SUGGESTIONS
FOR AN
APPROACH
TO THE
MANAGEMENT
OF THYROID
DEFICIENCY
by Dr
Barry J Durrant-Peatfield
M.B.,
B.S., LR.C.P., M.RCS.
Approved
Civil Aviation Medical Examiner
The clinical syndrome of thyroid deficiency
is very much more common than is generally realized; Barnes, in several
publications, drew attention to this in the last two decades, as has the
present writer more recently. One reason for this, is a tendency to think of
hypothyroidism and myxoedema as one of the same thing, when this is quite
wrong. Myxoedema, as doctors were taught in medical school, is the end result
of a progressive disease process resulting in more or less total absence of thyroid
hormone; whose symptoms and signs are no doubt perfectly familiar. But this
state of deficiency has to start somewhere, winding down over a variable period
to the terminal state of myxoedema. Symptoms and signs will naturally vary
according to the extent of the level of deficiency reached. Clearly, a 10% loss
may have little to show for it; whereas a 25% loss may have several very
definite symptoms and signs; and a 40% loss even more so. Furthermore, patients
show very individual response to any given level of dysfunction; while one may
complain of excessive fatigue and weight gain, another may be more troubled by
depression and menstrual problems.
That the diagnosis is all too frequently
missed, is an inevitable result of
this fundamental misunderstanding, and is commonly the result of an
incomplete clinical appraisal in favor of the standard thyroid function tests.
These tests are the real problem in diagnostic failure since there are
inherent problems in interpreting blood levels of thyroxine and/or thyroid
stimulating hormone (TSH) when blood levels may differ widely from tissue blood
levels. Since the diagnosis may very properly, and easily, be made clinically, unreliable
blood levels should NOT take precedence over clinical judgment.
Equally unsatisfactory is the acceptance by
doctors and patients alike of poor response to thyroid replacement.
The present writer has been constantly
alarmed and dismayed by hypothyroid patients who for years, all too often, have
been obliged to accept a much less than satisfactory amelioration of their
illness, being taught to expect no more than some improvement. It is perfectly
possible that complete and long lasting remission should be obtained, and
neither doctor nor patient should accept anything less. Further, the response
should be monitored, not just by the doctor, but by the patients themselves.
Since there often is a dynamic situation, the patients should be educated and
taught to monitor themselves, making their own adjustments to dosage. In this
connection, frequent monitoring by blood tests may be quite misleading and
unhelpful. Surely it must be more satisfactory for the physician to ask the
patients how they feel; and guide the informed patient in establishing the
right dosage levels of replacement therapy.
One of the most taxing problems in diagnosis
is the multiplicity of symptoms, which need not be rehearsed here. It is all
too easy to pigeonhole the polysymptomatic patient as one of the heart sink
variety, and much too often, for example, inappropriately prescribe
anti-depressants. Thyroid deficiency may cause all sorts of major and minor
symptoms and their very frequency should raise an index of suspicion for
thyroid deficiency. The simple Basal Temperature Test, (see below), wrongly
derided by many authorities, can provide valuable clinical backup. Finally,
there is nothing wrong with a thoughtfully planned trial of treatment with an
informed and cooperative patient.
Hypothyroidism is due either to:
A. Deficiency of thyroid hormone production;
B. Failure of thyroid hormone to reach the
tissues.
Both may operate together in varying degrees.
Deficiency of hormone production is due to:
1. Environmental
toxins/deficiencies
2. Genetic
thyroid failure
3. Thyroid
failure secondary to pituitary insufficiency
4. Thyroid
surgery
5. Treatment
of previous over-activity
6. Major
surgery
7. Tonsillectomy
8. Major
trauma
9. Glandular
fever
Failure of hormone to reach the tissues
results from:
1. Receptor resistance, or failure
2. Dysfunction of T4-T3 conversion
3. Adrenal insufficiency
Dealing in turn with the therapeutic
management of these problems, we may turn first to (A)Thyroid hormone
production failure. This will be due to:
1. Environmental
toxins and deficiency
a)Toxins
-A number of chemical agents tend to interfere
with the manufacture of thyroid hormone. -Notables among these are:
-Poly chlorinated Biphenyls (Paints and wood
preservatives)
-Resorcinol (Millet)
-Phthylate Esters (Plastics)
-Thiouracil (Cabbages, Turnips, Cassava.)
-Anthracin
-Bromoform
-Cyanides (Barbiturates)
-Fluorides
-Thiocyanates (Smoking)
-Caffeine
-Aspirin
-Lithium
-Amiodarones
The elimination of these from the diet may be
desirable, if not always practical.
b)Nutritional
Deficiencies
(i) Iodine. Endemically absent in certain inland
areas e.g. (Peak District, UK)
(ii)Minerals,
in particular:
Selenium
Iron
Magnesium
Zinc
(iii)
Vitamins.
Vit
A - Conversion of Carotene to Vit A is inhibited by low thyroid states, and may
cause yellow pigmentation. It controls uptake of Iodine into the thyroid gland.
Deficiency also reduces TSH
Vit
B Riboflavin, Niacin, Pyridoxine play a role in thyroid hormone manufacture.
VitC
& VitE - Deficiency has been shown to cause hyperplasia at cellular level
in the thyroid. Clearly, part of the management of hypothyroidism requires some
dietary advice; the provision of iron and vitamins and other minerals is simple
and obvious.
2. Genetic
Thyroid Failure.
This will have become apparent soon after
birth; but may not be obvious cretinism. A sickly child, with poor weight gain,
frequent infections, lethargy, or oddly enough, hyperkinesia, and is a
candidate for genetic poor thyroid function. Thyroid replacement is mandatory
as early as possible.
3. Pituitary
Failure.
This is a more common problem than is
recognized, and apart from its specific clinical features, it may be a cause of
secondary hypothyroidism. The pituitary may have a genetic deficiency, when it
will have been probably recognized early. Not uncommon is Sheehan’s Syndrome,
resulting from major trauma from accidents or surgery. Adenomas of the
pituitary may cause pressure atrophy and / or abnormal hormone outputs. But the
pituitary may be involved in the general multiple deficiency state, and more
specifically in low thyroid states. This partial failure in hypothyroidism may
well be a cause of low TSH, so that a vicious spiral may slip into being. The
danger of a low or normal TSH in this situation being misinterpreted when
thyroid function tests are carried out is quite clear. In this situation,
correction of the thyroid state will bring benefits to the pituitary; and may
explain why some patients on thyroid replacement therapy begin to need lesser
doses as time passes. Correction of the thyroid deficiency is clearly
necessary; but adrenal insufficiency, considered in more detail later, as a
consequence of lowered ACTH output, may require cortisone and
Dehydroepiandrosterone (DHEA) in addition.
4. Thyroid
Surgery.
This is undertaken as a treatment for
pathology of the thyroid itself, or as a treatment for over-activity, discussed
below. Thyroid cysts, adenomas or carcinomas are necessarily removed by
surgery; and it is sometimes necessary to remove goiters where the size is
causing respiratory or oesophageal embarrassment. Hashimoto’s disease may come
into this category.
Replacement by thyroid hormone is an obvious
consequence.
5. Treatment
of previous thyroid over-activity, by surgery or I131 ablation.
Grave’s disease is widely treated, where
medical methods are deemed unsatisfactory, by partial thyroidectomy, or
Radioactive Iodine ablation. This is often unsatisfactory, since it is very
difficult to get it right. Either too much is removed or destroyed; (in which
case replacement therapy is a permanent necessity) or too little, and it may
have to be done again.
For such patients, replacement therapy is an
obvious no-option requirement.
6. Major
Surgery
Most particularly in this context comes
cholecystectomy and hysterectomy. Many doctors are aware that women may suffer
weight gain and loss of well being after this surgery; and this will be found
to be due to early loss of thyroid function. Replacement therapy is required.
7. Tonsillectomy.
Quite why in adults, tonsillectomy may result
in slow running down of thyroid function is not clear, but may be the result of
interruption of the blood supply. The present writer has noted a number of
cases of young adults misdiagnosed as M.E sufferers in this situation.
Replacement therapy provides a most satisfactory return to normal.
8. Major
Trauma
Major road traffic accidents, and surgical
accidents are known to precipitate thyroid and/or pituitary insufficiency. In
this category have been noted the major psychic trauma of certain life events.
Replacement indicated, with regard given to pituitary/adrenal function.
9. Glandular
Fever.
This is an often met with cause of failure of
the thyroid/adrenal axis. Evidence has pointed to pituitary damage causing
secondary hypothyroidism, but progressive loss of thyroid-producing cells
within the thyroid has been noted. In either event, replacement is required.
Discussion of failure of uptake at tissue level may be conveniently dealt with
in the section below on therapeutic options. Consideration should now be given
to the aims of replacement therapy.
The overall purpose is to restore
metabolism to normal, so as to eliminate all hypothyroid symptoms, and to
secure a sense of normal well being.
This implies that thyroid hormone levels in each and every cell are nominal;
that all the exchange reactions are taking place, as they should be. Sadly,
this ideal is at least as often as not, simply not reached, often by a long
way. Residual tiredness, lack of drive, or depression is frequently admitted
to. Menstrual dysfunction may remain a feature. Skin problems, fluid retention,
digestive problems, or arthralgia may remain in some degree. Many patients will
continue to complain of weight gain, or great difficulty in losing it, and
receive scant sympathy.
In this situation, the physician may estimate
thyroid function by Free Thyroxine Index (Free T4), or Thyroid Stimulating
Hormone (TSH) and be confronted by normal readings. It is the present
writer’s view that these estimations may be seriously flawed, and their value
fundamentally limited. The most popular, at the moment, is the TSH. This
may be much affected by poor pituitary function itself due to hypothyroidism;
it may be low or normal, rather than raised. The Free T4 test is subject to
several errors. Poor tissue uptake is probably the most telling. If the actual
use by the tissues is reduced by poor conversion of T4 to T3 (see below) and/or
receptor block, then high or normal Free T4 blood tests will result.
Haemoconcentration may be an additional factor.
There can be no substitute for proper
clinical appraisal. If the patient sounds and looks hypothyroid, then probably
that is the problem, irrespective of pathological testing.
The net result very much too often in
clinical practice is to under-dose. To provide full remission of symptoms, the
level in the tissues of thyroid hormone should be as high as possible, short of
too much. (The patient/doctor
monitoring to achieve this is described later). The situation is worsened by a
tightly held misapprehension in many quarters that there are grave risks
associated with overdose. These are largely apocryphal and must be
corrected. Probably most widely held, is that thyroid overdose is bad for the
heart. The risk is there if coronary artery insufficiency, previous M.l or
incipient failure already compromises the heart; the risk of over working a
damaged heart is obviously undesirable. The healthy heart will not be
damaged by minor degrees of overdose, whether by accident or design; and is
rarely much affected even by high levels of thyroid hormone, as in Grave’s
Disease.
Another anxiety is osteoporosis. There is a
risk in sustained overdose, and untreated hypothyroidism, but this is still not
certain. There is NO risk of osteoporosis in thyroid supplementation in
correct, physiological doses obviously; and in any inadvertent minor overdose is
rapidly detected by monitoring, and therefore of no consequence either.
Suppression of the thyroid gland as a result
of treatment is another frequently expressed anxiety. There is a sensitive
negative feedback operating through the hypothalamus and the pituitary Overdose
will suppress the thyroid; but this will come back to normal at once when the
dose is adjusted. Not treating a patient with an under-active thyroid for
tear of promoting further depression is quite unrealistic.
Vague fears that thyroid is like
"speed"; that any deliberate or accidental overrunning of the
metabolism will result in early "burn out"; have been expressed. All
that can be said is that is simply not true.
The correct management of thyroid replacement
requires a flexible approach; full explanation to the patient, and monitoring, relying
as much on the patient’s assessment as the physician’s own clinical
impression. One may often be obliged to deal with partial response to
replacement therapy, with failure to respond to an increase of dose; and more
wrongly, some symptoms of overdose on small levels of treatment. These will
include raised pulse rate, tremor, breathlessness, headaches. Sometimes an
encouraging response levels off and drops back.
To understand what is happening, it should be
clear that five matters have to be considered in planning replacement
therapy:
1. Dose
2. Vehicle
3. Conversion T4 - T3
4. Receptor resistance or deficiency
5. Adrenal insufficiency
1. Dose.
This has to be infinitely variable. It starts low and will be increased
progressively and incrementally, until full response is obtained. Neither
doctor nor patient should be satisfied with 60% response, or 80%. 100% is the
target. The patient will be asked to monitor her response to treatment.
This is satisfactorily done by three simple exercises.
a. Basal
Temperature, this is the temperature (10 mins axillary, or 3 mins in mouth)
immediately on waking. It is low in hypo-metabolic states, but will rise,
albeit slowly, in response to treatment, (as reported elsewhere this is
valuable diagnostically). A sudden rise may indicate, all things being equal,
the start of overdose.
b. Basal Pulse. This
may be taken at the same time as temperature; overdose will result in a rise of
the resting pulse. 80 bpm will usually signify overdose.
c. "Feel good
factor". It is possible to ask the patient to make a subjective
assessment, say, one out of ten, on the same days as temperature or pulse.
Since improvement in thyroid replacement may be quite slow, placebo effect does
not occur; if the patient feels better, then she is better.
Considerations will be given to actual dosage
shortly.
2. Vehicle.
There are three options to choose from.
a.
Thyroxin (T4)
b.
Tertroxin (T3)
c.
Dried, natural thyroid
U.S.P
a. In this country (Great Britain), Thyroxin
(marketed usually as Eitroxin—Synthroid in the US), is almost invariably used.
Of the naturally occurring thyroid hormones it is the most plentiful. The
thyroid hormone in the natural state is made up of around 80% Thyroxine (T4),
15% Triiodothyronine (Tertroxin T3—Cytomel in the US), and 5% Diiodothyronine
(T2),Mono idothyronine (T1), and Thyronine (T0).
Thyroxine has a
half-life of 8 days and works fairly well for the more simple, uncomplicated,
early, not too severe, hypothyroid patient. But note should be made that this
is not how thyroid hormone is naturally produced. There is a body of opinion,
sympathetically supported by the writer, that if natural thyroid is not to be
used, then at least T4 should be combined with T3 for a more satisfactory and
more logical replacement.
b. Triiodothyronine – (T3) Tertroxin or
Cytomel. This is quite considerably more potent than T4, four or five times so,
but unlike T4, the half life of T3 is about 8 hours.
c. Dried Natural Thyroid. Used from about
1900, desiccated thyroid fell into disfavour in Great Britain and availability
ceased in 1985. The synthetic Thyroxine (T4) was considered to be a better,
purer preparation. Though, of course, it is purer in that it does not
contain the other thyronines. However, this may be its weakness and
ignores the fact that thyroid replacement need not be exact. The amount
required varies from day to day, even hourly, and this dynamic variation may be
compensated for by the patient’s own thyroid - which although deficient, may
still be taking some of the load. Natural thyroid is widely used in USA, as
Natural Thyroid U.S.P., but in the UK has to be specifically imported. It
almost invariably works better than the synthetic T4, and is generally preferred
by the patient. About half of the patients in the writer’s practice are
maintained on this preparation. (obtained from Gold Line Laboratories, Fort
Lauderdale; or Armour thyroid, from The Barnes Foundation, Trumbull,
Connecticut).
3. Conversion.
Thyroxine (T4) has a low biologic activity and is transported linked to a
binding globulin in a non-active state. The removal of one of the four Iodine
atoms from the Thyronine molecule converts it to the biologically most active
Triiodothyronine (T3) - available as Tertroxin (Cytomel in the US). This is
achieved by the (largely liver produced), 5’deiodinase enzyme. In this form, it
will be passed, via receptors, into the cell, where passage of protein and
sugars across cell membranes is encouraged, and mitochrondrial activity
stimulated. It is now clear that prolonged and/or severe hypothyroidism may be
associated with partial failure of the 5’deiodinase enzyme. Although suspected,
this situation may be diagnosed in default when failure of response in thyroid
replacement occurs. The effect of Thyroxine (T4) in this situation is to
cause an overload of unused T4 due to conversion failure. This will cause some
symptoms of thyroid excess, high pulse, tremor, headache for example, while
the hypothyroid symptoms remain (It is of remark that on occasions, high T4
levels in this situation have resulted in inappropriate hypothyroid medication,
or thyroid ablation). Thyroid function tests will show high Free T4 and low
TSH; resulting in thyroid supplementation actually being withdrawn by the
physician.
Management, where this problem is believed to be present, consists
in discontinuing some or all T4 and substituting with T3, preferably in
divided doses. Since poor conversion may be associated with a raised sex
hormone binding globulin (SHBG) and high levels of exogenous oestrogen,
re-appraisal of any HRT may need to be considered. Ensuring correct levels of
vitamins A & B, Iron and Magnesium (as above), is also mandatory.
4. Receptor
resistance or deficiency:
Resistance to the passage of T3 via the receptors has been seen
in a number of cases. Why this occurs is not clear, but long periods of thyroid
dysfunction are associated. The replacement dose of the chosen thyroid
hormone has to be much larger than usual, which may cause some heart
searching. Deficiency results from a protracted low
thyroid state; prolonged low levels de-sensitizes the receptors. This will
improve with time, and treatment of any Adrenal insufficiency present.
5. Adrenal Insufficiency
This might be more properly described as low
adrenal reserve. Since hypothyroidism adversely affects every cell, every
tissue, and every gland in the body it is clear that the endocrine system as a
whole will be also similarly affected. The adrenals will be subject firstly to
lowered efficiency resulting from a lowered vitality primary to hypothyroidism,
and secondarily, to reduced ACTH stimulation from the pituitary. As a result,
in general, patients with a protracted and/or severe hypothyroid state will
have some degree of adrenal insufficiency. A significant level of this
will be suspected in these situations:
a. Longstanding and severe hypothyroidism.
b.
Episodes of
extreme exhaustion, or collapse.
c.
Bad response to
minor illness.
d.
Multiple
allergies.
e.
Digestive
problems – alternate diarrhea and constipation
f.
Flatulence
g.
Weight loss
h.
Increasing
arthralgia (fibromyalgia) and morning stiffness.
i.
Pallor, yellow
pigmentation (due to poorly metabolized carotene)
j.
Fainting,
dizziness
These patients often present with dark rings
under their eyes, looking quite ill. Blood pressure is low, with a positive
Raglan’s sign. (Pressure fails to rise on standing). These symptoms and signs,
it will be appreciated, are those of the early phases of Addison’s Disease.
A single estimation of blood Cortisol is
usually unhelpful, but De-hydroepiandrosterone sulphate (DHEA), the main
hormone output from the adrenals, will be found to be low. Depressed levels in
the endocrine system as a whole are likely to be found. The low adrenal reserve
means patients are more or less well, until challenged by the stress of illness
or life events--even the thyroid replacement therapy itself initially. And this
partial failure will affect adversely T4-T3 conversion and the integrity of the
thyroid receptors.
It is essential to manage this insufficiency
where present, or where suspected. Remarkably, patients with symptoms, signs
and blood pathology of low thyroid, may improve completely on management and
correction of the adrenal problems alone; as conversion and receptor efficiency
improves, the thyroid hormone circulating - partly unused - is brought
into play.
Adrenal insufficiency is dealt with by the
provision of the two hormones most likely to be lacking; Cortisonehydrocortisone,
and DHEA. (as pointed out above, low DHEA may be used to infer low cortisone
output). The treatment therefore, is the exhibition of, ideally,
Hydrocortisone. This should be given in divided doses initially of 5mg qds;
after a week, 10 mg qds may be used. This remains a physiological dose, not
challenging or suppressing the adrenal function, but supplementing it. In these
doses all of the usual anxieties associated with
cortisone do not apply, since restoration of
normality is being aimed at.
This may need to be explained to patients
long subject to media-induced fears of the horrors of corticosteroids (Their
physicians may share these anxieties, unnecessarily). Dr McCormack Jeffries’
papers on the subject are most worthy of study. DHEA has reached prominence in
recent times as a hormone of multiple, and magic properties. Certain it is that
the adrenals secrete more DHEA than anything else, and the amount is inversely
proportional to age. It is metabolized to oestrogen and/or testosterone, but
also has been shown to play a role in reducing obesity; in reducing
atherosclerosis and cholesterol; it inhibits the glucose -6-dehydrogenase
enzyme in cancer; it improves immune response, and, possibly, acts as a neural
facilitator. In physiological doses, there seems to be no problem in its
long-term use. If levels are demonstrably low, it is reasonable to provide
replacement therapy.
Treatment Protocol
1. General
consideration. Correction of Nutritional deficiencies, and elimination of
environmental challenges and toxins, has been noted above.
2. Simple,
early hypothyroidism. Readily available tablets of Levothyroxine
50mg may be used. Initial dose is low (in the elderly as low as 25mg daily) and
will usually start at 50mg daily. This may be increased 25mg daily every two or
three weeks. The ceiling is reached at the judgement of the physician with
feedback from the patient. It is unusual to go higher than 300mg.
3. Moderate
hypothyroidism. If the synthetic products are to be used, many
patients will benefit if, when a dose of 100mg or more levothyroxine is used,
Tertroxin (T3) is added. 10mg for each 100mg of T4 is to be preferred. The dose
may be increased incrementally at the physician (and patient’s) discretion.
If natural thyroid is to be used, a start may
be made with 1/2 grain (30 mg). (Commensurate with its 100 years of use by the
medical profession, natural thyroid is still measured in grains). Dosage is
increased by 1/2 gr. every two weeks; usually by six weeks the dose will level
off. Improvement on any given dose continues for weeks and weeks, and the
temptation, scenting victory, to increase the dose too soon, should be
resisted. (One grain equivalent 60mg of natural thyroid is equivalent to 38mg
T4 and 9mg T3). The definitive dose may remain unchanged for months or years,
but the patients should be allowed to make small adjustments themselves,
depending on activity, ambient temperature, for example.
4. Severe
hypothyroidism. As indicated above, simple replacement is unlikely to
be sufficient. Receptor block and adrenal insufficiency require adrenal
support; preferably initiated a week before thyroid supplementation is started.
A satisfactory protocol is to, start with 5mg hydrocortisone qds, and after a
week, double the dose. Alternatively Prednisolone 2.5 mg (or the enteric-coated
Deltacortril) may be used, doubling after a week. Clinical judgment, based on
the patient’s condition being normal - perhaps after about three months - will
enable the dose then to be halved, and then discontinued. It will be a matter
of clinical judgment and preference to use T4 and T3, or natural thyroid.
Some patients already on levothyroxine
(T4), but far from well, have to be considered separately. If the condition is
really quite severe, and increasing thyroxine makes matters worse, it should be
stopped for a short while and cortisone prescribed. The sudden improvement in thyroid uptake brought
about by the cortisone may actually result in overdose symptoms if exogenous
thyroid is continued. The treatment of choice is to restart thyroid hormone, using
instead T3, after a 7 day interim period; 10 mg for a few days, then 20 mg
and so on. After the improvement is seen to be full, and sustained,
natural thyroid can be reintroduced. The general improvement may,
secondarily, improve endogenous thyroid production, which can result in the
overall exogenous dose being reduced.
As regards DHEA, its significance in the
management of adrenal insufficiency is unsure, but where low levels have been
found, it seems proper and logical to restore them to normality. In women 25mg
daily, and men 50mg daily sometimes produces significant benefit. In this
practice, its use has always been an advantage.
The management of hypothyroidism in children
requires fine clinical judgement; but one quarter to one half of the adult dose
seems to be a satisfactory starting point. Reliance on blood testing should be
modified by clinical appraisal of the child and his parents’ observations. The
diagnosis is often missed in children; and should be considered in any child
often ill. The basal temperature test may prove a helpful pointer.
Thyroid insufficiency may have a number of
different causes and its symptoms may masquerade as a number of different
illnesses. It should always be considered in patients with prolonged ill
health, and the diagnosis rely on history and examination. The reliance of
the profession on the pathological tests in favor of thoughtful appraisal is to
be deplored. The treatment is inexpensive and low tech, requiring a few simple
guidelines and a listening approach by the physician. Rarely is
consultant advice necessary; the family physician is well able to initiate and
monitor the treatment even in quite severe cases. The rewards are invariable;
with no fuss, and with delight, the patients always get better. This common
condition is one of few where simple measures can transform patients’ lives.
REFERENCES
1. The
Unsuspected Illness. Barnes. Harper and Row. 1976
2. Jackson.
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And Environmental Medicine. 6: 4: Dec 1996
4. ORD
W.M, On Myxoedema, a term proposed to be applied to an essential condition in
the critinoid infection observed in middle aged women. Transactions Of The
Medical - Chirurgical Society Of London 57:6(~611877
5. E.
Hertzogue. Treatment Of Myxoedema International Clinic Week. New York 4:
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6. The
Fallacy Of Thyroid Function Tests. The Riddle Of Heart Attacks. Barnes &
Barnes 1976. ROBINSON PRESS. ISSN 0-913730-27-0
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Differences in The Pituitary-Thyroid Axis Influence The Interpretation Of
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8. 8. Staub
et aI. Spectrum Of SubClinical And Overt Hypothyroidism. American Journal Of
Medicine 92: June 1992 pp 631
9. 9. Barnes.
Temperature v Basal Metabolism. Journal Of American Medical Association.
119:1072,1942
10. 10. Klause
Wenzel. Osteoporosis. Lancet 340 15. 8. 92 pp 435-6
11. 11. Franhyn
et al. Long-term Thyroxine treatment and bone mineral density. Lancet 340
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12. 12. Jeffries.
W.M. Safe Uses Of Cortisone. Charles C. Thomas. 1981
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14. Barnes.
Etiology And Treatment Of Lowered Resistance To U.R.I.s Federation Proceedings
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