Aspects of a common missed diagnosis: Thyroid dysfunction...

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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.

Keywords: thyroid, basal temperature, clinical appraisal, adrenal insufficiency.

INTRODUCTION
The syndrome which results from a deficient output of thyroid hormone or deficient utilization is at once extraordinarily common and as commonly misdiagnosed [ 1]. Why it is that the diagnosis of such a frequently seen illness is so often missed is the primary purpose of this survey and attention will be given to the failure of correct management of an easily and rewardingly treatable illness. The term 'myxoedema' was used by Ord [ 2] (in 1878) when he found atrophy and fibrosis of the thyroid in association with the presence of a water-containing mucopolysaccharide throughout the tissues. These patients had died in coma following a protracted illness where increasing lethargy had combined with bloating and weight gain; they had become increasingly troubled by cold and subject to hair loss, intractable constipation and a number of other distressing symptoms. It is this syndrome which doctors see in their mind's eye as myxoedema and herein is one of the reasons for diagnostic failure. Thyroid output or utilization of thyroid hormone, may fall slowly over many years, indeed over much of a lifetime and, depending on the degree of failure, will depend on the pattern of symptoms. A 15% loss will be quite different from a 50% loss and greater or lesser involvement of the adrenals and gonads will also alter the picture. It was Murray [ 3, 4], in 1898, using ground-up animal thyroid as a replacement, who effected the first cures. His work was paralleled by Eugene Hertoghe [ 5], in Belgium, who wrote a series of papers which form the basis of our clinical appreciation of thyroid insufficiency. He described its influence on growth in the young; its role in infectious disease; and mild hypothyroidism, culminating in his monograph published in New York in 1915 [ 5] and his paper in the Practitioner the year before. His son and, later, his grandson, Jacques, continued the work. We owe much to these able and conscientious physicians and a great debt to Broda Barnes [ 6], in the US, who untiringly, from before the war to his death 5 years ago, wrote papers to draw doctors' attention to thyroid deficiency and founded the Barnes Foundation to disseminate knowledge to, regretfully, a less than enthusiastic medical fraternity. His book, Hypothyroidism: The Unsuspected Illness [ 6], is a classic of clinical acumen and clear thinking. Much of the present writer's interest stems from his books and papers and this paper is a further effort to draw clinicians' attention to a condition all too often passed over in diagnostic assessment.

HYPOTHYROIDISM: THE UNSUSPECTED ILLNESS
The thyroid endocrine gland, bilobal in structure and highly vascular, occupies much of the anterior aspect of the neck. It is made up of a dozen follicles containing a protein-rich colloid--a glycoprotein--called thyroglobulin. Iodine is formed from oxygenation of iodide and under the action of peridoxases is converted to thyroxine (T4) and triiodothyronine (T3). Most of the T3 is made from the deiodination of T4, chiefly in the liver and kidneys, by the removal of one of the four iodine atoms under the action of the enzyme 5'-diiodase. T4 has a low biologic activity and is transported in the bloodstream by thyroid binding globulin, thyroid-bound prealbumen and an albumen complex. It is relatively stable and has a half-life of approximately 8 days, while T3 has a half-life of approximately 8 h and is biologically active. The production of T4 and T3 is regulated by thyroid-stimulating hormone (TSH) and by the amount of iodine available. Approximately 100-150 mug of I2 is required daily. Its function is to regulate all the energy transformations within the cell and, hence, control all the biochemical changes of metabolic activity. The site of action is on receptors in the cell membrane, stimulating entry of amino acids and sugars and it stimulates adenosine triphosphate production within the mitchrondria. Hence, the following functions are regulated by the thyroid: heat and energy output of the cell, the blood circulation and removal of cellular waste products, growth and the integrity of immune systems. The amount produced is at its maximum in early adult life, after which it falls slowly. The thyroid is easily damaged by many disease processes and is five times more likely to be damaged in women than men; autoimmune diseases in particular may affect its integrity. Environmental hazards are having an increasing affect on thyroid activity in the present day. Placing on one side carcinomatous change, there are two pathological changes with which we must be concerned.

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. The TSH receptors become the victim of autoimmune attack; antibodies bind to them and either provoke pathological stimulation or block them off. The former situation will cause excessive production of T4 and T3. This may be seen at any age or in either sex, but most commonly in young women. The symptomology is well known but may bear repetition. The symptoms include weight loss, restlessness and anxiety, diarrhoea, tremor, breathlesshess, tiredness, palpitations, unusual sweating and abnormal thirst. On examination, a bounding pulse and tachycardia, a wide pulse pressure, tremor, unusual warmth, prominent eyes, with lid lag, evidence of weight loss and possible soft diffuse enlargement of the thyroid will be found. Marked elevation of free T3 and T4 will almost invariably be found but not necessarily TSH depression. The management of hyperthyroidism cannot be said to be satisfactory and is not without its hazards. A mild overactivity may be treated symptomatically with careful monitoring since in these patients the condition may resolve spontaneously. beta-Blockers, with or without anxiolytics, may be used with considerable success; Carbimazole in small doses, which inhibits thyroid hormone manufacture, will be found to control many patients until spontaneous resolution occurs. The more intractable hyperthyroid patient may come to cautious radioactive iodine ablation or partial thyroidectomy. The problem with this line of management is that it is very difficult to get it right. Almost invariably the guesswork involved may mean that too much or too little thyroid tissue remains. And, since the condition usually resolves spontaneously in time, the patient usually becomes hypothyroid sooner or later, requiring replacement therapy.

Hypothyroidism is very much more common; 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
One of the diagnostic difficulties is the fact that the symptoms are legion; they vary from patient to patient and may be put down to any number of other causes [ 8]. Yet taken together, with a high index of suspicion on the part of the physician, there should really be no problem. A list of common presenting symptoms illustrates the point.

weight gain;
lethargy;
sensitivity to cold;
heat intolerance;
fluid retention;
mood swings and depression [ 9];
poor memory and concentration [ 9];
hair loss;
arthralgia and morning stiffness;
skin problems and furunculosis;
headaches;
vertigo and deafness;
hypoglycaemia;
constipation;
menstrual problems;
pre-menstrual tension (PMT);
digestive problems;
infertility;
loss of libido.
The signs of hypothyroidism again may be conveniently listed:

puffy faecies and periorbital oedema;
hair loss, classically the outer third of the eyebrows;
cold extremities and dry skin;
rashes, eczema and boils [ 10];
enlargement of the tongue;
hoarse voice;
soft pulse and bradycardia;
goitre or absent thyroid tissue;
slowed achilles tendon reflex [ 11].
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]. The resting temperature provides a useful strong indication, since it is directly related to the basal metabolic rate. Regrettably, this valuable tool has been ignored or derided by a number of authorities. The axillary temperature, after l0 rain, is taken immediately on awakening over several days. If it is significantly below 97.8 degrees F (36.6 degrees C), there is a strong indication of a low metabolic rate. (In menstruating women, this is of diagnostic value only during the second to fourth days of menstruation.) Hypopituitarism, malnutrition and adrenal insufficiency have to be excluded as other causes of low basal body temperature [ 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 T3. 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
The satisfactory management of the hypothyroid state is extraordinarily rewarding for both the clinician and patient. It is not difficult and does not require repeated blood estimations as is commonly believed and, again contrary to common belief, has almost no hazards. The aim is to restore tissue levels to normal, correcting all the functional deficits in the working of all the organs of the body. In this, clinicians should take as their primary purpose the treatment of the patient and not the disease and, most especially, not the blood test. There must be a flexible approach to patient needs and the patient should be taught to monitor him/herself. The level of replacement will be different from patient to patient, depending on the severity of the deficiency. However, the level will also vary dynamically in each individual. This is affected by such factors as variability in absorption and a possible antibody effect, the level of physical activity, the season and ambient temperature, other co-existing deficiencies and other illnesses and the further deterioration in endogenous thyroid hormone production. The management has to take account of the causative mechanism of the hypothyroid state. The approach is likely to be different if the thyroid underactivity is primary or secondary, if there is receptor deficiency or receptor resistance, and if there are other endocrine deficiencies. The first requirement is the provision of proper nutrition and the correction of vitamin and mineral deficiencies. Iodine is of course obvious, but is not usually a problem in this country, where there is usually a sufficiency in the diet. This does not apply in certain inland areas, notably central Europe, or areas with general malnutrition. The zinc, selenium, magnesium and iron intakes should receive attention. Environmental toxins, polychlorinated biphenyls, cassava and caffeine, for example, need to be eliminated. As important is a healthy, active life-style.

Usually, thyroid hormone replacement is the treatment required. In this country, thyroxin T4 (Eltroxin from Glaxo) is nearly always used. Triiodothyronine T3 (Tertroxin) is sometimes used. The present writer has found that most patients respond better and more completely to natural desiccated thyroid which, though not normally now available in the UK, is much used in Europe and the US.

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. Improvement is likely to continue for months and the temptation to increase the dose too soon must be avoided. The patient must be reassured not to expect too much too soon. However, within 2 or 3 weeks, there will be some aspect which will have undergone improvement, for example an increase in energy or body warmth may be admitted to. 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, Considering receptor deficiency first: the integrity of the receptors is damaged by prolonged hypothyroidism; the vitamin, mineral and trace element levels need to be correct and (of paramount importance) depend on normal glucocorticoid levels and, hence, adrenal function. Thyroid hormone acts to some degree as an adrenal challenge; if adrenal reserve is poor or the adrenals are underactive [ 14-16], an adrenal insufficiency state may be precipitated, with the patient feeling quite ill or undergoing a cardiovascular collapse. 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. Should it be suspected, thyroxin should be stopped and tertroxin used instead. With glucocorticoid cover, 10 mug, in micrograms of T3 (half a tablet), is given. The 8 h half-life of T3 means an initial variable response, but within a few days 10 mug may be given morning and evening. The response should be monitored over several weeks, increasing the dose as necessary. After several months, the conversion process is likely to have re-established itself and thyroxin may be substituted (20 mug T3 equivalent 100 mug T4).

Receptor resistance is uncommon and is unlikely to be suspected until the above measures have been found to be insufficient to provide a response. An increase in replacement must be invoked under careful monitoring until the patient is well. High doses in this situation require thought and conviction but are necessary. Attention should be given to alternatives to standard thyroxine supplementation. 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; the response may well be improved where the outcome of conventional replacement is disappointing. The present writer greatly prefers natural desiccated thyroid, using Armour Thyroid, or URL thyroid USP, both of which are natural and come from the US. These high-quality preparations are preferred by nearly all patients, who say, simply, that they feel better than on the synthetic replacement. Since it cannot be refuted that the organism will respond better to natural molecules than synthetic ones in general, this should be the treatment of choice. The objection that the potency is variable is not relevant; since the system's needs vary dynamically anyway, both Armour and URL are extremely consistent in their strength. Dosage regimes start at 0.25-0.5 grain daily and may be increased to 2 to 4 grains or more grains as needed, preferably chewed and taken before breakfast.

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. Proper clinical appraisal and careful monitoring with careful dosage adjustment are clearly mandatory in such cases. In a lifetime's study, Barnes has shown that arteriosclerosis was much reduced by the maintenance of the euthyroid state [ 19-22]. Further, he showed that serum cholesterol was always raised in hypothyroidism and always reduced by replacement therapy [ 23]. Another study showed that hypertension was steadily lowered by thyroid replacement [ 24, 25]; increased renal perfusion resulting from increased cardiac output reduced renin and hence the blood pressure.

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. (As if, by furious activity, the metabolism may be stimulated.) They will always be poor achievers. The basal temperature will usually provide clear evidence; blood pathology may help but not exclusively. A trial of treatment will usually be most rewarding.

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. Subsequent menorrhagia and worsening PMT with early signs of the menopause are a frequent feature. The failure to diagnose a common and easily treatable deficiency condition is an unfortunate reflection on a prevailing attitude on the part of the profession where the patient is not listened to sufficiently and examination takes second place to a blind and unwarranted confidence in laboratory diagnosis. 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.

REFERENCES
[1] Jackson AS. Hypothyroidism. JAMA 1957; 163: 2.

[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.

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By B. J. DURRANT-PEATFIELD MB BS LRCP MRCS 86 Foxley Lane, Purley, Surrey CR8 3EE, UK

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