Thyroid History
diagnosing
thyroid deficiency diagnosing thyroid deficiency updated
with: emotional and behavioral problems updated
with: reproductive problems updated
with: research into thyroid updated with:
treating thyroid deficiency updated
with:
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The all too
common misdiagnosis of hypothyroidism is the result of poor clinical appraisal
and undue reliance on flawed blood tests. The condition is simply and
satisfactorily treated by replacement therapy and a plea is made for greater
awareness among clinicians.
....
HYPOTHYROIDISM: THE UNSUSPECTED
ILLNESS
First, overactivity of the thyroid,
properly called hyperthyroidism or Grave's disease. This is much less common
than underactivity and its incidence is largely unchanged at present.
....
Barnes [6] estimated that up to one-third of people approaching
mid-life could be affected, though not all require treatment. The term
'myxoedema' should probably be reserved for those patients with little or no
thyroid activity. Hypothyroidism may occur in any degree, from a few per cent
down on nominal to true myxoedema. Probably anything more than a 15% loss will
produce symptoms, which will vary widely from patient to patient leading to
diagnostic confusion, which regrettably leads to a diagnosis being missed more
often than it is made.
The causes of hypothyroidism may be summarized as
follows:
(1) primary or secondary failure of hormone production;
(2)
receptor uptake deficiency;
(3) receptor resistance;
(4) conversion
failure of T4 to T3.
Failure of Thyroid Hormone Production
This may be conveniently classified into the following:
(1)
iodine deficiency;
(2) genetic;
(3) secondary to antibody damage;
(4) pituitary failure (i.e. failure of TSH production), secondary to
antibody damage;
(5) environmental toxins or insufficiencies;
(6)
surgery, i.e. a major operation--hysterectomy, cholecystectomy or tonsillectomy
(damage to blood supply);
(7) major trauma;
(8) infectious mononucleosis
[7];
(9) treatment of previous thyroid overactivity.
Receptor
Uptake Deficiency
This may be primary, owing to failure at the site
of the portal of entry into the cell, or secondary, due to a lowered metabolic
activity at the receptor site, resulting from long exposure to hypothyroidism.
Receptor Resistance
Less often seen, this may prove a
puzzling diagnostic problem, since all thyroid levels may be normal, yet the
symptoms are perfectly clear. It may be associated with partial adrenal
insufficiency.
Conversion Failure of T4 to T3
The
5'-diiodase enzyme system may be damaged (often as the result of prolonged
hypothyroidism) so that, with normal levels of T4, the T3 levels are low. This
is again seen in adrenal insufficiency and other conditions as in iodine, iron
and selenium deficiency.
SYMPTOMS AND SIGNS OF HYPOTHYROIDISM
....
DIAGNOSIS
This should be a clinical one and
should already be clear to the clinician. Further useful evidence is the basal
body temperature, first described by Broda Barnes [6, 12].
....
In many
cases, a careful history, physical examination and the basal body temperature
should be quite enough to establish the diagnosis.
Clinicians rely
unreasonably on the blood pathology, estimating the serum T4, the THUT, the free
T3 and TSH. The reference ranges are impossibly too broad [13] and a number of
factors may vitiate the results. A reduced blood volume concentrates the blood
levels, there is slow clearance from the blood and thyroid hormone varies in a
dynamic way. Receptor failure may mean that the blood level bears little
relation to the intracellular T[sub 3]. For these and other reasons the blood
chemistry must be used with great care and not used only diagnostically. Undue
reliance on the chemistry has meant that, in the present writer's experience, in
nine cases out of ten, where the symptoms and signs are perfectly clear, the
diagnosis is missed. This is regrettable and sad, since hypothyroidism is so
easily and successfully treated and the main purpose of this paper is to draw
clinicians' attention to this common and unfortunate diagnostic omission. If the
history, examination and basal body temperature add up, the diagnosis may be
properly and successfully made. A trial of treatment will soon confirm the
diagnosis.
TREATMENT
....
In its
simplest classical form, replacement therapy employs 50 mug thyroxine tablets.
Treatment may be initiated by the use of 25-50 mug daily. This dose, over a
period of 2 or 3 months, may be slowly increased every 2, 3 or 4 weeks according
to response. It is most important to realize that the response is slow and
requires 2 or 3 weeks to evaluate.
....
Replacement is for life, albeit
with dosage variations. It can be discontinued at any time, of course; the
improvement will then slowly wear off over weeks and provide any further
conviction the clinician or patient needs.
While this simple management is
satisfactory for simple, uncomplicated hypothyroidism, of not too long duration,
many patients will not fully respond or, worse, report unpleasant palpitations
or flushes or headaches, sometimes within days, thus casting doubt on the
diagnosis. It is of great importance that the reason these problems occur should
now be considered. First, a poor response may simply be due to insufficiency in
the dose. If the dosage regime outlined above is adhered to, there should be a
positive response within 4 weeks. If not, clearly there is a failure of uptake
and/or utilization. Similarly, apparently toxic symptoms may be the result of an
initial overdose, but may equally well be due to the above, causing an effective
overdose owing to non-utilization. Assuming the vitamin, mineral and trace
element levels are acceptable, the problem is due to either receptor deficiency,
adrenal insufficiency or conversion deficiency of T4 to T3 by a weak 5'diiodase
enzyme,
....
A low adrenal reserve is a likely problem with marked and
long-standing hypothyroidism and the poor response or toxic symptoms may be
completely prevented by the use of a low, physiological dose of hydrocortisone [
17]. A dose of 5 mg of hydrocortone qds is usually sufficient. However, 2.5-5 mg
of prednisolone, or deltacortril, daily is often a preferred alternative. This
should be continued for 2 months or so and then stopped, since the general
improvement the thyroid hormone will have provided will normalize the adrenal
function and supplementary glucocorticoid is not then required. It is not
usually necessary to stage the reduction; at most halve the dose for a week,
then stop. This regime will provide a speedy, safe and smooth response to
thyroid hormone and should be used whenever a poor adrenal reserve is suspected.
A low blood pressure--which does not rise on the patient standing--a history of
collapses and prostration and arthralgia should raise suspicion, and prolonged
undiagnosed hypothyroidism will most frequently be paralleled by adrenal
insufficiency. The most satisfactory regime is to initiate glucocorticoid for a
week prior to the use of thyroid hormone; there may be a general improvement at
once since receptor uptake may rapidly be increased. If, in spite of these
precautions, problems of response are still worrying, T4 to T3 conversion
deficiency may be suspected. Five or ten per cent of cases may suffer this
problem.
....
The thyroid produces two thyroid hormones, T4 and T3 in a
5:1 ratio, but a third is suspected [18]. Since replacement should logically be
as close to the natural as possible, there is a strong case for the use of T4
and T3 in combination. While most authorities consider this to be an unnecessary
complication, it is a rational approach and consideration should be given to
it;
,,,,
Two further matters require attention. One is the fear of
precipitating cardiovascular collapse, which worries many clinicians. It cannot
be too strongly emphasized that the risk to the healthy heart, using the correct
dosage regimes outlined above, is non-existent. It is overworking a heart
damaged by disease and coronary artery insufficiencies or in failure that
problems arise.
....
The detection and treatment of hypothyroidism in
children is desperately important but sadly often missed. Cretinism is rare and
well recognized, but lesser degrees of hypothyroidism may blight a life if
untreated. The child may be sleepy, with an overweight tendency and may develop
slowly and below its percentile. Often, however, the child may be of poor
stature, with a lumbar lordosis and protuberant belly, underweight and sickly,
with a tendency to acquire any infection that is going and, surprisingly,
hyperkinetic.
....
Hypothyroidism i.n women is of special importance and
some elaboration is necessary. The first symptoms may occur at the menarche;
menses may occur unusually early--age 10 or 11 years--or unusually late--16 or
17 years. They may be irregular and unusually heavy or light, often with more
dysmenorrhoea and clots than is usual. As the years pass, these symptoms may
worsen and severe PMT is frequently found [26]. Fertility is downgraded and
pregnancies may be associated with all sorts of problems, including inexplicable
miscarriages. The production of extra T3 by the foetus which may occur results
in unusually large babies; if diabetes of pregnancy can be excluded, a birth
weight over 8 lb 8 oz (4 kg) should raise suspicion.
....
The diagnosis
should be essentially clinical and a trial of treatment instituted. Thoughtful
management of the trial eliminates any risk of inappropriate treatment and in
the writer's view is an entirely acceptable method of confirming the diagnosis
without any risk to the patient. Many people suffer needlessly and have their
lives blighted by the failure to treat this common and easily diagnosable
illness.
[2] Ord W. On myxoedema. Trans Med Chiurg Soc 1878; 6061: 57.
[3] Murray GR. Notes on the treatment of myxoedema by hypodermic injection
of extract of thyroid gland of sheep. BMJ 1891; ii: 796.
[4] Murray GR. Life
history of first case of myxoedema treated by thyroid extract. BMJ 1920; ii:
359.
[5] Hertzog E. Treatment of myxoedema. Int Clin Week 1915; 14 April.
[6] Barnes B. The Unsuspected Illness. London: Harper & Row, 1976.
[7] Demitract et al. Evidence for impaired activation of hypothalamic axis
in chronic fatigue. J Clin Endocrin 1991; 73.
[8] Editorial. Puzzling cases
and low thyroid function. BMJ 1970.
[9] Whybrow PC, Prange AJ, Treadway CP.
Mental changes accompanying thyroid dysfunction. Arch Gen Psychiatr 1969; 20:
48-63.
[10] Furunculosis: aetiology & treatment. J Clin Endocrinol 1943;
3.
[11] Chaery WC. Tendon reflexes in myxoedema. JAMA 1924; 82: 2013-16.
[12] Barnes B. Basal temperature verses basal metabolism. JAMA 1942; 119:
1072.
[13] Barnes, Barnes. The Fallacy of Thyroid Function Tests. Riddle of
Heart Attacks. Robinson Press, 1976.
[14] Jeffries WM. Safe Uses of
Cortisone. Charles C. Thomas, 1981.
[15] Present status of ACTH, cortisone
and related steroids. New Engl J Med 1955; 253: 441.
[16] Jeffries WM.
Cortisol and Immunity. Medical Hypotheses. Longman, 1991.
[17] Jeffries WM.
Low dosage glucocorticoid therapy. Arch Int Med 1967; 119: 265.
[18] Barnes
B. Is there a third thyroid hormone? J IAPM 1982.
[19] Barnes B. Eighteen
year follow up on thyroid therapy in prophylaxis & treatment of coronary
heart disease. Fed Proc 1969; 28516.
[20] Buslenio PA et al. Pre clinical
hypothyroidism: a risk factor in coronary heart disease. Lancet 1971; 1: 203-4.
[21] Barnes B. Prophylaxis of ischaemic heart disease by thyroid therapy.
Lancet 1958; 11: 149.
[22] Fishbeng. Atherosclerosis in thyroid deficiency.
JAMA 1924; 82: 463.
[23] Modesc, Danoski. Alterations in cholesterol and
lipoprotein in euthyroid adults. Circulation 1958; 18: 761.
[24] Barnes J.
Clin Exp Pharmacol Physiol 1975; 167 (suppl. 2): 170.
[25] Menof. New method
for control of hypertension. S Afr Med J 24: 172-80.
[26] Bradshaw et al.
Thyroid hypofunction in premenstrual syndrome. New Engl Med 1986; 315: 23.
2001 Serum Thyroglobulin and Urinary Iodine Concentration Are the
Most Appropriate Indicators of Iodine Status and Thyroid Function under
Conditions of Increasing Iodine Supply in Schoolchildren in Benin1 Tina van den Briel*, Clive E. West2, Joseph G.A.J. Hautvast*, Thomas Vulsma**, Jan J. M. de Vijlder** and Eric A. Ategbo Journal of Nutrition
2001:131, 2701-2706
*
Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen,
The Netherlands; Department of Gastroenterology, University Medical Center
Nijmegen, The Netherlands; **
Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The
Netherlands; and Department of Food and Nutrition, Faculty of Agriculture,
National University of Benin, Cotonou, Benin, West Africa
Abstract:
Iodine deficiency control programs have greatly
reduced iodine deficiency disorders worldwide. For monitoring changes in iodine
status,different indicators may be used. The aim of this study wasto evaluate
the suitability of indicators of iodine status and thyroid function,
thyroglobulin (Tg), thyroid-stimulating hormone(TSH) and free thyroxine (FT4) in
serum, thyroid volume and urinary iodine concentration, in iodine-deficient
schoolchildren under conditions of increasing iodine supply. The study was
established as a double-blind, placebo-controlled oral administration of a
single dose of iodized oil to schoolchildren (710 y old), living in an
iodine-deficient area of Benin, with an observation period of 10 mo. However,
34 mo after supplementation, iodized salt became available in the area. The
study population therefore comprised an iodized oilsupplemented group and a
nonsupplemented group, both of which had variable, uncontrolled intakes of
iodized salt during the last 6 mo of the study. Initial mean serum
concentrations of TSH and FT4 were within the normal range, whereas serum Tg
concentration, urinary iodine concentration and thyroid volume were indicative
of moderate-to-severe iodine deficiency. At the end of the study, all indicators
had improved significantly, except thyroid volume, which had decreased only in
the supplemented group. The supplemented group also still had significantly
lower serum Tg and higher urinary iodine concentrations than the nonsupplemented
group. Serum Tg and urinary iodine concentrations are the indicators most
influenced by a changing iodine supply. Current normal reference ranges of serum
concentrations of TSH and FT4 are too wide for detecting iodine deficiency in
this age group.
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1999 IF DEPRESSION TREATMENT ISN'T WORKING, DO A THYROID
EVALUATION . (cover story) Psychopharmacology Update, 1999:10, Issue 4, 1
The simply did better and felt better when we gave them some T3 in
place of some of the T4 -- Arthur J. Prange, Jr., M.D.
In a
double-blind study, investigators compared the effects of thyroxine alone with
thyroxine plus triiodothyronine in 33 hypothyroid patients.
....
Patients
had lower serum free and total thyroxine concentrations and higher total
triiodothyronine concentrations after treatment with thyroxine plus
triiodothyronine than after thyroxine treatment alone.
....
....
"A euthyroid person can adapt his
or her own endogenous secretion, and tolerate bigger doses of thyroid hormone,"
he adds. "If you're treating hypothyroidism, you start quite cautiously, because
you don't want to put somebody into adrenal insufficiency."
....
If
depressed patients don't respond to a one-month trial of antidepressant therapy,
Prange recommends that they be started on thyroid supplementation. Since about
two-thirds of patients will respond in a week or so to T3, that is preferable to
switching patients to a second antidepressant, he says.
Johnson says many
physicians use only the TSH test to determine if patients are hypothyroid.
"But in depressed patients with low thyroid hormone levels, the TSH may
still be on the low end," he explains. "Total levels of T3 and T4 also are very
unreliable clinically. Almost always, they'll be normal, [but] when you check
the free levels, they may actually be low. So you have to check the free levels
or you'll miss a lot of people with low hormone levels."
.... The
normal range for free T4 levels is about 0.7 to 1.9 mcg per ml; for free T3, the
normal range is about 2.3 to 4.0 mcg per ml. The normal range for free thyroid
levels is divided into four quarters, which are called quartiles. If the free T4
level is either low or in the bottom quartile of the normal range, he prefers to
use thyroxine first and then add triiodothyronine later if they don't show
improvement. If, however, the free T4 is in the second quartile or above, he
will initiate treatment with triiodothyronine only.
"I generally find that
most patients ultimately need both," Johnson says.
The doses he usually
finds helpful are between 5 mg to 25 mcg of triiodothyronine and between 50 mcg
and 250 mcg of thyroxine.
....
Cooke RG, Joffe RT, Levitt AJ:T3 augmentation of
antidepressant treatment in T4-replaced thyroid patients. Journal of Clinical
Psychiatry 1992; 53:16-18.
2000 The role of brain thyroid hormones in
the mechanisms of seasonal changes in mood and behavior Sher Rockville,
Maryland, USA Medical Hypotheses Vol. 55, No. 1, July 2000
Abstract: Many individuals experience seasonal changes in
mood andbehavior. Various theories have been suggested to explain the mechanisms
of these changes. However, the mechanisms of seasonal mood and behavioral
changes remain unclear. The author suggests that brain thyroid hormones may play
an important role in seasonal changes in mood and behavior. This suggestion is
based on the facts that seasonal changes in light and temperature may affect the
metabolism of brain thyroid hormones and that small alterations of the brain
thyroid economy, independent of peripheral changes in thyroid status, may
produce significant behavioral effects. The author further suggests that there
may be a fault in the thyroid metabolism in the brain in seasonal affective
disorder patients, and that fault cannot be identified by studying the
peripheral thyroid hormone metabolism. Seasonal mood and behavioral changes may
also be related to the interaction between thyroid hormones and different
neurotransmitter systems in the brain.
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1998 HUMAN REPRODUCTION AND IODINE DEFICIENCY: IS IT A
PROBLEM IN THE UK? Wynn, Margaret; Wynn, Arthur Journal of Nutritional &
Environmental Medicine, Mar98, Vol. 8 Issue 1, p53
Women suffer from
thyroid disorders between four and ten times as frequently as men of the same
age. This has been shown to be due to iodine deficiency causing damage to the
thyroid during pregnancy and is not true of women who have never been pregnant.
Iodine deficiency not only damages women but causes impairment of brain
development in their babies. These are the main reasons for the recent increase
in the World Health Organization (WHO) recommendation for an iodine intake to
200 mcg/day during pregnancy. Many British women have iodine intakes much below
this recommendation and indeed below 100 mcg/day. The WHO was, however, informed
by the British government that tile population at risk of iodine deficiency in
the UK was `zero'. The WHO recommendations for action ore discussed.
A paper in this journal by
Durrant-Peatfield [1] gave an interesting account of `thyroid dysfunction and
management' in clinical practice and suggested that hypothyroidism in particular
has a higher prevalence than is generally thought.
....
Pregnancy
demands higher thyroid hormone secretion and stresses the thyroid, which may be
permanently damaged if the iodine supply is inadequate. This discovery was one
reason why the WHO sponsored a conference in Brussels in 1992 under the title
`Iodine Deficiency in Europe: a Continuing Concern'. The proceedings have been
published [2].
....
Following the 1992 conference the WHO had further
meetings at regional and global levels and increased the recommended iodine
intake for pregnant women to 200 mcg/day [3]. The present review shows that
there are large numbers of women in Britain with iodine intakes below the
current WHO recommendations and. indeed, below the recommendations before the
present increase. Does this matter? If it does matter, what is to be done?
The WHO report emphasizes that iodine deficiency in
pregnant women may cause irreversible brain damage in the developing fetus [4]:
Infants and young children exposed to iodine deficiency may also suffer from
brain damage, psychomotor retardation and intellectual impairment. Thus IDD
include a broad spectrum of conditions that vary in severity ... iodine
deficiency also affects reproductive function, leading to increased rates of
abortion. still births, congenital anomalies, low birth weights and infant and
young child mortality (p. 2).
It is the effect of iodine deficiency in a
mother on the mental and psychiatric development of her children that has come
to be regarded during the last 15 years as of the greatest social importance,
exceeding any direct consequences of iodine deficiency in adults. European
countries are no longer troubled by extreme iodine deficiency resulting in
cretinism, but by lesser degrees of maternal iodine deficiency resulting in
losses in the mental ability of their children recorded at school age and
expressed as a loss in learning ability. The introduction to a paper by Connolly
and Pharoah [5. p. 317] (from the University of Sheffield and University of
Liverpool, respectively) discusses hearing loss, motor competence and cognitive
function. It states:
That iodine deficiency diseases present a spectrum of
developmental consequences which vary from the gross to those detected only by
careful and precise quantitative measures is of considerable significance
biologically and socially. The less severe manifestations may in fact be of
greater social significance because many more individuals are affected and put
at developmental risk.
....
Few clinical studies have been found on the
effects of paternal iodine deficiency oil children. A few studies on
experimental and farm animals have recently been reviewed 191. In male animals,
hypothyroidism is reported to reduce libido and sperm number, motility and
density, delay puberty onset and reduce the final testis size. final conception
rate and fertility.
Women report
more thyroid disorders than men. Data from the US National Health Interview
Survey 1992 are shown in Table 1 [10]. Statistics understate the prevalence of
thyroid disorders. particularly cases of a less serious character which are
often not diagnosed or reported. ....
in a minority of cases of thyroid
dysfunction following pregnancy, the thyroid has been shown not to return to
normal even several years post-partum. A study from the University of Wales
found that 23% of patients with post-partum thyroiditis were hypothyroid 3.5
years post-partum [141. A study from Sweden reported 31% long-term
hypothyroidism following post-partum thyroiditis [15].
Thyroid dysfunction
has been reported in women who have had a miscarriage [16]. Iodine deficiency
can, in fact, cause miscarriage. In women who are even mildly iodine deficient
the thyroid dysfunction may be aggravated by each successive pregnancy.
Permanent thyroid dysfunction can generally be treated successfully. but the
milder disorders in particular are often not treated. Depressed levels of
thyroid hormones reduce the body's capacity for protein synthesis and tissue
renewal and accelerate ageing [17]. Thyroid dysfunction should be diagnosed and
treated.
....
The UK chapter in the symposium [2] says nothing at
all under the heading `Conclusions' about the effect of iodine intake on
pregnancy outcome but says that: "There are no plans for any national regulation
of iodine supplementation. Attention has been drawn to the dangers of iodine
supplementation in susceptible individuals" (pp. 326-7),
Iodine
supplementation can aggravate thyrotoxicosis in individuals with defective
thyroid glands. The tenth edition of the American report Recommended Dietary
Allowances suggests that iodine intake only causes thyrotoxicosis in individuals
who have been exposed to years of iodine deficiency and who have, in some
measure. adapted to a low iodine intake [21]
.....
A statement in 1994 by
the WHO [22, pp. 6-7] entitled Iodine and Health concluded that:
Issues
relating to the safety of universal salt iodization have been carefully examined
by WHO ... The benefits to be derived from universal salt iodization ... and the
absence of significant adverse effects among others in the same areas who are
not iodine deficient, far outweigh any risk of excess intake for a small
minority.
The WHO [4] estimated the
number of people probably `at risk' of iodine deficiency in Europe at many
millions. The WHO [4] report lists the world's nations and their own estimates
of the size of populations `affected' and `at risk' from iodine deficiency
diseases. Thus, for example, the report shows the populations affected as being
5% in Belgium, 5% in France, 10% in Germany and 2.5% in The Netherlands. The UK
reported to WHO that: "Population affected 0. population at risk 0 ... No
national data ... it is generally considered that the iodine status of the
general population is adequate" (p. 39). The daily intake of women as recorded
by the Dietary and Nutritional Survey of British Adults in 1990 [23] is shown in
Table 2 and Fig. 2 [24].
How do these recorded intakes compare with the
recommendations? As can be seen from Table 2 and Fig. 2, a large percentage of
women in the UK have iodine intakes well below the allowances recommended by the
Department of Health [25]. Further, as evidenced in Table 4 and Fig. 2, the
iodine intake of many women in the UK is even further below the recommendations
of the WHO [3].
The main difference between Tables 3 and 4 is in the
recommendations for pregnancy and lactation. The UK Dietary Reference Values
report says: `Pregnancy--no increment' and `Lactation--no increment'. The WHO
recommends an extra 50 mcg/day of iodine during both pregnancy and lactation.
The WHO had previously recommended only an extra 25 mcg/day for pregnancy and
lactation in line with American recommendations, but the symposium on iodine
deficiency in Europe in 1993 recommended an increase in the supplements for
pregnancy and lactation to 50 mcg/day [2].
....
The monitoring of the iodine intake of mothers and
infants in Europe by periodic analysis of urinary iodine levels, and the
measurement of thyroid stimulating hormone (TSH) and other thyroid hormones T4
and T3 `to the extent feasible', are recommended in the symposium. It is also
recommended that the "mother's diet should be systematically supplemented with
iodine whenever necessary by vitamin/mineral tablets as prescribed by
physicians" [2, p. 478].
There are great
difficulties in these recommendations because the evidence shows that, to be
wholly effective, iodine deficiency has to be corrected before ovulation and
conception.
....
Animal experiments have shown that if iodine deficiency
begins during the period preceding mating, it causes a much more serious range
of congenital malformations than if it begins only a few days after mating [37].
Low T[sub 4] levels, which may be a consequence of iodine deficiency, can cause
mutations in males and females that may be inherited in their F[sub 1] offspring
and in the following F[sub 2] generation [38, 39].
The WHO
recommends that the iodization of salt should be introduced by legislation in
all countries which have not already done so, as already discussed. There have
now been three generations of experience of the iodization of salt, which has
been found not to be completely effective. The soundness of the WHO
recommendation is not questioned, but implementation leaves some people still
iodine deficient.
The fortification of salt is likely to prove increasingly
inadequate as the populations of Britain and other countries respond to the
advice that they are eating too much salt for the good of their health.
....
The World Bank, in its 1993 World Development Report, stated that the
fortification of foods was one of the most cost-effective public health
interventions. A decision to introduce iodine fortification in the UK needs to
he preceded by a study of the distribution of iodine deficiency. if it is
decided to enrich manufactured foods, a limited number of manufacturers who can
provide good population coverage have to be chosen and procedures have to be
agreed. Every programme must then be monitored. There are historical examples of
the recrudescence of iodine deficiency following the relaxation of monitoring
[44]. A programme to increase the intake of iodine in the UK should be under
statutory control.
Under 45 45-64 65-74 75
years
years years years and over
Male 3.3 11.4 18.2 9.1
Female 13.4
53.7 59.0 51.7
Source: [10, Table 58].
TABLE 2. Mean daily iodine intake (mcg), Great Britain,
1990
16-64 16-24 25-34 35-49 50-64 16-64
years
years years years years years
Median 226 146 158 172 171 163
Lower
2.5
percentile 99 61 53 75 67 63
Source: [23].
0-3 months (formula fed) 50
4-12
months 60
1-3 years 70
4-6 years 100
7- 10 years 110
11-14 years
130
15-18 years 140
Over 18 years 140
Pregnancy No
increment
Lactation No increment
Source: [25].
Age range or state (mcg/day)
0-12
months 50
1-6 years 90
7-12 years 120
12 years to (and through)
adulthood 150
Pregnancy 200
Lactation 200
[a] For virtually all
practical purposes, these allowances can
be regarded as serving the same
purpose as estimates of
Population minimum mean intakes sufficient to meet
normative
requirements.
Source:[3].
Food (mcg/day) intake (%)
Milk and milk
products 72 39
Cereal products 26 14
Total beverages 18 10
Fish 15
8
Confectionery, sugar and preserves 12 6
Meat and meat products 10
5
Egg and egg products 9 5
Potatoes 4 2
Fruit 4 2
Vegetables 3
2
Source: [24].
Fish (cod) 110 342
Eggs 53 87
Whole
milk 15 55
Bananas 8 20
Meat (beef) 6 8
Bread (white) 6 6
Potatoes
(old) 3 9
Cabbage 2 18
Pulses (peas) 2 6
Fruit (pears) 1
6
Source: [40].
FIG. 1. Thyroid of German and Swedish women, 1986. Source: [20].
Published by permission of the Society of the European Journal of
Endocrinology.
FIG. 2. Daily iodine intake of British women from
food, 1994 (n = 1110). Source: [24]. Published by permission of
HMSO.
REFERENCES
[2] Delange F, Dunn JT, Glinoer D. Iodine deficiency in
Europe: a continuing concern, Vol. 241. New York: Plenum Press, 1993.
[3]
WHO. Trace Elements in Human Nutrition and Health. Geneva: WHO, 1996.
[4]
WHO. Global Prevalence of Iodine Deficiency Disorders. Geneva: WHO, 1993.
[5] Connolly KJ, Pharoah POD. Iodine deficiency, maternal thyroxine levels
in pregnancy and developmental disorders in the children. In: DeLong GR, Robbins
J, Condliffe PG, eds. Iodine and the Brain. New York: Plenum Press, 1988;
317-31.
[6] Churchlll JA, Neff JW, Caldwell DF. Birthweight and
intelligence. Obstet Gynecol 1966; 28: 425-9.
[7] DeLong GR, Robbins J,
Condliffe PG, eds. Iodine and the brain. New York: Plenum Press, 1988.
[8]
Hetzel BS. The story of iodine deficiency. Oxford: Oxford University Press,
1989.
[9] Jannini EA, Ulisse S, D'Armiento M. Thyroid hormone and male
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AP, Parkes AB, et al. A long-term follow-up of postpartum thyroiditis. Clin
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page)
Editorial - Drummond Rennie, MD April 16, 1997
JAMA. 1997;277:1238-1243
Thyroid Storm
In this issue of THE
JOURNAL, we are publishing a report of work that started 9 years ago, was
concluded in December 1990, and the data from which were published in another
journal in July 1995. Given that we at JAMA like to keep up-to-date and
that we try never to republish what others have already put in print, the reader
might well ask what is going on. The story necessary to answer this question
provides a cautionary tale that illustrates the sharply differing views of
research taken by the university researcher and the company sponsoring that
research, if the company's product is at stake. At a time when an increasing
proportion of research funding is provided by private companies the story holds
lessons for both, as well as for university faculties, administrators,
regulatory agencies, and for physicians who prescribe on the basis of evidence.
In this Editorial, I shall be discussing events that took place at the
University of California, San Francisco (UCSF), which is where the West Coast
office of JAMA is situated. I should make it plain that until JAMA
became involved, I did not know, and had never had contact with, any of the
research workers involved.
Background
The issue of the
potency, reliability, and bioequivalence of levothyroxine preparations has
continued to raise controversy. Natural thyroid extracts were marketed before
the regulations of 1938 and so were exempted from amendments to the Food, Drug,
and Cosmetic Act requiring that drugs be proved safe and effective. Synthroid,
the first synthetic version, had come to dominate a $600 million a year market
that was essentially unregulated because the Food and Drug Administration (FDA)
had no approved standards for bioavailability and bioequivalence and no
mechanism to evaluate them, and there were no adequate well-controlled trials.
Such dominance was unusual, given that other competing formulations of
levothyroxine had been available for years, and it was greatly assisted by the
manufacturer's claims that other preparations were not bioequivalent.
In
1987, to establish that Synthroid was truly more effective than competing
preparations, Flint Laboratories, then the manufacturers of Synthroid,
approached Betty J. Dong, PharmD, at UCSF. This seemed a good choice because in
1986, Dong et al had published a letter showing that the levothyroxine content
of different thyroid products, 2 brand-name products and 7 generic, differed
widely. They noted that the 2 brand-name preparations, 1 of them Synthroid, were
the preparations of choice. Flint and Dong signed a lengthy protocol/contract to
finance comparative studies of the bioequivalence of Synthroid and 3 other
preparations, and both sides expected the study to show that Synthroid was
superior (letter from B. J. Dong to N. M. Kurtz, March 31, 1994). The contract
detailed the experimental design and analysis of the data. Representatives of
Flint, and after their takeover, Boots Pharmaceuticals Inc, made regular site
visits, about 3 a year, to satisfy themselves that the work was being done
properly. During these visits small problems were ironed out, but there was no
hint of any bigger cloud.
In January 1989, at a time when there was a move
to add a competitor's preparation to the Massachusetts formulary,[4] Boots, in
the first of their site visits, began asking for the preliminary results of a
parallel in vitro study in which tablets were compared, and because this would
have meant breaking the masking code and therefore invalidating that particular
study, Dong et al refused to comply. By the end of 1990, the major in vivo study
was finished, and Dong sent all the results to Boots: it was clear that all 4
preparations were bioequivalent.
Over the next 4 years, Boots waged an
energetic campaign to discredit the study and prevent publication of the drafts
Dong and her colleagues sent to them for comment, claiming that the study was
seriously flawed. Boots cited scores of purported deficiencies, including
failure to carry out procedures not called for in the protocol.
....
Boots had alleged numerous breaches of research ethics, but when
asked by UCSF to make specific allegations that UCSF could formally investigate,
Boots did not respond. Noting that all records and data had been open to Boots,
who had monitored the study closely, UCSF told Boots, in August 1994, that there
was no reason to suppress the manuscript and to do so would be an unprecedented
intrusion upon academic freedom (letter from P. Lurie and S. M. Wolfe to D. A.
Kessler, May 29, 1996). Later, they agreed to meet again with Boots, but
suggested that this time it should be in the presence of officials from the FDA.
That meeting never took place. Dong et al made numerous changes in their
manuscript to accommodate Boots, but finally decided they would publish.
....
What Are the Lessons?
For Researchers and
Faculty.Even if researchers have been approached by sponsors, investigators
should not assume that the sponsors will encourage publication of unfavorable
results and should never allow sponsors veto power. Dr Dong was naive, but
faculty members are the last line of defense against industry interference, and
she and her colleagues deserve credit for standing up for their academic rights.
....
For the FDA.Thyroid preparations were grandfathered in by
the 1938 Food, Drug, and Cosmetic Act, which required demonstration of safety,
and the 1962 amendment, which required that drugs be shown to be effective. As
is the case with other preparations of levothyroxine, Synthroid, introduced in
1958, could reasonably be regarded as a reformulation. The FDA has the authority
to designate important pre-1938 drugs that have been reformulated as "new" drugs
and require a New Drug Application (NDA).
....
A simpler and possibly
more fruitful approach to setting standards for both bioequivalance and clinical
interchangeability might be for scientific organizations with the best expertise
in this area, such as the American Association of Pharmaceutical Scientists, the
American Society for Clinical Pharmacology and Therapeutics, and the American
Thyroid Association, to establish guidelines by consensus, which they could then
publish for the benefit of all.
....
Is This Common?
The Synthroid case, where publication was delayed about 7 years, seems
an extreme case. However, in this issue of THE JOURNAL, we publish a paper from
Blumenthal et al on withholding of research results by researchers. These
authors found that almost 20% of 2100 life science faculty reported delay of
over 6 months in the publication of their research results.
....
if
"undesired results" are withheld by only about 5% of all researchers, the fears
induced by the increased part industry is playing in the funding of research are
not dispelled. And before we decide the danger is past, workers at
Carnegie-Mellon University reported that in their sample of university-industry
research centers, 35% of the signed agreements allowed the sponsor to delete
information from publication, 53% allowed publication to be delayed, and 30%
allowed both.
....
Rosenberg,sounding the alarm, makes the point that
secrecy in research is increasing and gives 4 examples from his personal
experience. He writes: "The goals of medical research are clear: to prevent
human suffering and premature death from disease.... Deliberately withholding
useful information ... is a violation of this principle." As I have pointed out
before, 25 a major problem in medicine is failure to publish the results of
studies that show no advantage to the intervention under study, so that
treatments tend to be based on biases in favor of the new. I take Chalmers'
position that it is unethical not to publish such negative results. The Olivieri
case, hinging as it does on the interpretation of data about the safety of a
therapy, shows that this is not just a theoretical position.
Rosenberg[24]
concludes, as do I, that scientists should never sign any agreements that give
their sponsors veto power over publication.
Marshall has recently described
the battle in genome research between those who wish to lock up results by
delaying publication and those, including sponsors both governmental and
commercial, who see a wider societal good in putting gene sequences promptly
into the public domain. Marshall notes that, for example, withholding DNA
sequence data on pathogens could cost human lives, but is "commonplace." It is
too early to see who will win, but unless the scientific community gives its
strong support and approval to sponsors who forbid secrecy, we will all suffer
the consequences.
Conclusion
We are proud to publish the
article by Dong and her colleagues. We believe it is good work, not merely
because it passed peer review by more than the usual number of experts, but
because it has also passed careful and prolonged scrutiny by the university in
response to widely disseminated allegations of scientific defects and ethical
violations. We are also confident in the work because of the university's
finding that none of the allegations had the slightest merit and because they
came from those who had most to gain if the work was discredited. Now that the
thyroid storm has passed, clinicians and third-party payers finally have the
information they need to best serve their patients.
....
References
1. Dong BJ, Hauck WW, Gambertoglio JG,
Gee L, White JR, Bubp JL, Greenspan FS. Bioequivalance of generic and brand-name
levothyroxine products in the treatment of hypothyroidism. JAMA.
1997;277:1205-1213.
2. Blumenthal D, Causino N, Campbell E, Louis KS.
Relationships between academic institutions and industry in the life sciences:
an industry survey. N Engl J Med. 1996;334:368-373.
3. Cooper DS.
Thyroid hormone treatment: new insights into an old therapy. JAMA.
1989;261:2694-2695.
4. King R. Bitter pill: how a drug company paid for
university study, then undermined it. Wall Street Journal. April 25,
1996:1.
5. Dong BJ, Young VR, Rapaport B. The nonequivalence of thyroid
products. Drug Intell Clin Pharm. 1986;20:77-78.
6. Benet LZ.
Morality play. Science. 1996;273:1782.
7. University of California
Contract and Grant Manual. 1-340 Guidelines on University-Industry
Relations, May 17, 1989.
8. University of California Contract and Grant
Manual. 11-110.
9. Kenyon G, Drake S. Statement regarding contract for
clinical trials. University of California, San Francisco, February 27, 1996.
Press release.
10. Mayor GH, Orlando T, Kurtz NM. Limitations of
levothyroxine bioequivalence evaluation: analysis of an attempted study. Am J
Ther. 1995;2:417-432.
11. Berg JA, Mayor GH. A study in normal human
volunteers to compare the rate and extent of levothyroxine absorption from
Synthroid and Levoxine. J Clin Pharmacol. 1992;32:1135-1140.
12.
Eckert C. Bioequivalence of levothyroxine preparations: industry sponsorship and
academic freedom. JAMA. 1997;277:1200.
13. Spigelman MK.
Bioequivalence of levothyroxine preparations for treatment of hypothyroidism.
JAMA. 1997;277:1199.
14. Dong BJ, Hauck WW, Gambertoglio JG, Gee L,
White JR, Bubp JL, Greenspan FS. Bioequivalence of levothyroxine preparations:
industry sponsorship and academic freedom. JAMA. 1997;277:1200-1201.
15. Dong BJ, Hauk WW, Gambertoglio JG, Gee L, White JR, Bubp JL, Greenspan
FS. Bioequivalence of levothyroxine preparations for treatment of
hypothyroidism. JAMA. 1997;277:1199-1200.
16. Zinberg DS. A
cautionary tale. Science. 1996;273:411.
17. Eckert C. Morality
play. Science. 1996;273:1784.
18. Blumenthal D, Campbell EG, Anderson
MS, Causino N, Louis KS. Withholding research results by academic life
scientists: evidence from a national survey of faculty. JAMA.
1997;277:1224-1228.
19. Cohen W, Florida R, Goe WR. University-Industry
Research Centers in the United States. Pittsburgh, Pa: Carnegie-Mellon
University Press; 1994.
20 Olivieri NF, Brittenham GM, Matsui D, et al.
Iron-chelation therapy with oral deferipronein in patients with thalassemia
major. N Engl J Med. 1995;332:918-922.
21. Nathan DG. An orally
active iron chelator. N Engl J Med. 1995;332:953-954.
22. Olivieri
NF. Randomized trial of deferiprone (L1) and deferoxamine (DFO) in thalassemia
major. Blood. 1996;88(suppl 1):651a.
23. Jeffrey S. Research
conflict. Med Post. 1997;33:1.
24. Rosenberg SA. Secrecy in medical
research. N Engl J Med. 1996;334:392-394.
25. Rennie D, Flanagin A.
Publication bias: the triumph of hope over experience. JAMA.
1992;267:411-412.
26. Chalmers I. Underreporting research is scientific
misconduct. JAMA. 1990;263:1405-1408.
27. Marshall E. Is
data-hoarding slowing the assault on pathogens? Science.
1997;275:777-780.
2 1997 Bioequivalence of levothyroxine
preparations Dong BJ, Hauck WW, Gambertoglio JG, Gee L, White JR, Bubp JL,
Greenspan FS. Bioequivalence of generic and brand-name levothyroxine products in
the treatment of hypothyroidism. JAMA 1997; 277: 1205-1213.
Reviewed
by
Kenneth G. Schellhase, MA, MD and Allan Ellsworth,
PharmD
Clinical question
Can different commercial preparations of
levothyroxine be used interchangeably in the treatment of
hypothyroidism?
Background
An estimated 8 million prescriptions
for thyroid replacement are written yearly in the U.S. Most of these
prescriptions are written for the Synthroid brand of levothyroxine due to
perceived lack of quality or therapeutic equivalency of generic versions. In
vitro bioequivalency data are available for several brand-name products, but the
bioequivalence of generics has not been tested. In this in vivo study,
therapeutic equivalency of two brand-name and two generic levothyroxine
preparations was compared.
Population studied
Twenty-four women
taking either 0.1 mg or 0.15 mg of levothyroxine were studied. Inclusion
criteria included at least two sets of normal thyroid function tests performed
at least six weeks apart. Exclusion criteria included conditions known to
interfere with the metabolism, absorption, or measurement of levothyroxine. Two
subjects were excluded from the final analysis due to protocol
violations.
Study design and validity
The study was a randomized,
single-blind (primary investigators only) four-way crossover trial comparing
bioavailability of two brand-name versions of levothyroxine (Synthroid(r) and
Levoxyl(r)) and two generic products (distributed by Geneva Generics and Rugby
Laboratories, though manufactured by the same company). Subjects were assigned
to one of four distinct four-drug sequences. Each product was taken for a
minimum of six weeks. Thyroid indices were determined at three-week intervals,
and conventional bioavailability parameters were obtained at the end of each six
week block. Medication and protocol compliance was monitored. The crossover
study design, in which each patient served as her own control, is very strong
and allows conclusions to be drawn from a small number of patients. However,
generalization to other brands of levothyroxine that were not a part of this
study may not be valid.
Outcomes measured
The main outcomes were
conventional bioavailability parameters at steady state of total thyroxine,
triiodothyronine, and resin thyroxine uptake, as well as thyrotropin levels.
Dosage forms of the same drug are considered bioequivalent when they yield
neither clinically nor statistically significant differences in these
parameters.
Results
There were no statistically significant
differences between these four levothyroxine products at either dose for total
thyroxine, total triiodothyronine, and free thyroid index. Moreover, all four
preparations produced substantially less variation in bioequivalence (-5% to
+7%) than the standard of -20% to +25% allowed by the Food and Drug
Administration. The statistical power of this study was high enough to find a
difference among the products if one truly existed.
Recommendations for
clinical practice
This well-executed study provides strong evidence for
the bioequivalence of common name-brand and generic forms of levothyroxine.
Although the study reports disease-oriented rather than patient oriented
evidence, it is clearly of clinical interest. Practitioners can now prescribe
these generic formulations with confidence that they will provide reliable,
effective, and equivalent therapy. The financial impact of this study could be
substantial. The authors estimate that if generics or Levoxyl(r) (which is close
to generic cost) were used for roughly half of levothyroxine prescriptions each
year, more than $350 million could be saved. The financial ramifications of this
study were not lost on the study sponsor, the manufacturer of Synthroid(r). An
editorial with this study details how publication of this work was delayed for
six years by a dizzying variety of specious complaints from the manufacturer,
ranging from flaws in study design to vague suggestions of ethical misdoings.(1)
The results of this study were improperly published by the company in another
journal, complete with a conclusion more favorable to Synthroid but failing to
acknowledge the original investigators.(2) Sadly, this cautionary tale does not
represent mere anecdote. As Blumenthal et al. showed, academic-private sector
partnerships are significantly associated with delays in publication.(3) While
the withholding of research results is far from commonplace, the increasing
frequency of academic-private partnerships may merit greater scrutiny to ensure
academic freedom is not impaired.
References
1. Drummond R. Thyroid
Storm (editorial). JAMA 1997; 277: 1238-1243.
2. Mayor GH, Orlando T, Kurtz
NM. Limitations of levothyroxine bioequivalence evaluation: analysis of an
attempted study. Am J Ther 1995; 2: 417-432.
3. Blumenthal D, Campbell EG,
Anderson MS, Causino N, Louis KS. Withholding research results in academic life
science. JAMA 1997; 277: 1224-1228.
1997 SCIENTIFIC AND ETHICAL
FOUNDATIONS OF NUTRITIONAL AND ENVIRONMENTAL MEDICINE Journal of Nutritional
& Environmental Medicine, Dec97, Vol. 7 Issue 4, p219
Part III:
Pharmacodoxy--The Teaching of Pharmacotherapeutics as a First Line of Treatment
in Clinical Medical Practice; A: Consideration of Hippocratic and
Darwinian-Evolutionary Principles
....
A major cornerstone of modern
medical therapeutics is the prescribing of pharmaceutical preparations--more
often than not, entirely novel man-made chemicals that were not necessarily
present during the evolution of our genes.
In the late 1940s and early
1950s, medicine saw a dramatic increase in the prescribing of pharmaceutical
preparations, following the arrival over a few short years of three major
medical therapeutic advances: penicillin in the treatment of a number of
previously untreatable infectious diseases (a graphic account of the remarkable
way in which the advent of penicillin transformed the clinical management of
pneumococcal pneumonia is to be found in the introduction to a fascinating book
on the effects of electromagnetics on health by Becker [3]); cortisone for
inflammatory conditions; and chlorpromazine for psychotic conditions, including
schizophrenia. These three major new therapeutic agents dramatically transformed
the face of medicine, and medicine truly entered what could be termed its
`pharmacodox era'.
That we are in the `pharmacodox era' is clearly evidenced
by the annual expenditure on pharmaceutical drugs by the National Health Service
(NHS) in the UK, which in 1995 was Ł 4982 million (approx. US$787] million) [4];
this represents an almost doubling of the percentage of the gross domestic
product (GDP) expended on pharmaceuticals by the NHS in the UK over the last 25
years [4]. Between 1970 and 1995, the total number of prescriptions written by
doctors in the NHS increased by about 80%,....
The straight teaching addressed in this paper is based on
two fundamental Hippocratic principles, which have nothing whatsoever to do with
technical advances, and are therefore not touched by the idea of `technical
out-of-dateness': `First do no harm' and `Assist nature'. To evaluate the
pharmacodox paradigm, i.e. the philosophical and technical basis upon which
pharmacodoxy is founded, is a particularly illuminating process when done with
particular reference to these two principles.
While the vast majority of
doctors enter the medical profession out of a genuine and admirable vocational
desire to help their fellow men and alleviate suffering, it is the author's
contention that these two basic Hippocratic principles appear not to have been
embraced by pharmacodox doctors who consider prescribing novel pharmaceutical
substances as the first line of treatment for the vast majority of the catalogue
of human ailments; that is to say `A pill for every ill'. (`Novel' in this
context means `not present in the environment during the evolution of the human
genome'.)
....
It is impossible to quantify the number of adverse
reactions to medically prescribed drugs that occur worldwide, but none of us in
medical practice would have been able to go through medical school without
witnessing several instances. In a career spanning 40 or 50 years, a busy,
conscientious physician will have seen dozens, if not hundreds, of patients
suffering from adverse reactions to one or more drugs; naturally, the more alert
a physician is, and the more willing to play devil's advocate to one's own
treatment, the more adverse reactions will be observed.
....
The
physician's awareness of the potential benefit of a new drug is almost entirely
based upon the promotional activities of the drug company that produces it. If
you, as a patient, are prescribed that drug, and happen to be the one in however
many patients who dies as a direct consequence, it would probably be regarded by
your doctor, and his or her peers, as `unfortunate', `bad luck' or
`idiosyncratic'. In any event, it is difficult to reconcile the outcome for that
particular patient with the Hippocratic principle of `First do no harm',
whatever the arguments presented to justify that prescribing action.
....
.....
The thalidomide tragedy resulted in drug regulation as we now know it.
Lip service is paid to the idea that there is no such thing as a safe drug, but
the pharmaceutical industry has largely avoided obtaining systematic information
on drug use in pregnancy [16], and pregnant women are still prescribed drugs on
a regular basis.
Yes, lessons have been learnt about avoiding such overt,
readily discernible consequences of the practical application of the philosophy
of pharmacodoxy, as in the phocomelia from thalidomide, but evidence of the
subtler, but nevertheless still devastating, disruptions of normal gene
expression, cell division and metabolic pathways may only emerge after many
patients have been prescribed the drug and when epidemiological studies can be
done as, for example, in the New Zealand asthma mortality epidemic cited
earlier, by which time many patients may have been harmed or killed.
In
September 1997, the Food and Drug Administration (FDA) in the US issued an
`approvable letter' to one of a number of drug companies wishing to market
thalidomide in the treatment of erythema nodosum of leprosy, AIDS-related
cachexia, aphthous ulcers and graft-versus-host disease [23].
The idea
underpinning pharmacodoxy, as it is still currently practiced, that novel
man-made chemicals can be given to patients as a first line of treatment, is
still basically the same philosophy that gave rise to the thalidomide tragedy in
the 1960s, and it is still a fundamentally dangerous approach, and difficult to
reconcile with the idea of `First do no harm'. NSAIDs, asthma inhalers and
thalidomide are just three categories of pharmacodox treatments which have
evidently caused harm and have resulted in many deaths; many more examples could
be cited. A full evaluation of the total number of deaths directly attributable
to all prescribed drugs would undoubtedly reveal disturbing statistics.
Before proceeding to a discussion of the relationship between pharmacodoxy
and the second Hippocratic principle of `Assist nature', it would be helpful to
bring to mind the mechanisms of disease processes from the viewpoint of
evolutionary theory, and the intrinsic concepts employed in the nutritional and
environmental medical approach to the clinical management of ill-health and
disease processes.
....
Examples of Drug Prescribing as Violating the Principle of `Assist Nature'
Having briefly summarized the Darwinian evolutionary approach, we are now in
a position to discuss the relationship that pharmacodoxy has with the second of
these Hippocratic aphorisms: `Assist nature'. Intrinsic in this concept is the
attribution of the wisdom of nature. Pervasive in modern medical thinking is
what can be regarded as a form of arrogance: introducing a novel (man-made)
pharmaceutical molecule, which does not exist in nature, can do what nature
cannot do. This is a cornerstone of the tacit philosophy underpinning the
pharmacodox approach.
Unlike the nutritional and environmental medical
approach to the assessment of the patient and the underlying molecular
mechanisms of disease, the pharmacodox approach gives little or no consideration
to whether or not there are adequate quantities of naturally occurring molecules
for optimum metabolic and system function (essential nutrients), or to the
presence of excess amounts of toxic molecules.
....
The degree to which
profit motivation drives the conceptual approach to the treatment of disease,
and the widespread introduction of toxic novel chemicals into the environment
and the human food chain, will be the subject of a future editorial.
In most
developed countries, doctors prescribe new drugs that have been approved by
regulatory authorities, and it is usually only after a period of time, when it
becomes evident that there are serious side-effects, that the drug is removed
from the market, and after many thousands of patients have been prescribed it.
The inevitable consequence of this approach to prescribing novel man-made
pharmaceuticals is exemplified by the case of practolol (one of the first
beta-blockers). A long time after it was introduced, and after many tens of
thousands of patients had been taking it, it was realized that the drug caused
severe eye problems and, in some cases, blindness, and it was finally withdrawn
from the market.
....
D. R. Laurence, past Professor of Pharmacology at
University College Hospital Medical School, London, is the author of a standard
medical student textbook of pharmacology [32], in which he describes the
oscillations in the development of a drug, where initial enthusiasm for a new
drug results in widespread prescribing, then recognition of adverse effects
leads to reduced prescribing and the level evens out to a point where the drug
is regarded as `the treatment of choice in selected cases'.
It is hoped
that, in the context of the history of medicine, there will be an oscillation in
pharmacodoxy, in which prescribing patterns shift from the current high rate of
prescribing to a more judicious level, in a pattern similar to that described
for a new drug by Laurence.
....
THE CHEMICAL INDUSTRY AND THE
PHARMACEUTICAL INDUSTRY
Not every doctor knows that the
pharmaceutical companies that produce potentially toxic and lethal
pharmaceuticals are the same companies that produce highly toxic agrochemicals
designed to kill life forms (pesticides, herbicides, fungicides, etc.), and that
they produce the novel chemical food additives (e.g. tartrazine) known to
produce adverse health effects in susceptible individuals.
....
ENTRENCHMENT IN PHARMACODOXY AND `BLINDING' OF RELEVANT DIAGNOSTIC
PROCESSES, MISSED DIAGNOSES AND THE LIMITING OF CONSIDERATION OF RELEVANT
THERAPEUTIC OPTIONS
The pharmacodox approach, with its `pill for every ill'
attitude, inevitably results in a blinding of the available therapeutic options,
with a failure to consider both the predisposing and the precipitating factors
(one meaning of the double-blind approach) of ill-health and disease.
Examples of Pharmacodoxy as the Prevailing Influence Over Therapeutic
Options and Decision-making
The following examples illustrate how the
pharmacodox approach can result in misdiagnosis, inappropriate drug treatment
and risk to the patient-in other words, bad medicine.
Case history 1:
Saturnine (relating to the toxic metal lead) gouty, hypertensive nephropathy
owing to a lead-containing hair preparation. RW is a 60-year-old male with
unwanted effects of his treatment for high blood pressure (beta-blocker and
diuretic), which his GP had told him he would have to take for the rest of his
life. He was also on a NSAID for his polyarthalgia. He complained of malaise,
depression and impotence, all of which he said had appeared since he started his
medications.
....
This case raises the question of how many other people
with hypertension and gout as a result of lead poisoning from lead acetate in
hair blackeners such as Grecian 2000 and Morgan's Pomade, and other sources of
environmental lead, are being treated, possibly inappropriately as here, with
antihypertensives, diuretics and anti-inflammatory drugs.
Case history 2:
Diabetes mellitus and chromium and other micronutrient deficiencies. The
prevalence of diabetes mellitus in industrialized society has reached almost
epidemic proportions, and pharmacodox treatment focuses on controlling blood
glucose levels and treating cardiovascular problems with medication with regular
follow-up to detect the onset of complications. Often, nothing is done to remedy
the nutrient deficiencies associated with glucose dysmetabolism [39]. The
following case illustrates [40]. A 30-year-old nurse had been insulin dependent
since she was 12 years old, and suffered from insulin oedema, a condition
whereby diabetics develop massive fluid retention at the insulin dosage required
to maintain good blood glucose control. The patient also described severe
fatigue and malaise when she experienced this phenomenon. A nutritional
biochemistry work-up revealed wildly abnormal low levels of red cell membrane
omega-3 and omega-6 EFAs, extremely low levels of several trace elements
including zinc, manganese, selenium and chromium, as well as very low levels of
magnesium and potassium, and a glycosylated haemoglobin (HbA1) of 22.8% (normal:
< 8.5%), indicating that she had very poor blood glucose control.
....
There is a substantial body of evidence, excellently reviewed by
Werbach [39], indicating that poor status of many trace elements, vitamins, EFAs
and amino acids is found in diabetes mellitus, which contribute not only to the
impairment of glucose control but also to the many complications of diabetes
mellitus. Failure to take heed of this body of literature in relation to the
treatment of diabetes mellitus and the prevention of complications, and
therefore failure to ensure that such nutrient inadequacies are corrected,
compromises the well-being of millions of diabetic sufferers alive today.
Case history 3: Thiamin-responsive congestive cardiac failure in the
elderly. When elderly patients are admitted to hospital in congestive cardiac
failure (CCF), standard pharmaceutical treatment is given, to which the patients
sometimes fail to respond fully. This is put down to `pump failure', for
whatever reason, and little more is done, apart from possibly adjusting the drug
regime. Yet it has long been known that these patients may be on a poor diet,
especially if they live on their own, and can be markedly vitamin B[sub 1]
deficient, and that their CCF is, in fact, wet beri-beri and responds
dramatically to intravenous vitamin B[sub 1]. However, many digitalis and
diuretic non-responsive CCF patients are often not tested for or given a
therapeutic trial of intravenous vitamin B[sub 1] for their condition, as well
as other nutrients essential for optimum cardiac function such as chromium,
manganese, carnitine, etc.
These are just three examples of how pharmacodox
training, with the thought modality `what is the diagnosis, and what is the drug
treatment of choice?', results in a failure to address what is really going on
with the patient. There are many more examples, beyond the scope of this paper,
of the `conventional' pharmacodox approach failing to address the patient's real
problems, such as nutrient deficiencies and food intolerances, and other
factors, which can give rise to a range of clinical conditions such as
ulcerative colitis, Crohn's disease, asthma, eczema, migraine, gynaecological,
endocrine and psychiatric conditions, and other system disorders [39, 41-45].
Such failure results, in many instances, in denying the patient the best and
safest available treatment.
There is a natural and laudable willingness on the part of
doctors to try to alleviate the suffering of the patient as soon and as
effectively as possible.
....
The combination of the doctor's desire to
help the patient, albeit well intentioned, and the profit-motivated marketing
techniques of the pharmaceutical industry is a powerful one, and one which does
not necessarily serve the best interests of the patient, but can lead to the
pharmaceutical-chemical industry becoming one of the wealthiest and most
powerful industries in developed countries.
The diagnosis-drug paradigm is the thought matrix adopted
by many of the practitioners of modern medicine, and simply means that once the
diagnosis is made, the most common mental mechanism that comes into play is
`What drug do I prescribe for this?' This limited thought process leads to a
pronounced barrier to thinking clearly about the individual patient, and thereby
acts as an inhibitor of understanding, and therefore, inevitably, of the quality
of care that a physician can give the patient.
....
Definitions and
descriptions of drug action, in drug company promotional literature, are usually
limited to the mechanism of action of the pharmaceutical being promoted, without
reference to the broader molecular, cellular and systemic mechanisms involved.
An excellent example of this is the extremely potent calcium channel-blocking
effects of manganese and magnesium, two trace elements that are often present in
inadequate amounts for optimum metabolic function. Instead of being advised to
make good the deficiencies of these potent calcium channel-blocking essential
nutrients, we receive high-intensity expensive advertising geared towards
persuading us of the need to prescribe one or more expensive, potentially toxic,
pharmaceuticals. This leads to a dysperception of the available therapeutic
options: the diagnosis is `A', the drug treatment of choice for this condition
is drug `B'. This sort of thought mechanism, entrenched in modern pharmacodoxy,
while it may lend itself to the short consultation time (an important
consideration when one is trying to understand how prevalent the pharmacodox
approach has become), does not require one to consider `what set of genetic,
nutritional and environmental challenges have caused this individual's adaptive
mechanisms to become exhausted, thereby causing illness, and why'.
....
Entering medical school with the two principles `First do
no harm' and `Assist nature' clearly in mind results in somewhat of a culture
shock for most sensitive, aspiring physicians. It is not long before medical
students see patients on the wards who have been on long-term drugs with
on-going progression of their disease; or some poor patient who is desperately
sick as a direct result of polypharmacy-the prescribing of two or more drugs
simultaneously-or patients with no hair as a direct result of chemotherapy for
malignant disease, for example.
It is also not long before the young medical
student, full of ideals and hopes to alleviate suffering, cure disease and save
mankind, is exposed to the full indoctrination process of pharmacology and
pharmacotherapeutics. Without passing the various exams in these subjects, the
student will never become a doctor. The amount that the student has to learn on
the subject of drugs and drug prescribing means that other therapeutic options,
other than surgery or radiotherapy or chemotherapy, hardly receive a mention in
the medical school curriculum, or in postgraduate medical education.
Furthermore, there is another mechanism operant, which causes aspiring
physicians to fall into the prevailing paradigm: as stated by Jaffe "...
thinking that diverges from the consensus is actively dissuaded by their seniors
and mentors as dangerous to their career advancement and hazardous to their
receiving grant support" [48].
A further point of concern when pursuing the
potentially hazardous course of drug prescribing is that the potential confusion
owing to the sheer number of drugs available for the clinician to prescribe can
also put the patient at risk from incorrect prescribing. A recent report of a
prescribing surveillance programme in one particular teaching hospital over a
9-year period reported an increase in prescribing errors from 522 in 1987 to
2115 in 1995 [49].
When the only tool you have is a
hammer, everything starts looking like a nail. In medicine, when the only (or
main) tool you have is pharmacotherapeutics, every condition tends to look like
something to be treated with a drug. It could be said that, in the light of the
two Hippocratic principles cited in this paper, the truly `orthodox' physicians
are the ones who ascribe to the principles of `First do no harm' and `Assist
nature', and that physicians entrenched in pharmacodoxy, to the exclusion of
almost every other therapeutic option, are a `bunch of drug-prescribing
renegades'. This viewpoint may make many pharmacodox physicians feel
uncomfortable, especially the majority who entered the noble profession of
medicine to alleviate suffering, and who have fallen victim to the pharmacodox
paradigm as a result of the powerful drug-oriented consensus.
A common
response, either to criticism of one's lifelong vocational activity or to the
arrival of a shift in thinking away from the entrenched paradigm [5, 20, 48], is
to attack since, in the words of Thomas Kuhn, such a shift is "generally
preceded by a period of pronounced professional insecurity" [50]. Compounding
this professional insecurity is the threat to pharmaceutical company vested
interests in maintaining the prescribing rate of doctors. It is, perhaps, for
this reason that non-pharmacodox approaches are generally looked down upon,
denigrated, or even attacked overtly or covertly by pharmacodox doctors and by
those whose income comes directly from the pharmaceutical industry.
....
In
medicine it cannot be denied that the well-being of the individual patient is
the central issue, and that the prescribing of potentially hazardous, if not
potentially lethal, drugs is inappropriate and unethical if more effective and
less dangerous therapeutic options are available. No longer can pharmacodoxy,
demanding evidence-based treatment strategies, disregard the nutritional and
environmental medical approach, simply on the grounds that they are only
familiar with the pharmacodox-based published literature, and that no other
published literature has any relevance. The time has come for pharmacodoxy to
realize that ignorance of existing knowledge is no excuse for prescribing toxic,
novel pharmaceuticals, which is a violation of the prime principle of ethical
clinical medical practice, which is, for the last time in this paper, cited:
`First do no harm'.
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Chicago: University of Chicago Press, 1970.
1997 Withholding
Research Results in Academic Life Science David Blumenthal, MD, MPP; Eric G.
Campbell, PhD; Melissa S. Anderson, PhD; Nancyanne Causino, EdD; Karen Seashore
Louis, PhD JAMA. 1997;277:1224-1228
Evidence From a National Survey of
Faculty
Objectives.--To identify the prevalence and determinants of
data-withholding behaviors among academic life scientists.
Design.--Mailed survey of 3394 life science faculty in the 50
universities that received the most funding from the National Institutes of
Health in 1993.
Participants.--A total of 2167 faculty responded to
the survey, a 64% response rate.
Outcome Measures.--Whether
respondents delayed publication of their research results for more than 6 months
and whether respondents refused to share research results with other university
scientists in the last 3 years.
Results.--A total of 410 respondents
(19.8%) reported that publication of their research results had been delayed by
more than 6 months at least once in the last 3 years to allow for patent
application, to protect their scientific lead, to slow the dissemination of
undesired results, to allow time to negotiate a patent, or to resolve disputes
over the ownership of intellectual property. Also, 181 respondents (8.9%)
reported refusing to share research results with other university scientists in
the last 3 years. In multivariate analysis, participation in an
academic-industry research relationship and engagement in the commercialization
of university research were significantly associated with delays in publication.
Odds ratios (ORs) and 95% confidence intervals (CIs) were 1.34 (1.07-1.59) and
3.15 (2.88-3.41), respectively. Variables associated with refusing to share
results were conducting research similar to the Human Genome Project (OR, 2.09;
95% CI, 1.75-2.42), publication rate (OR, 1.02; 95% CI, 1.01-1.03), and
engagement in commercialization of research (OR, 2.45; 95% CI, 2.08-2.82).
Conclusions.--Withholding of research results is not a widespread
phenomenon among life-science researchers. However, withholding is more common
among the most productive and entrepreneurial faculty. These results also
suggest that data withholding has affected a significant number of life-science
faculty and further study on data-withholding practices is suggested.
2001 Blood levels of selected hormones in patients with multiple
sclerosis Elżbieta Zychwardowska, Andrzej Wajgt 1st Chair and Department of
Neurology, Silesian Medical University in Katowice, Poland Med Sci Monit, 2001;
7(5): 1005-1012
Summary:
Background: Hormonal studies in
patients with multiple sclerosis are rare and they often produce results which
are difficult to interpret. These investigations, however, are becoming more and
more important as they may cast some light on possible interrelationships
between hormonal and immune systems. The aim of the present work was to
investigate endocrine function in patients with multiple sclerosis on the basis
of blood levels of selected pituitary (TSH, ACTH, GH) and thyroid hormones (T3,
T4), and cortisol.
Material and methods: Forty-nine MS subjects,
including 25 menstruating women, 6 post-menopausal women and 18 men were
included in the analysis. The hormones were measured by radioimmunoassay and
immunoradiometric assay kids.
Results: Pituitary function in respect
of TSH, corticotropin and growth hormone secretion was normal. Both men and
women suffering from multiple sclerosis manifested low serum T3 concentrations
coexisting with normal T4 levels which may indicate changed peripheral
conversion pathway of thyroid hormones. On the other hand, the disturbances in
pituitary-adrenal cortex system in respect of glycocorticosteroid secretion were
not observed.
Conclusion: Normal function in respect to pituitary
hormones (TSH, corticotropin, growth hormone) and normal T4 level versus low
serum T3 concentration may indicate changes in peripheral conversion pathway of
thyroid hormones in MS patients.
1105
Background:
In the
etiopathogenesis of multiple sclerosis various factors such as genetic,
autoimmune and environmental ones are considered [1]. Not many studies
emphasised the role of hormonal disturbances in patients with multiple
sclerosis.
Our earlier works on the concentrations of hormones in patients
with multiple sclerosis showed hyperprolactinemia in men and women suffering
from MS and elevated oestradiol levels in men with MS with normal testosterone
concentrations.Serum levels of gonadotropic hormones (FSH and LH) in patients
with MS was found normal [2].
In recent years, it has become particularly
important to investigate the nature of interrelationships between immune and
neurohormonal systems [3-7]. Patients suffering from multiple sclerosis manifest
abnormal humoral and cellular response to CNS antigens as well as intensive
immunoglobulin synthesis and insufficient suppression mechanisms related to T
cells [8-10].
....
1009
....
DISCUSSION
The present
paper focuses on the function of endocrine glands in patients with multiple
sclerosis which was evaluated on the basis of selected pituitary, thyroid and
adrenal hormones. Some MS patients manifest thyroid dysfunction [19-21].
....
Thyroxin is the main hormone produced by thyroid gland, and it plays
the role of prohormone.
Thyroxin undergoes gradual deiodination. The
deiodination of external ring in 5' position results in the formation of
bioactive hormone - triiodothyronine (T3) which acts on the target cell through
nuclear receptor. Reduced triiodothyronine levels with normal TSH and thyroxin
concentrations may indicate a change in peripheral conversion of thyroid
hormones in patients with multiple sclerosis.
The most likely hypothesis
accounting for this fact is the presence of low T3 syndrome, determined by
impaired T4 conversion to T3 and enhanced T4 conversion to T3 reverse.
As a
result, this syndrome is characterised by low total T3 and fT3 levels and
elevated rT3 concentration as well as either low, normal or even increased
(rarely) fT4 levels. The concentration of TSH is normal. Low T3 syndrome occurs
in numerous acute and chronic diseases, not directly related to pathologies of
thyroid gland [26,27].
....
The hypothesis advocating the role of
autoimmune mechanisms in the development of thyroid dysfunction is also
supported by the presence of anti--thyroglobulin and anti-microsomal antibodies
detected in MS patients [22-24].
....
The assessment of ACTH and cortisol
secretion in MS subjects has been investigated by some authors, although the
main focus was usually on the treatment with glycocorticosteroids
[32-35].
The results of numerous works indicate that steroids are an
effective tool in the reduction of MS attacks [36-39]. However, there are
controversies concerning the final outcome of steroid therapy in
patients
with multiple sclerosis.
Adverse reactions to corticotherapy in these
patients include mainly a depressive effect of pituitary - hypothalamic system
as well as secondary, post--steroid adrenal cortex insufficiency.
A distinct
problem is the evaluation of hypothalamic-pituitary-adrenal axis in patients
with multiple sclerosis remaining on glycocorticosteroid therapy or treated long
time before the assessments. Analy-
1010
sed patients manifested
normal blood levels of adrenocorticotropic hormone and cortisol under normal
conditions (tables 4 and 5).
....
Patients with MS remission usually
manifested normal cortisol level, however, function tests revealed the presence
of significant disturbances in hypothalamic-pituitary-adrenal
axis
.....
Further studies are required to define the role of
glycocorticosteroids in MS pathogenesis, and particularly their effect on
inflammatory-demyelinisation processes in central nervous system.
Our study
showed normal pituitary function in patients with multiple sclerosis concerning
the secretion of growth hormone (Table 6).
So far, only few reports have been
published on the analysis of growth hormone in patients with
inflammatory-demyelinisation processes taking place in central nervous system
[44,45].
....
The observations on the role of growth hormone in immune
system function may be of some importance for better understanding of GH role in
MS etiopathogenesis.
The results presented in this paper indicate the
presence of hormonal disorders in patients with multiple sclerosis. These
disturbances include mainly a change in peripheral conversion pathway of thyroid
hormones. The alterations in endocrine system functions observed in subjects
with multiple sclerosis may contribute to better understanding of the
etiopathogenesis and clinical characteristics of this disease. The presence of
hormonal disorders in MS subjects may also be an indication for therapy
modification.
CONCLUSIONS
Low T3 levels were observed in all
analysed groups of patients with multiple sclerosis. The coexistence of low T3
levels with normal T4 and TSH concentrations may be the evidence for changed
peripheral conversion pathway of thyroid hormones.
The disturbances in
pituitary-adrenal cortex system in respect of glycocorticosteroid secretion were
not observed in analysed patients.
Pituitary function concerning TSH,
corticotropin and growth hormone secretion was found
normal.
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A, Backmund H et al: Heterogeneity of hypothalamic--pituitary-adrenal system
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Neurochir Pol, 1987; 21: 315-318
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Reporting Financial
Conflicts of Interest and Relationships Between Investigators and Research
Sponsors Editorial JAMA Vol. 286 No. 1, July 4, 2001
Catherine
D. DeAngelis, MD, MPH; Phil B. Fontanarosa, MD; Annette Flanagin, RN,
MA
The financial aspects of biomedical research currently are under
intense examination. Increasing attention and concern have been directed toward
the financial ties of individual investigators as well as the complex
relationships among researchers, academic medical centers, commercial clinical
research entities, and industry.
Medical journal editors are responsible for
evaluating the scientific validity and credibility of research submitted for
possible publication. Editors also have an obligation to present pertinent
information related to the financial aspects of the articles they publish so
readers can interpret the findings in light of this information. THE JOURNAL has
policies governing financial aspects of manuscripts submitted, reviewed, edited,
and published. Herein, we describe a more specific policy for reporting authors'
financial conflicts of interest and a new policy for reporting relationships
between investigators and research sponsors.
....
Since 1985, THE JOURNAL
has requested authors to disclose financial interests related to the subject
matter of their research and since 1989 has required authors to submit signed
financial disclosure statements. In the years that have followed, and because of
increased concern about conflicts of interest, we have made our policies for
reporting financial interests more stringent and more specific.
....
In
addition to requiring information on financial interests from authors, THE
JOURNAL has, since 1987, routinely requested all peer reviewers who complete a
manuscript review to disclose any potential conflicts of interest, financial or
otherwise, they may have related to that manuscript. Such information is kept
confidential and is not revealed to the authors of the manuscript or to other
reviewers. Peer reviewers who believe they have a conflict of interest
(financial or otherwise) that prevents them from providing an objective review
are instructed to disqualify themselves from reviewing that paper and to return
the manuscript without completing a review.
....
Another important and
increasingly prevalent aspect of medical research that can lead to conflicts of
interest involves the relationships between scientific investigators and
industry and the direct involvement of study sponsors in the research. Industry
invested approximately $55 to $60 billion in research and development in 2000
(compared with $25 billion in US federal spending on research), and industry
also provides an estimated 70% of funding for clinical drug trials in the United
States. Without industry-sponsored research, some important advances and
discoveries in medical research might not occur.
However, active involvement
in and control of research investigations (such as control of data, performance
of statistical analyses, complete authority over manuscript preparation and
decisions to submit for publication) by companies whose products are being
evaluated and who have a vested financial interest in the study outcome
represents a clear conflict of interest. Moreover, this level of involvement and
control of the research could be viewed as the sponsor having the potential to
influence the study results and might create doubts about the validity of the
research. These concerns are not without foundation; previous reports have
documented several major problems in some industry-sponsored studies, including
issues related to trial design, data availability, and control over
publication.
....
As another mechanism to help assure complete
reporting of study outcomes, the editors may request and review the original
study protocol for any research investigation. These approaches should help
convince readers about the integrity of the data and analyses presented, and
should help eliminate uncertainty that some readers might have because of the
sponsor's involvement in the research.
In an ideal world, physicians,
patients, and the public would not have to be concerned about conflicts of
interest related to medical research or have questions about the role of
sponsors in industry-funded research. However, to respond to these current
real-world concerns, THE JOURNAL will require clear reporting of authors'
financial conflicts of interest and clear description of the involvement of
sponsors in medical research. Even though we recognize that these efforts are
not fail-safe, we hope that such reporting will help to ensure the integrity of
medical science, enable readers to interpret the results of scientific studies
appropriately, and maintain public confidence in biomedical
research.
REFERENCES
Moses H, Martin JB. Academic
relationships with industry: a new model for biomedical research.
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2001;285:933-935.
Boyd EA, Bero LA. Assessing faculty financial
relationships with industry: a case study. JAMA.
2000;284:2209-2214.
DeAngelis CD. Conflict of interest and the public trust.
JAMA. 2000;284:2237-2238. Stelfox HT, Chua G, O'Rouke K, Detsky AS. Conflict of
interest in the debate over calcium channel antagonists. N Engl J Med.
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Angell M. Is academic medicine for sale? N Engl J Med.
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Bodenheimer T. Uneasy alliance: clinical investigators
and the pharmaceutical industry. N Engl J Med. 2000;342:1539-1544.
Martin JB,
Kasper DL. In whose best interest? breaching the academic-industry wall. N Engl
J Med.2000;343:1646-1649.
Krimsky S, Rothenberg LS. Conflict of interest
policies in science and medical journals: editorial practices and author
disclosures. Sci Eng Ethics. 2001;7:205-218.
Flanagin A. Ethical and legal
considerations. In: Iverson CI, Flanagin A, Fontanarosa PB, et al. American
Medical Association Manual of Style: A Guide for Authors and Editors. 9th
ed. Philadelphia, Pa: Williams & Wilkins; 1998:87-172.
Korn D. Conflicts
of interest in biomedical research. JAMA. 2000;284:2234-2237.
Friedman PJ.
The troublesome semantics of conflict of interest. Ethics Behav.
1992;2:245-251.
Flanagin A. Conflict of interest. In: Jones AH, McClellan F,
eds. Ethical Issues in Biomedical Publication Baltimore, Md. Johns Hopkins
Press; 2000:137-165.
Guidelines for dealing with faculty conflicts of
commitment and conflicts of interest in research. 1990. Available at:
http://www.aamc.org/research/dbr/coi.htm
Cohen JJ. Trust us to make a
difference: ensuring public confidence in the integrity of clinical research.
Acad Med. 2001;76:209-214.
Constantian MB. Conflicts of interest in medical
writing and the concept of disclosure. Plast Reconstr Surg.
2000;105:796-797.
Knoll E, Lundberg GD. New instructions for JAMA authors.
JAMA. 1985;254:97-98.
Lundberg GD, Flanagin A. New requirements for authors:
signed statements of authorship responsibility and financial disclosure. JAMA
1989;262:2003-2004.
Instructions for Authors. JAMA. 2001;286:101-108.
Cho
MK, Shohara R, Schissel A, Rennie D. Policies on faculty conflicts of interest
at US universities. JAMA. 2000;284:2203-2208.
Lo B, Wolf LE, Berkeley A.
Conflict-of-interest policies for investigators in clinical trials. N Engl J
Med. 2000;343:1616-1620.
McCrary SV, Anderson CB, Jakovljevic J, et al. A
national survey of policies on disclosure of conflicts of interest in biomedical
research. N Engl J Med. 2000;343:1621-1626.
Cech TR, Leonard JS. Conflicts of
interest: moving beyond disclosure. Science. 2001;291:989.
Southgate MT.
Conflict of interest and the peer review process. JAMA.
1987;258:1375.
Blumenthal D, Causino N, Campbell E, Louis KS. Relationships
between academic institutions and industry in the life sciences: an industry
survey. N Engl J Med. 1996;334:368-373.
Rennie D. Thyroid storm. JAMA.
1997;277:1238-1243.
International Committee of Medical Journal Editors.
Uniform requirements for manuscripts submitted to biomedical journals. Updated
May 2000. Available at: http://www.icmje.org
Rennie D, Flanagin A, Yank V.
The contributions of authors. JAMA. 2000;284:89-90.
2001 Letter in
response to Colin Dayan's article ' Interpretation of thyroid function tests'.
Lancet 2001; 357: 619-24. Dr PBS Fowler The Lancet, Volume 357, Number
9273 23 June 2001
....
Probably, thyroid function tests are
done at least 50 times more commonly to assess thyroxine dose than to diagnose
thyroid dysfunction.
....
Every qualifying medical student knows that
thyrotoxicosis can cause atrial fibrillation or osteoporosis and makes the
illogical extrapolation that a patient given a dose of thyroxine that suppresses
or brings the serum thyroxine concentration to higher than the reference range
is receiving too much replacement. It is excusable for doctors to believe that
if the serum thyroxine concentration is higher than the so-called normal range
that the dose of thyroxine should be decreased. In fact, the thyroxine is
replacing the thyroxine and tri-iodothyronine, which is produced by a normal
gland. The only function of doing a thyroxine estimation is to confirm that the
patient is taking the thyroxine and that it is being absorbed. Serum thyroxine
concentration, if raised, confirms that the thyroxine replacement dose is
inadequate but a suppressed concentration does not necessarily show that the
dose is too high. Serum T3 must be kept within the normal range.
Before the
days of hormone assays, hypothyroid patients received about double the average
dose of thyroxine given today, but did not develop osteoporosis or atrial
fibrillation. Doses should be judged clinically rather than be governed by
misinterpreted hormone results.
P B S Fowler
1 Dayan CM.
Interpretation of thyroid function tests. Lancet 2001; 357:
619-24.
2001 Thyroxine treatment in patients with symptoms of
hypothyroidism but thyroid function tests within the reference range: randomised
double blind placebo controlled crossover trial M Anne Pollock, principal
biochemist a, Alison Sturrock, senior house officer b , Karen Marshall, trainee
clinical psychologist c, Kate M Davidson, research tutor c, Christopher J G
Kelly, Specialist registrar b, Alex D McMahon, consultant statistician and E
Hamish McLaren, consultant physician b BMJ 2001;323:891-895 (20
October)
a Department of Clinical Biochemistry, Stobhill Hospital,
Glasgow G21 3UW, b Department of Medicine, Stobhill Hospital, c Department of
Psychological Medicine, Gartnavel Royal Hospital, Glasgow G12 0XH, d Robertson
Centre for Biostatistics, University of Glasgow, Glasgow G12
8QQ
.....
Introduction
The classic symptoms of hypothyroidism
are wide ranging and non-specific, therefore biochemical testing has become the
cornerstone of diagnosis in patients for whom there is a clinical suspicion of
thyroid dysfunction. However, recent anecdotal evidence has suggested there may
be some clinical benefit in giving thyroxine to patients with symptoms of
hypothyroidism who have thyroid function tests within the reference range. 1-3
After a series of reports in our local newspaper suggesting that such patients
benefited from thyroxine therapy we treated two patients empirically with
thyroxine, and they both reported symptomatic relief. 4
To investigate this
further, we conducted a double blind placebo controlled crossover trial of
thyroxine in patients who had symptoms of hypothyroidism but whose thyroid
function tests were within the reference range. A group of controls, who were
similar in age and sex to the patient group, took part in a parallel trial. The
same protocol was used for controls and patients to test the clinical belief
that thyroxine treatment would have an effect on wellbeing even in participants
without symptoms of hypothyroidism. We assessed response to thyroxine by using a
battery of biochemical, physical, and psychological
tests.
.....
Discussion
This is the first randomised double
blind placebo controlled trial of thyroxine treatment in patients who have
symptoms of hypothyroidism but are biochemically euthyroid
.....
Controls
showed no significant changes in psychological measurements after treatment with
either thyroxine or placebo. This suggests that, contrary to widespread belief,
thyroxine does not have a non-specific effect on wellbeing. In the participants
who received placebo first, patients showed a small but significant improvement
in general health, physical wellbeing, and anxiety and depression after placebo
when compared with baseline. Thyroxine treatment, however, had no greater effect
than placebo in this group of patients. This contrasts with previous studies in
biochemically hypothyroid patients, where thyroxine treatment was associated
with psychological improvement.
....
Conclusion
We can find no
support for the hypothesis that people with symptoms of hypothyroidism but
thyroid function tests within the reference range benefit from treatment with
100 ?g thyroxine daily. However, our results require confirmation in a larger
study. The improvement noted anecdotally and in open studies may be due to the
placebo effect shown in our study.
Referencees
1. Skinner,
GRB., Thomas, R., Taylor, M., Sellarajah, M., Bolt, S., & Krett, S.
Thyroxine should be tried in clinically hypothyroid, but biochemically euthyroid
patients. BMJ 1997; 314: 1764.
2. Williams, G. Distinguishing hypothyroid
symptoms from common non-specific complaints is difficult. BMJ 1997; 315: 814.
3. Holmes, Diana, . Tears behind closed doors. London: Avon, 1998.
4.
Mclaren, EH., Kelly, CJG., & Pollock, MA. Trial of thyroxine treatment for
biochemically euthyroid patients has been approved. BMJ 1997; 315: 1463.
5.
Wechsler, D. Wechsler memory scale-revised manual. San Antonio: Psychological
Corporation, 1987.
6. Reitan, RM. A research programme on the psychological
effects of brain lesions in human beings. In: Ellis, NR., ed. International
review of research in mental retardation. New York: Elsevier, 1966.
7.
Zigmund, AS. & Snaith, RP. The hospital anxiety and depression scale. Acta
Psychiatr Scand 1983; 67: 361370.
8. Ware, JE. SF36 health survey: manual
and interpretation guide. Health Institute: New England Medical Centre,
1997.
9. Skinner, GRB., Holmes, D., Ahmad, A., Davies, JA., & Benitez, J.
Clinical response to thyroxine sodium in clinically hypothyroid but
biochemically euthyroid patients. J Nutr Environ Med 2000; 10: 115124.
10.
Beckwith, BC. & Tucker, DM. Thyroid disorders. In: Tarter, RE., Van Thiel,
DH., & Edwards, KL., eds. Medical neuropsychology: the impact of disease on
behaviour. New York: Plenum Press, 1998.
11. Denicoff, KD., Joffe, RT.,
Lakshmanan, MC., Robbins, J., & Rubinow, DR. Neuropsychiatric manifestations
of altered thyroid state. Am J Psychiatr. 1990; 147: 94
12. Osterweil, D.,
Syndulko, K., & Cohen, SN. Cognitive function in non-demented older adults
with hypothyroidism. J Am Geriatr Soc 1992; 40:335
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page)
1998 Bone Changes in Pre- and Postmenopausal Women with
Thyroid Cancer on Levothyroxine Therapy: Evolution of Axial and Appendicular
Bone Mass E. Jodar (*), M. Begona Lopez (*), L. Garcia, D. Rigopoulou, G.
Martinez, F. Hawkins(1) Service of Endocrinology, University Hospital 12 de
Octubre, Madrid, Spain Osteoporosis International Volume 8 Issue 4 (1998) pp
311-316
Abstract: The effects of suppressive doses of
levothyroxine (LT 4 on bone mass are controversial. Our aim was to evaluate the
effects on axial and appendicular bone mineral density (BMD) and bone metabolism
of long-term LT4 suppressive
therapy in women by means of cross-sectional and longitudinal studies, and also
to assess the potential influence of menopausal status and LT4 dose. Seventy-six women (aged 47 + 13 years,
37 pre- and 39 postmenopausal) on suppressive therapy (67 + 34 months duration,
mean LT4 dose 168 + 41
mg/day) from our Thyroid Cancer Unit without previous hyperthyroidism or
concomitant hypoparathyroidism were studied. Serum TSH, T3 free T4, calcium, phosphorus, alkaline phosphatase,
BGP, iPTH and urinary calcium (uCA) were measured. BMD was measured by
dual-energy X-ray absorptiometry (DXA) at lumbar spine, femoral neck, Ward's
triangle, ultradistal and distal third radius and expressed as a Z-score. In a
subset of 27 women aged 46 + 15 years (14 pre- and 13 postmenopausal) a second
densitometry scan was performed 27 + 5 months later. Patients on suppressive
therapy showed a small reduction in BMD at the distal third radius (Z-score:
70.77 + 0.98; 95% confidence interval: 71.11, 70.44) without differences between
pre- and postmenopausal women. Significant relations with the regimen of
suppressive therapy and bone turnover markers were detected except at the lumbar
spine. In the longitudinal study a significant although mild reduction in
femoral neck BMD was found that correlated with prior T3 and iPTH. In conclusion, our data show a
small detrimental effect of cautious LT4 suppressive therapy on bone mass assessed by
DXA; it remains to be established whether this increases the prevalence of
fractures.
Thyroid cancer (*) The contributions of Esteban Jodar and
Maria Begona Lopez are equal and the order of authorship is arbitrary. (*) The
contributions of Esteban Jodar and Maria Begona Lopez are equal and the order of
authorship is arbitrary.
1999 Syndromes of resistance to
thyroid hormone: Clinical considerations Vlaeminck-Guillem, V.; Wemeau, J.L.
Revue de Medecine Interne, Vol: 20, Issue: 12, 1114-1122, 1999
Abstract
(English):
Introduction. - Syndromes of resistance to thyroid
hormone correspond to variable clinical states which are usually transmitted as
autosomal dominant traits and characterized by the lack of sensitivity of target
tissues to triiodothyronine (T3). The diagnosis has to be performed in order to
offer an appropriate therapy.
Current knowledge and key points. -
Clinical states range between two extremes: the generalized form, with global
euthyroidism, and the predominantly pituitary form, with thyrotoxicosis.
Surprisingly, these various clinical situations are usually determined by the
same genetic defect, i.e., an anomaly of one of the two alleles of the gene
encoding the thyroid hormone receptor TRâ. High levels of circulating thyroid
hormones in the presence of detectable thyroid stimulating hormone (TSH) levels
is the characteristic biological feature. Pituitary thyreotropic adenoma,
another etiology of inappropriate secretion of TSH, needs thus to be ruled out.
No treatment is required in case of generalized resistance to thyroid hormone,
whereas two specific drugs (TRIAC and D-T4) appear to be useful in the
predominantly pituitary form.
Future prospects and projects. -
Mechanisms of resistance have been well documented, therefore allowing better
understanding of T3 action on its nuclear receptor. Several transcriptional
cofactors or corepressors have been identified and have to be investigated to
explain the intriguing inter- and intra-familial, and even intra-individual,
phenotypic variability. New insights should, furthermore, be gained from these
studies to precisely determine how therapeutic agents work in resistance to
thyroid hormone.
2001 AACE Press release: January 18,
2001
New Campaign Urges People to "Think Thyroid" at Critical Life
Stages and Get Tested
JACKSONVILLE, FL, January 18, 2001
January is
Thyroid Awareness Month
New York, NY - January 18, 2001 - Fewer than
fifteen percent of Americans correctly identified the post childbirth
(postpartum) period, menopause, or over 60 years of age, as key life stages when
thyroid disease often strikes, according to a national survey released today by
the American Association of Clinical Endocrinologists (AACE). To combat this
lack of awareness, AACE is launching a new campaign, "The Neck's Time is Now,"
to educate Americans about the pivotal times, from birth to advanced age, when
people are at increased risk for developing a thyroid disorder. Americans need
to "think thyroid" and see their doctor for a TSH (thyroid stimulating hormone)
blood test when: pregnant women go for their first prenatal visit; following
pregnancy if postpartum depression strikes; a child's growth or behavior
patterns change; mood swings and other symptoms of menopause persist despite
hormone replacement therapy; fatigue, depression and forgetfulness plague older
Americans. The thyroid is a butterfly-shaped gland located in the neck, just
below the Adam's apple and above the collarbone. Left untreated, thyroid disease
causes serious long-term complications such as elevated cholesterol levels and
subsequent heart disease, infertility, muscle weakness and osteoporosis. Thyroid
disease affects more than 13 million Americans, yet more than half remain
undiagnosed.
"The millions who remain undiagnosed reflect the widespread
lack of awareness of this serious, but easily treatable condition. While more
than half of the respondents can tell you their blood pressure, and more than
one in five can identify their cholesterol (39%) and glucose levels (21%), only
fifteen percent know their thyroid function - even though the thyroid gland
influences these levels, according to the AACE survey. "For the millions of
Americans affected by thyroid disease, it is important that they learn to
recognize and evaluate the subtle signs and symptoms that can be significant
markers of thyroid disease for themselves or for a loved one," says Paul
Jellinger, M.D., F.A.C.E., President of AACE and Clinical Professor at the
University of Miami School of Medicine.
Detecting and Understanding
TSH
"Despite the critical need for detecting thyroid disorders early to
avoid serious complications, the survey also revealed that almost 60 percent of
Americans have never been tested for a thyroid condition. An overwhelming
majority of survey participants (85 percent) failed to know the most common,
gold standard measure of thyroid function - the TSH test. The TSH is a simple
yet highly sensitive blood test that enables physicians to detect even slight
abnormalities in thyroid function. It determines the level of thyroid
stimulating hormone which regulates thyroid hormone production, indicating
whether the thyroid gland is overactive (hyperthyroid), underactive
(hypothyroid) or normal (euthyroid).
"AACE encourages patients whose TSH is
outside the normal range (.5-5.0 uU/ml) to see an endocrinologist for treatment
and thyroid disease management. Even though a TSH level between 3.0 and 5.0
uU/ml is in the normal range, it should be considered suspect since it may
signal a case of evolving thyroid underactivity. The new thyroid stimulating
hormone test is sensitive enough to detect both hypothyroid and hyperthyroid
conditions. "TSH tests play a vital role in helping physicians diagnose and
manage thyroid disorders," says Hossein Gharib, M.D., F.A.C.E, a Vice-President
of AACE and Professor of Medicine at the Mayo Medical School. "Constant
monitoring of a patient's TSH level is critical in early detection and treatment
of thyroid disease."
The Neck's Time is Now: Thyroid Through the
Ages
There are several principal life stages at which the risk for
developing a thyroid disorder increases. Because of the advanced prevalence of
thyroid disease, AACE advises TSH testing during the following
times:
Birth through Adolescence: Effects on Mental and Physical
Growth
One out of every four to five thousand babies born in the U.S. has
hypothyroidism. Fortunately, screening for hypothyroidism is done routinely in
North America on all newborns by administering a heelpad test to uncover
cretinism, a growth and mental disorder brought on by a lack of thyroid
hormone.
Parents need to be aware that thyroid disorders may also appear
later in their child's development. A change in a child's growth rate is
sometimes the only evidence that thyroid trouble is present because children are
less likely to complain of feeling sick or to ask for help. Hyperthyroid
children will rapidly outgrow new clothes, while hypothyroid children may
mysteriously stop growing. But difficulty concentrating and inattentiveness in
school, unexplained change in grades, hyperactivity, or unexplained daytime
fatigue, may all be symptoms of an underlying thyroid condition. Children who
come from families with a history of thyroid disease are especially likely to
develop thyroid disorders.
The Reproductive Years: Effects on
Pregnancy
Women who are unable to conceive should have their thyroid
function assessed since thyroid disorders can impair fertility. In addition,
recent studies have shown that untreated thyroid disease during pregnancy may
negatively impact a child's psychological development, resulting in a lower I.Q.
score and a decrease in motor skills, attention, language and reading abilities.
Other studies suggest that pregnant women with hypothyroidism have a four-times
greater risk for miscarriage during the second trimester. In fact, six out of
every 100 miscarriages may be associated with autoimmune thyroid disease during
pregnancy. AACE advises expectant mothers to take a TSH test before pregnancy or
as part of the standard prenatal blood work.
The symptoms of thyroid illness
are often vague and hard to recognize, especially when they are present after a
woman gives birth. In many cases, the symptoms are mistaken for other conditions
such as depression. In reality, many new mothers who are diagnosed with
postpartum depression may actually be suffering from a common but seldom
diagnosed thyroid disorder known as postpartum thyroiditis. During this time,
women may suffer from an increased heart rate, insomnia, anxiety, as well as
depression. This condition usually occurs during the first few weeks after the
baby is born, and can continue for up to a year. A TSH test will pinpoint
postpartum thyroiditis and medication will return thyroid function to normal,
and often reverses the depression.
Midlife: Menopause Doesn't Have to Mean
"Pause"
One in three women over the age of forty still experience the
common symptoms of menopause despite treatment with hormone replacement therapy
(HRT), according to AACE data. In fact, common menopausal symptoms - mood
swings, depression, sleep disturbances, fatigue, forgetfulness, weight gain,
change in hair, skin, and nails - could actually be signs of an underlying
thyroid condition. AACE recommends that all women over forty have a TSH test
since studies have shown that 10 percent of women in this age group have
undiagnosed thyroid disease.
The Senior Years: Aging Without Feeling
Aged
For some older people, the golden years of life are not what they
expected, due to the onset of symptoms such as fatigue, depression,
forgetfulness, insomnia, and changes in appetite and weight. Most seniors
erroneously assume that these feelings are a natural part of aging, when in fact
these may be signs of an underlying thyroid condition. Seniors who report these
symptoms to their doctors may be misdiagnosed with depression or even mild
dementia. AACE underscores that aging, in the absence of disease, should not
automatically be associated with the above symptoms. Since incidence of thyroid
disease increases with age, and almost 20 percent of women over the age of sixty
have some form of thyroid disease, TSH testing is particularly important for
this age group.
The American Association of Clinical Endocrinologists and
the Neck CheckTM:
While the TSH blood test is the most sensitive and
accurate diagnostic tool, as a first step, AACE recommends that patients perform
a simple self-examination called the Thyroid Neck CheckTM. This self-exam,
unveiled by AACE in 1997, will help Americans detect an enlarged thyroid gland.
If a patient finds an abnormality, they should speak with a physician about
getting tested and treated for thyroid disease.
The American Association of
Clinical Endocrinologists (AACE) was established in 1991 and is the country's
largest professional organization of clinical endocrinologists. Its membership
consists of more than 3,500 clinical endocrinologists devoted to providing care
for patients with endocrine disorders. The association strives to improve the
public's understanding and awareness of endocrine diseases and the added value
of the clinical endocrinologist in the diagnosis and treatment of these
diseases.
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