INTRODUCTION

E. is a teenager and a sort of grand niece. She has a small goitre (a swelling in the neck caused by an enlarged thyroid gland). She has had it for some time and I was told that the cause is Hashimoto’s disease – an autoimmune disease of the thyroid gland, whereby thyroid hormone production is compromised. I don’t have a goitre but I have been taking thyroid hormone replacement for a few years. There are both similarities and differences between the thyroid pathology that is affecting E. and myself so perhaps a review of the subject might be useful. I am out of date with what I learned at Medical School and during my own clinical practice, but my starting point will be to first review my own notes and text books and not go looking at Wikipedia and the web for immediate answers.

I will concentrate on the thyroid gland and its production of thyroid hormones. The gland also produces another hormone, called calcitonin (which is involved with calcium metabolism) but I will not talk about it here. It is also worth saying that there are four small parathyroid glands that exist very close to the thyroid gland and which have very different functions. Their only relevance here is to be aware that when there is surgery to the thyroid gland it is vital that the parathyroid glands are not damaged in the process.

THE THYROID HORMONES, IODINE AND SELENIUM

There are two basic thyroid hormones made by the thyroid – Thyroxine (called T4 because it contains 4 iodide molecules) and Triiodothyronine (called T3 because it contains 3 iodide molecules). Iodine is necessary for the creation of both T3 and T4 and the element selenium is needed for the conversion of T4 to T3. The thyroid is the only organ in the body that contains significant amounts of iodine, which is an element obtained in the diet. Some iodine is secreted by the breast and there is some evidence to show that iodine deficiency predisposes people to an increased risk of breast cancer. Iodine is also being trialed to treat fibrocystic breast disease. Many parts of the world are deficient in iodine (particularly remote mountainous regions or areas where there are calciferous rocks or where there has been glaciation). In much of the developed world iodine deficiency has been addressed by the addition of iodine to salt. Goitres, diminished intelligence and cretinism are all found in areas where iodine deficiency is endemic.

The thyroid produces much more T4 than T3 but when the T4 reaches its target organs it is converted into T3 thus making T3 the “active ingredient”. The secretion of thyroid hormones by the gland is primarily regulated by the production of TSH (Thyroid Stimulating Hormone) from the Pituitary gland, which itself is regulated by the production of TRH (Thyroid Regulating Hormone/Thyrotropin Releasing Hormone) from the hypothalamus (a vital part of the brain close to the pituitary and especially involved in regulation of hormones and the autonomic nervous system). Low levels of thyroid hormones, for whatever reason, usually lead to raised levels of TSH in the blood.

Both T3 and T4 levels can be measured to assess the patient’s production of them but measurement of TSH levels is equally vital since high levels of TSH indicate that the thyroid gland is underperforming and needs to be stimulated because it is struggling to produce enough thyroid hormone – as detected by the hypothalamus and pituitary. Normal serum TSH levels are 0.4-4.0 mIU/L (or 0.5-3.0 mIU/L if the patient is actively undergoing replacement therapy).

As has been outlined, the role of iodine (and probably selenium as well) is very important and adequate dietary iodine is needed to make sufficient T4 and T3. Some iodine is freely available but about 99.95% of iodine is bound normally to plasma proteins in a nearly constant ratio so that measurement of PBI (protein bound iodine) can give a useful interpretable amount; the range for serum PBI in healthy patients is 4.0-7.5 mcg/100ml. This is a useful, but not complete, test since other factors can affect iodine binding.  In modern laboratories both free and bound T4 and T3 can be measured. The normal ranges for adults are: Total T4 = 5.0-12 mcg/dL; Free T4 = 1.0-3.0 ng/dL; Total T3 = 80-190 mcg/dL; Free T3 = 0.25-0.65 ng/dL. Radioiodine uptake of I¹³² or I¹³¹ can also be used to help with diagnosis and to differentiate between Primary (high TSH) and Secondary (low TSH) hypothyroidism.

Sometimes there can be adequate dietary iodine but if it gets bound to other substances (known as goitrogens) then inadequate amounts of iodine actually reach the thyroid. Goitrogens include the inorganic ions perchlorate, pertechnetate, thiocyanate and nitrate as well as the drugs phenylbutazone, the sulphonamides and lithium. They are usually ingested in medications for other diseases or if taken by a pregnant mother they can affect the foetus inside her.

THYROID STATUS

Overproduction of thyroid hormones leads to the condition known as hyperthyroidism. Underproduction leads to the condition known as hypothyroidism. A person who appears to have normal production is called euthyroid but note that a person can be clinically euthyroid but sub-clinically hypothyroid or hyperthyroid! Sub-clinical hypothyroidism means that the person feels and appears to be normal, but they have blood tests, notably a raised TSH level, indicating that their thyroid is struggling to produce enough hormone. Sub-clinical hyperthyroidism also occurs in clinically euthyroid patients but who have lower than normal TSH levels. The presence or absence of a goitre (an abnormal swelling of the thyroid) can occur regardless of the thyroid hormone status. The actual appearance and feel of a swollen thyroid may indicate a specific pathology.

• HYPOTHYROIDISM (Under production of thyroid hormone).

The predominant clinical features arise largely from a reduced metabolic rate, which may fall to 40% of normal in severe cases. The symptoms are insidious and thus often missed for some time but generally consist of undue tiredness, weakness, lethargy, increasing sensitivity to cold, hoarseness, a general slowing of activity, increase in weight, constipation, muscle cramps and menorrhagia (excessively heavy periods). Neurologically there may be impairment of memory, depression, slowness of comprehension and eventually a descent into coma (the “myxoedema madness” first described by Dr Richard Asher).

As the disease progresses, deposits of mucin in the tissues alter the appearance and this phenomenon is known as myxoedema. The face becomes puffy with a thickened tongue and the hair thick and coarse. Infiltration of the vocal cords causes hoarseness and infiltration of the inner ear causes deafness. The heart becomes enlarged and the plasma lipids change for the worse increasing all the risks associated with ischaemic and embolic disease. Carpal tunnel syndrome is common. Microcytic (small red cells) iron deficiency anaemia may be caused by menorrhagia and macrocytic (large red cells) anaemia may also present because of an associated pernicious anaemia, which affects 10% of cases.

Hypothyroidism may or may not be accompanied by goitre. Most, not accompanied by a goitre, seem to arise without a cause though they are probably examples of an auto-immune disease and IgG antithyroid antibodies can be demonstrated in many cases. Hypothyroidism can also be caused by radioactive Iodine therapy or following thyroidectomy for the treatment of hyperthyroidism.

Hypothyroidism with a goitre most commonly occurs where simple goitre is endemic as a result of insufficient intake of iodine. Other causes are the ingestion of goitrogens (which interfere with the synthesis of thyroid hormones) or by infiltration of the gland by cancer cells and also occasionally because of primary disorders of the pituitary gland.

Juvenile hypothyroidism is most commonly associated with autoimmunity (as in Hashimoto’s disease) but can also be due to congenital under-development (even absence) of the thyroid, which may only become apparent when the need for extra thyroid hormone appears during later childhood and adolescence. Just as in adults the onset may be slow and insidious and many of the features are the same as in adults. Growth may be retarded, and the bone epiphyses may be fragmented. Blunting of intellectual development may become apparent during school years.

Congenital hypothyroidism can be caused by (a) rare inborn errors of metabolism (b) in areas of endemic goitre and (c) when the mother has been taking anti-thyroid or iodide medications during pregnancy. Foetal and neonatal hypothyroidism can have severe effects leading to cretinism, which can be either immediately obvious after birth or missed for some time.

• HYPERTHYROIDISM (over production of thyroid hormone).

This is a group of disorders that involve excessive synthesis and secretion of the thyroid hormones T3 and/or T4. The raised levels lead to a hypermetabolic state with wasting, tachycardia, palpitations, irritability, sweating and heat intolerance. Part of this syndrome is due to an increased stimulation of the sympathetic nervous system with excessive outpouring of adrenalin and associated neurotransmitters. The most severe manifestations are called thyrotoxicosis, when there are toxic effects, which may need emergency intervention. There are four main forms: (a) diffuse toxic goitre (Grave’s disease), (b) toxic multinodular goitre (Plummer’s disease) (c) toxic adenoma along with (d) subacute thyroiditis.

The thyroid normally contains a large supply of its preformed hormones kept in its follicular lumen. These are released in response to TSH but also to LATS (Long Acting Thyroid Stimulator) which is an autoimmune immunoglobulin with TSH-like actions. LATS (and other similar autoimmune antibodies) may be raised is some forms of hyperthyroidism. It is the excess of free and not bound levels of T3/T4 that gives rise to the symptoms of hyperthyroidism. Thus, any process that causes an increase in the peripheral circulation of unbound thyroid hormone can cause thyrotoxicosis. Regardless of the aetiology the result is an increase in the basal metabolic rate with many of the signs and symptoms resembling a state of catecholamine excess. Adrenergic blockade may be useful in management of toxic effects.

Thyrotoxicosis is marked by suppressed TSH levels (unless the pituitary is secreting excessive amounts of TSH due to a tumour) and elevated T3 and T4 levels. Subclinical hyperthyroidism is still marked by suppressed TSH levels though the T3 and T4 levels may be normal. There are two main tests for autoantibodies: anti-TPO (anti-thyroid peroxidase) and TSab (thyroid stimulating antibody) also known as TSI (thyroid stimulating immunoglobulin) or LATS (long-acting thyroid stimulator).

In Graves disease, raised levels of LATS or other stimulatory immunoglobulins provide continuous stimulation of the thyroid as well as increased iodine uptake, protein synthesis and thyroid gland growth. An associated ophthalmopathy is a common accompaniment (exaggerated in cigarette smokers) and in which the eyeballs are pushed forward by tissue behind the eye. The autoimmune disorders found in both hyperthyroid Grave’s Disease and hypothyroid Hashimoto’s disease have a genetic correlation, with clusters occurring in families.

When subjects who live in areas where there is endemic iodine deficiency move to areas where there is sufficient iodine then hyperthyroidism can also result.

Toxic multinodular goitre and toxic adenoma have low or absent anti-TPO and TSab levels.

There are three mainstays of treatment for hyperthyroidism: (a) antithyroid medications such as methimazole, (b) radioactive iodine treatment and (c) thyroidectomy, which is reserved for special circumstances such as severe hyperthyroidism in children, some pregnant women and those with very large goitres or severe ophthalmopathy.

Hyperthyroidism from toxic multinodular goitre and toxic adenoma are permanent but may become euthyroid (normal levels) following treatment. Patients with Grave’s disease may eventually become hypothyroid.

Long-standing hyperthyroidism can result in left ventricular thickening and the risk of heart failure as well as excessive bone resorption and osteoporosis.

• THYROIDITIS (an inflammation or infection of the thyroid).

Chronic forms (a. Diffuse goitrous also known as the lympadenoid goitre of Hashimoto’s disease, b. Focal forms in association with hyperthyroidism or other goitres & c. Diffuse atrophic which can be mild or severe (primary hypothyroidism).
Subacute (De Quervain’s viral thyroiditis)
Acute forms (Bacterial infection)
Invasive fibrous (Riedel’s thyroiditis)

Chronic diseases such as tuberculosis, sarcoid and syphilitic gummata rarely involve the thyroid gland so the term chronic thyroiditis usually refers to the autoimmune thyroiditis known as Hashmimoto’s disease.

There exist other known organ-specific autoimmune diseases such as Pernicious anaemia, Addison’s disease, Type I Diabetes and Multiple Sclerosis. In Hashimoto’s disease there is lymphocytic infiltration and fibrosis with eventual atrophy of the thyroid which then ceases to fulfil its physiological function. This process is accompanied by the presence in the blood of organ-specific antibodies. It is the intense chronic inflammation and fibrosis that accounts for the goitre. The thyroid is almost uniformly enlarged, smooth, lobulated and firm and it is possible that the trachea and oesophagus may become compressed. The changes are seen at all ages and in both sexes but typically the patient is a middle-aged female with a rubbery diffuse goitre. Patients may be either euthyroid or hypothyroid but thyroid function tests may show evidence of impaired thyroid reserve with a raised plasma TSH.

If the patient with Hashimoto’s has a large goitre, an initial short course of prednisolone often rapidly reduces its size. However, most patients are treated with thyroxine in doses of 0.2-0.3 mg/day and appropriately less in Children. The reduction in size is often slow. When a patient with a large goitre fails to respond or if there are pressure effects on adjacent organs then thyroidectomy may be indicated.

Sub-acute viral thyroiditis is a usually a self-limiting process lasting from months to a couple of years, typically in a young or middle-aged female. The initial goitre is usually of rapid onset and associated with pain. The patient is usually euthyroid.

Acute bacterial thyroiditis is rare and usually spreads from an adjacent infected area.

Invasive Fibrous thyroiditis (Riedel’s struma or woody thyroid) is a rare disorder of unknown origin that can spread into adjacent tissues causing localised compression and discomfort. No medications seem to be effective and excision may be necessary to prevent local complications.

• MISCELLANEOUS GOITRES

Goitrogen induced goitres are caused by the ingestion of substances that inhibit thyroid hormone synthesis. A simple goitre is defined as one that appears when the other types have been excluded. They may be endemic or sporadic and are either diffuse or nodular. Most are due to a dietary insufficiency of iodine. The requirements for iodine are increased both by goitrogens and by stress and a high calcium intake also seems to have a goitrogenic effect as does drinking polluted water. Rare anomalies such as cows eating too much kale can create milk that is high in thiocyanate and create a local epidemic of goitres in those who have drunk the milk.

Dietary intake of iodine should not be below the recommended intake of 150 mcg per day and this may be insufficient with the additional demands of adolescence and pregnancy.

A simple goitre has hyperplasia of tall columnar epithelial cells resulting in a uniformly enlarged thyroid and is the type of goitre often seen in children and younger adults. Such goitres can go through alternating periods of expansion and contraction such that eventually the thyroid becomes non-uniform and nodular.

The last group of goitres to mention include both benign and malignant neoplasms about which I don’t intend to write about here.

SUMMARY

I have been prompted to review this topic for myself following E’s recent infection of Herpes Zoster affecting her 7^th and 8^th cranial nerves. I had thought she had a Bell’s palsy of the 7^th nerve but did not know about the small rash and a small degree of hearing loss. In the course of investigations she was discovered to have anaemia. The diagnosis of her Hashimoto’s disease also resurfaced and thus also whether management of it should be changed.

E. may still have unresolved questions that may not have been adequately answered. If so, I hope that this résumé may be of some help to her (or similar sufferers) if only to be able to help to pose any questions more effectively. This is not my field of expertise, though I do still have access to some doctors (whom I have a good opinion about) and probably I should talk to them.

In the first place it would be helpful to know that a diagnosis of Hashimoto’s disease is accurate. I believe that the diagnosis is primarily reliant on the detection of specific autoimmune antibodies, so this would need to be confirmed.

In the second place it is necessary to know how hard the thyroid is having to work to provide adequate amounts of thyroid hormones. The actual levels can be measured but the TSH level is also important. E. appears to me to be clinically euthyroid but if the TSH levels are above normal the question arises as to whether she should start taking thyroxine replacement therapy or not. I will return to this later.

In the third place is the presence of anaemia for which she is being treated with iron and a wide-spectrum of B vitamins including oral Vitamin B12. It is very important that the cause of this anaemia is correctly diagnosed. Simple iron deficiency anaemia is seldom due to a lack of intake of iron and is commonly due to excessive blood loss. If she is anaemic because of vitamin B12 deficiency she will obviously need enough iron to allow the new cells to form properly but any underlying pathology (such as in pernicious anaemia stemming from an autoimmune attack on part of her stomach which then prevents the normal absorption of vitamin B12) should to be taken account of and she should be given adequate amounts of vitamin B12 and folate. Vitamin B12 is necessary for more than red blood cell production. Lack of it can affect both DNA synthesis and the normal development of the nervous system. Lack of vitamin B12 and folate during pregnancy can lead to “neural tube defects” in the embryo which can result in spina bifida.

TO TREAT OR NOT TO TREAT SUB-CLINICAL HYPOTHYROIDISM

E. and I both seem to be clinically euthyroid (lacking symptoms of under or over production of hormone). I am, however, definitely sub-clinically hypothyroid because I have high levels of TSH circulating in my body. When this was first diagnosed (my nurse just took a blood sample during a routine check) I thought little about it because I knew that I was clinically euthyroid; I felt absolutely normal. Some knowledgeable doctor friends from England told me I was mad and that I should start taking thyroxine medication. For a long time I ignored them – but not any more.

Thyroid hormones are essential for normal health. They are especially important during various stages of development, notably during pregnancy and adolescence. Possibly I have enough T3 and T4 in my body but the fact that my pituitary is having to pour out excessive amounts of TSH is not normal. What is not clear is whether the over production of these stimulating hormones from my hypothalamus and pituitary could be having effects elsewhere in my body. The whole endocrine system (and indeed the whole neurological system) is so very interlinked that it is unlikely that any part of it should ever be considered in isolation.

In recent times I, myself, have noticed a loss of libido but I had put this down to the normal ageing process. Perhaps it could actually be related to my thyroid function because I now read that adequate thyroid function is necessary for normal potency and libido in both men and women.

I can’t answer for, or advise, E. on whether to start taking thyroxine or not. I just don’t know but first of all I think the diagnosis of Hashimoto’s needs to be confirmed and for her to also know, more precisely, what her thyroid hormone and TSH levels are. I do think she should review any thinking about both vitamin B12 and thyroxine if she is ever contemplating becoming pregnant.

I, unlike E., have no goitre and am nearer the end of my life than its beginning so aspects of my hypothyroidism are of much less importance. I have only just realised that I, myself, don’t have an accurate diagnosis so I will be doing more blood tests at the next visit to my nurse to determine the actual cause and indeed whether or not I have late onset Hashimoto’s disease.

I realise it is not nice to contemplate having to take any medication for the rest of one’s life but at least it is just a pill a day and not 1 or 2 o 3 injections a day that is the bad luck for many diabetics.