Lp(a) are frequently markers for hypothyroidism. ( Please note that cholesterol is not the problem and does not need to “treated”. The problem is with the thyroid gland and which needs to be addressed. )
  3. A delayed Achilles reflex time may suggest hypothyroidism.
  4. An elevated CK fraction may suggest an underactive thyroid.

SUBCLINICAL HYPOTHYROIDISM (SCH):

Subclinical or borderline hypothyroidism is a common finding in the clinical setting and may cause uncertainty within the minds of some clinicians regarding the need to treat.

It is defined as a thyroid gland which produces free thyroxine (T4) and triiodothyronine (T3) levels which are within the normal range, but associated with a TSH which is higher than 4.5 and lower than 10.

I have had many patients report that their clinician, in these circumstances, has decided not to treat, and to rather “wait and watch”.

Patients with these lab readings may either be without obvious symptoms, or present with florid symptoms, and their need for thyroid replacement therapy has become a matter of controversy.

In my own experience many  patients with elevated TSH and normal T4 and T3 levels do well when treated, and report reductions in severity of symptoms.

The TSH levels in many cases of borderline hypothyroidism do not need to be significantly elevated in order to benefit from treatment, where successful treatment may be thyroid support with either T3 or T4, or a combination of T3 and T4.

I have personally witnessed several cases of subclinical hypothyroidism where a TSH level between 5 and 10 has been left untreated, and the patient assured that he or she does not have an underactive thyroid, despite their insistence that they have symptoms of weight gain and fatigue, as well as some of the many classical symptoms.

The AACC REPORT in 2003 suggests that treatment of subclinical hypothyroidism may reduce the risk of atherosclerosis, and cardiovascular disease, and even in cases of a normal TSH with elevated thyroid antibodies there is the risk of progressing from borderline to full blown hypothyroidism, unless appropriately treated. (17)

 

TREATMENT OF HYPOTHYROIDISM:

 

The standard treatment by medical doctors for hypothyroidism is Levothyroxine better known by the trade name of Eltroxin.

Medical students would have been introduced to Eltroxin, during their training, as the appropriate drug to be used for this condition, since it provides thyroxine (T4) which the underactive thyroid cannot produce effectively.

In 1970  triiodothyronine hormone (T3) was documented as being the biologically active product of peripheral conversion from T4 to T3, and became an option for combined therapy, with T4, in the treatment of hypothyroidism. (18)

During 1999 – 2002 a series of studies conducted by Dr Bunevicius and Dr Prague were published in the New England Journal of Medicine (19) describing the effects of combined therapy with Thyroxine (T4) and Triiododthyronie (T3) compared with Thyroxine (T4) treatment alone.

Using a combination in the ratio of 4:1 (T4- 50 mcg and T3- 12,5 mcg) patients using combined therapy reported marked improvement in mood, energy and concentration.

In a 2000 study by the same researchers, combined therapy resulted in improved cognition and mood in a group of hypothyroid women.(20)

Contradictory findings were reported by researchers in a small study of 46 patients with Hashimoto’s disease, who concluded that no benefits were evident from combined therapy, and that “T4 alone should remain the standard treatment for hypothyroidism”. (21)

In a 2006 study reported in the Journal of Endocrinol Metabolism researchers found that many patients do indeed experience improvement in mood and concentration and have a positive response to either T3 alone, or T3 and T4 in combination therapy. (22)

The question as to whether a patient with normal range TSH and raised thyroid antibodies should be treated was answered by German researchers who showed a significant decrease in thyroid antibody level after a year of treatment with thyroxine replacement,  concluding that preventative treatment of Hashimoto’s disease with hormone treatment could contain the progression of the disease and prevent the development of hypothyroidism. (23)

It is likely that dosages and combinations may need to be varied to establish the appropriate effective formulae for individual patients, and that a “one size fits all “ approach is not likely to yield the required response in every patient.

In the 2009 European Journal of Endocrinology, Wiersinger concluded that there was a strong case for further randomized controlled trials (RCTs) comparing L-T4 monotherapy with L-T4/L-T3 combination replacement therapy.

I have found that varying the dosages of T4 and T3, in combination, is the best approach until the patient reports improvement in symptoms.

I have on one occasion found a patient who could not tolerate T3 and preferred a low dose of T4, but in most cases a combination of T4/T3 in a ratio of 4:1 is effective.

A small study reported that a ratio of 3:1 might be effective. (24)

 

DESSICATED THYROID HORMONE:

Many researchers report that hypothyroid patients experience improvement when given dessicated thyroid hormone of porcine origin which provides a ratio of 4:1 of T4 /T3.

ARMOUR is a popular choice for this purpose, and many patients will report a marked improvement in symptoms when ARMOUR is substituted for ELTROXIN.

A grain of ARMOUR (60 MG) contains  36 mcg T4 and 9mcg T3, and therapy is usually commenced at a half grain to one grain in a divided daily dosage.

Studies have shown that L-Thyroxine (T4) is better absorbed 4 hours after a meal, rather than 30 minutes after a meal (25) while another study found that treatment 60 minutes before breakfast on an empty stomach was better than within 2 hours of supper. (26)

The same requirements are recommended for replacement therapy with Armour, or with any of the several available dessicated thyroid hormones which, unlike Eltroxin, are non-synthetic.

Dose adjustments are guided by serum TSH determinations 4 to 8 weeks after initiation of therapy, together with reports of well being, and dosage adjustments or changes in therapy made accordingly, with patient instructions to be consistent and compliant.

 

COMMON DRUG INTERFERENCES WITH ABSORPTION:

 

Certain drugs may interfere with ingestion and absorption of thyroid medication.

The following drugs are implicated when used concomitantly with thyroid medication :

Protein Pump Inhibitors (PPI) used for gastro-oesophageal reflux, bisphosphonates given for osteoporosis prevention, multivitamins containing calcium carbonate, ferrous sulphate,  calcium salts, H2 receptor Antagonists.

Ciprofloxacin, amioderone, sulfonylureas, Lithium are commonly prescribed drugs that interfere with thyroid medication absorption, and conditions like malabsorption syndrome, coeliac disease and biliary cirrhosis..

Metformin and Glucocorticoids may decrease TSH levels.

Any ingested food may impair absorption, and especially high fibre diets, grapefruit, expresso coffee and soy products.

Iodine, or kelp containing dietary supplements affect iodine uptake by the thyroid gland, as do a large range of environmental toxins, including chlorine.

Kelp supplements may contain 150 – 250 mcg of iodine per capsule, whereas the required daily intake od iodine is about 150mcg for non pregnant adults, and an excess intake may significantly increase TSH.  (27)

( I had a patient who took kelp in addition to Armour causing his TSH to increase to a high level of 140, while T3 and T4 remained within normal limits)

In pregnancy, thyroid hormone requirements are increased, producing a low normal TSH which generally reverts back to baseline after delivery.

Aging patients and those with weight loss require lower doses of thyroid hormone because of decreased lean body mass.

 

SELENIUM:

Many patients with hypothyroid disease take selenium as a supporting dietary supplement. Is there good evidence for its use ?

In a well designed European study involving 2143 euthyroid females, 200 mcg of selenium was associated with a reduction in autoimmune thyroid disease, post partum thyroiditis and hypothyroidism, (28) while another UK trial in 2008 did not show such benefit. (29)

Supplementing with Selenium in addition to thyroxine therapy in patients with Hashimoto’s thyroiditis produced a reduction of anti TPO antibody titres and elevation of mood in a 2011 study, but the researches claim that evidence does not support its use as a sole therapy in hypothyroidism. (30)

SCREENING FOR HYPOTHYROIDISM :

 

There is no universal agreement amongst Thyroid expert panels regarding screening protocols.

The AACC recommends routine TSH measurements in older patients, especially women.

The American Academy of Family Physicians recommends routine screening in asymptomatic patients  older than 60 years, while the American College of Physicians recommends an age of older than 50 years in females.

By contrast, the Royal College of Physicians of London do not recommend routine screening for thyroid disease in adults.

While there is currently no consensus about population screening for hypothyroidism, clinicians need to be mindful of those patients at risk, and of those who present with any, or all, of the wide array of symptoms which may be an expression  of subclinical or overt thyroid dysfunction.

Dr. Neville Wilson.

The Leinster Clinic,

Ireland.

www.drnevillewilson.com

 

REFERENCES:

 

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  17. Thyroid 2001 Mar; 11 (3); 249-55.
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  20. Int J of Neuropsychopharmacology 2000, June 3 (2): 167-174, Bunevicious R.
  21. J Clin Endocrinol Metab 2003, 88(10), 4543-50, Walsh J P et al.
  22. J Clin Endocrinol Metab 2006, 91:2592-2599, Grozinski- Glasberg, S.
  23. Thyroid 2001 Mar, 11(3): 249-55, Padberg S.
  24.  Clin Endocrinol (Oxf) 72;709-715, Celi P S.
  25. Intern Med 2000; 170: 19996, 2003, Bolk, N.
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  29. Am J Clin Nutr 2008; 87:370-378, Raymon M P.
  30. NEJM 2011; 364:1820-1931.

 

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