Hospital Pharmacist Vol 7 No 1 p6-13
January 2000 Special Features

Thyroid disease

The aetiology and pathology of thyroid diseases

By A. Bhattacharyya, DM, MRCP (UK) and P.G. Wiles, MD, FRCP

Our special feature this month is thyroid disease. This first article classifies the various diseases which could affect the proper functioning of the thyroid gland. The second article discusses the available treatments

The thyroid gland is one of the largest endocrine organs, weighing approximately 15-20g in adults. The gland is composed of closely packed sacs, called acini or follicles, which are invested with a rich capillary network. The interior of the follicle is filled with proteinaceous material called colloid. The thyroid gland also contains parafollicular or C cells that are the source of the calcium lowering hormone, calcitonin. Normal function of the thyroid gland is to secrete thyroxine (T4) and triiodothyronine (T3), the active principles with various influences on metabolic processes. T3 is the more metabolically active of the two, and is mostly produced from T4 in the peripheral tissue, mainly in the liver. Thyroid stimulating hormone (TSH) is the trophic hormone, secreted from thyrotrophs of the anterior pituitary gland, which stimulates the secretion of thyroid hormones from the thyroid gland. TSH is regulated by thyrotrophin releasing hormone (TRH), which is produced in the hypothalamus.Thyroid hormones in circulation control both TRH and TSH for thyroid hormone homeostasis.
Anatomical (structural) and physiological (functional) abnormalities of the thyroid gland are common. Diseases of the thyroid gland can occur at any age, from intrauterine life (foetal Graves' disease) to the elderly, and in both genders (although there may be gender differences, for example, autoimmune thyroid disease [AITD] is more common in women). Some of the thyroid diseases are relatively benign (simple goitre) whereas some are life threatening (thyroid crises). Hypothalamo-pituitary disorders can be responsible for inducing underactive or overactive thyroid states. In this article, we shall be describing the aetiology and pathology of common thyroid diseases.
Thyroid diseases can be subdivided into three broad groups:

• Diseases of the thyroid gland itself (the vast majority)
• Hypothalamo-pituitary diseases
• Thyroid hormone resistance syndrome

First, however, we will consider the condition known as sick euthyroid syndrome.

Sick euthyroid syndrome

Several systemic illnesses can upset thyroid hormone secretion, transport and/or metabolism. Thus, biochemical assessment of the thyroid state can vary widely without there being an intrinsic problem with the gland. This situation has been called sick euthyroid syndrome (SES).
A very high percentage (40-70 per cent) of patients with a non-thyroid illness may have one or more abnormalities of the thyroid function tests.¹ The severity of illness is usually more important than its nature. This can be divided into three main types - low T3 state, low T3 - T4 state and a high T4 state, all with normal TSH. The common conditions encountered in day-to-day clinical practice are caloric deprivation (usually secondary to systemic illness), liver disease, poorly controlled diabetes mellitus, nephrotic syndrome, chronic renal failure, systemic infection and psychiatric disorders. The vast majority is euthyroid and requires no specific thyroid related therapy.
Many pharmacological agents affect the results of the thyroid function tests, either by acting on the thyroid gland or by altering the peripheral distribution and metabolism of the hormone. Common drugs that alter the thyroid hormone indices are glucocorticoids, dopamine, androgens, salicylates, frusemide, heparin, amiodarone (discussed later) and propranolol. Some of these effects can be exploited in clinical practice, for example, the use of propranolol and corticosteroids in thyrotoxic crisis.

Diseases of the thyroid gland

Diseases of the thyroid gland are manifested by alterations in hormone secretion, enlargement of the gland (goitre) or both as shown in Table 1. Inadequate secretion causes hypothyroidism or myxoedema, and an excess of it causes hyperthyroidism. Generally, the terms hyperthyroidism and thyrotoxicosis are used interchangeably. Hyperthyroidism, however, should imply an overactive thyroid gland secreting excess thyroid hormones whereas thyrotoxicosis may be induced by excess exogenous T4, ie, thyrotoxicosis factitia, which will be discussed later.

Table 1: Diseases of the thyroid gland
A. Congenital	1. Absent thyroid
	2. Ectopic thyroid
	3. Dyshormonogenesis
B. Autoimmune	1. Graves' disease
	2. Hashimoto's thyroiditis
C. Infective
D. Neoplastic	1. Benign
	2. Malignant:	a. Papillary carcinoma
		b. Follicular carcinoma
		c. Anaplastic carcinoma
		d. Medullary carcinoma
		e. Lymphoma
E. Miscellaneous causes

Goitres may be associated with increased, normal or decreased hormone secretion. Focal enlargement usually reflects a neoplastic process, which can be either benign or malignant. Circulating thyroid hormone levels may vary during the course of a disease process. For example, Hashimoto's thyroiditis may present with hyperthyroidism, later becoming hypothyroid.

Congenital thyroid diseases Congenital thyroid diseases can cause neonatal hypo- or hyperthyroidism, or can present in early childhood as goitre or growth failure. Inherited defects in hormone synthesis may occur due to impairment of iodide transport, defective iodination of thyroglobulin, deficient iodotyrosine dehalogenase (the enzyme that converts T4 to T3), abnormalities in thyroglobulin synthesis and coupling of iodotyrosines (dyshormonogenesis). In these cases, the lack of thyroid hormone causes an increased release of TSH, which induces diffuse hyperplasia of the gland, producing goitre.
Ectopic thyroid tissue is frequently found in neonatal hypothyroidism (either lingual thyroid or anywhere in the line of the thyroglossal duct) although the commonest cause of neonatal hypothyroidism is total failure of development of the thyroid gland. Neonatal hyperthyroidism is almost always due to foetal Graves' disease. Transient hypothyroidism is also known to be due to transplacental passage of TSH-blocking immunoglobulin. These are discussed later.

Hashimoto's thyroiditis The abundance of lymphocytic infiltration in the thyroid gland, along with circulating thyroid microsomal antibody and thyroglobulin antibody, are characteristics of Hashimoto's thyroiditis. In contrast to Graves' disease, destruction of the thyroid gland is the key feature in Hashimoto's thyroiditis. In some cases the gland is atrophied and the term primary thyroprivic hypothyroidism is used.
As in Graves' disease, there is a significant but weak association of particular human lymphocyte antigen (HLA) types with Hashimoto's thyroiditis. Familial predisposition has been well documented and both cellular and humoral arms are involved in the pathogenesis.
The gland is usually enlarged and firm on palpation. The diffuse dense lymphocyte infiltration with germinal centre formation, obliteration of thyroid follicles and fibrosis, are hallmarks in the histology. The epithelial cells and the follicles are destroyed in most places. The remaining epithelial cells may be larger and show oxyphil changes in the cytoplasm. These so-called Askanazy cells are virtually pathognomonic. The initial inflammatory state may induce transient thyrotoxicosis, but the final outcome is hypothyroidism.

Subacute thyroiditis Subacute thyroiditis (also called de Quervain's thyroiditis) is thought to be caused by a viral infection and often is associated with viral sore throat. The viruses implicated are influenza, echo, adeno and Coxsackie virus. Some of these patients eventually develop autoimmune thyroid disease.³ A characteristic clinical feature is pain in the region of the thyroid gland with or without fever. The gland is firm and tender to palpation.
Histologically, the cells differ from Hashimoto's thyroiditis by their patchy distribution. Affected follicles are infiltrated by mononuclear cells with partial or complete loss of colloid. The follicular changes may progress to granuloma with multinuclear giant cells. When the disease process subsides, an essentially normal histological appearance is restored.

Postpartum thyroiditis Postpartum thyroiditis is recognised as an autoimmune thyroid disease (AITD) presenting three to six months after giving birth, with a transient phase of destruction followed by a period of primary hypothyroidism and eventual return to a euthyroid state within a year.⁴ A painless goitre on clinical examination and a positive result for thyroid microsomal antibody in immunological screening are usually found. The incidence varies from 2 to 16 per cent depending on the population.^4,5 The identified risk factors are:

• Family history of AITD
• Positive thyroid microsomal antibody during pregnancy
• Previous postpartum thyroiditis
• Cigarette smoking
• Excessive iodine intake⁶

Miscellaneous conditions Silent or painless thyroiditis is that form of AITD where there is no pain over the thyroid area. The underlying mechanism is autoimmune dysregulation with extensive lymphocyte infiltration, presence of plasma cells and circulating autoantibodies. The course is mostly benign and self-limited. Reidel's thyroiditis (chronic sclerosing thyroiditis) is very rare. A very hard, painless goitre is usual and this can be associated with fibrosis elsewhere (retroperitoneal or mediastinal fibrosis).

Infective Acute pyogenic (suppurative) thyroiditis is fortunately rare. The commonest infective organism is Staphylococcus aureus. Usually the infection is from a septic focus outside the thyroid gland. Surgical drainage is indicated when pus is present. It is characterised by excruciating tenderness over the thyroid area associated with systemic symptoms. Needle biopsy is often required to differentiate this condition from subacute thyroiditis and to obtain a specimen for culture of the organism.Other rare infective causes of thyroid disease are tuberculosis, coccidiodomycosis and pneumocystis. Acid fast bacilli are not always found but multiple coalescing and caseating epithelioid cell granulomas along with giant cells are considered to be diagnostic of tuberculous affection of the gland.⁷ Tuberculous or Pneumocystis carinii infection could indicate an acquired immunodeficiency state as the underlying disease process.⁸

Thyroid neoplasia Thyroid tumours are the most common endocrine neoplasms and most cases are localised to the thyroid gland by palpation. The majority of these are benign. The prevalence increases with advancing age and is more common in women.⁹
Malignancy risk increases with previous history of irradiation in the head and neck region, family history of thyroid or multiple endocrine neoplasia, and with increasing age. Thyroid malignancy can also be secondary to a primary tumour in another part of the body (haematogenous spread).

Papillary thyroid carcinoma Papillary thyroid carcinoma (PTC) makes up 50-90 per cent of differentiated thyroid malignancies and is the most common type of differentiated thyroid cancer. Typically, PTC shows a predominance of papillary structures but the papillae are usually mixed with neoplastic follicles having similar nuclear features. The nuclei of PTC cells have a distinctive appearance in aspiration cytology and are helpful in diagnosis before surgery. The new appreciation of histological subtypes of papillary carcinoma has provided fresh clues to identify the cancers with poor prognosis.¹⁰ Papillary carcinomas spread via lymphatics and distant metastasis confers a poorer prognosis.¹¹

Follicular thyroid carcinoma Follicular thyroid carcinoma (FTC) shows evidence of follicular cell differentiation. This is the second most common thyroid malignancy, predominantly seen in older people. It is twice as likely to occur in women as in men. The overall incidence of FTC is 1-10 per 100,000 of the population in most countries.
Histologically, the cells are characterised by varying degrees of resemblance to normal follicular architecture and function (including colloid formation), capsule formation with capsular invasion and local tissue and vascular invasiveness. Lymph node invasion is uncommon. Virtually all FTCs are monoclonal in origin.¹² Genetic factors may have a role in determining susceptibility to the disease. With the widespread adoption of iodination programmes, the incidence of follicular thyroid carcinoma is decreasing.
Anaplastic thyroid cancer Anaplastic carcinoma is the most aggressive type of thyroid cancer and virtually all patients die from progression of this tumour. This disease usually occurs after the age of 60 and, again, are more common in females. Anaplastic carcinoma is non-capsulated, extends widely and invades skin, muscle, nerve, blood vessel, larynx and oesophagus.
Histological examination shows atypical cells with numerous mitoses, multinuclear giant cells, areas of necrosis, internuclear cytoplasmic invagination, in addition to invasion of the neurovascular bundle and adjacent structures.

Medullary thyroid carcinoma Medullary thyroid carcinoma (MTC) accounts for around 10 per cent of thyroid malignancies, usually occurs after the age of 40 years, and invades intergranular lymphatics and regional lymph glands. MTC arises from C cells or parafollicular cells. Histologically, they present as round, polyhedral, spindle shaped cells which form a variety of patterns but do not form papillary folds or follicles. There is an abundance of hyaline connective tissue stromata that stain positively with Congo red for amyloid.¹³
MTC occurs in both sporadic and familial forms, and may be associated with neoplasia in other endocrine glands. A familial form occurs in younger age groups, mostly bilateral, and with a better prognosis. Other prognostic factors related to the outcome of MTC are:

• Age at diagnosis
• Male gender
• Vascular invasion
• Calcitonin immunoreactivity
• Amyloid staining in the tumour tissue
• Abnormal post-operative calcitonin levels¹⁴

Other thyroid malignancies The other thyroid carcinomas include primary lymphoma of the thyroid, which is the commonest, squamous cell carcinoma and insular thyroid carcinoma.

Miscellaneous There are other rare causes of thyroid disease. Recently, alpha interferon used for treatment of chronic active hepatitis has been shown to increase the incidence of hyper- and hypothyroidism.^15,16 Sarcoidosis has been shown to produce a non-caseating granuloma in the thyroid.¹⁷ The more the infiltration, the greater is the chance of hypothyroidism. Sometimes this may be mistaken for thyroid tumour.¹⁸

Hypothalamo-pituitary diseases

In hypothalamo-pituitary diseases such as pituitary tumour, removal of the pituitary gland, hypothalamic tumour and following external radiation, lack of TSH results in hypothyroidism. In contrast to primary hypothyroidism (disease of the thyroid gland), TSH is low or undetectable in hypothalamo-pituitary disorders (so-called secondary and tertiary hypothyroidism). Low thyroid hormone levels associated with low TSH is a pointer to investigate for hypothalamo-pituitary diseases.
Rarely, there can be a TSH-secreting tumour of the anterior pituitary gland which can make the patient hyperthyroid. Raised thyroid hormones, with a raised TSH or normal TSH is an indicator for such a situation.

Thyroid hormone resistance syndrome

Thyroid hormone resistance has only been described in relatively recent times. In this, there is a decrease in sensitivity of peripheral tissue receptors to thyroid hormones. The clinical syndrome of hypothyroidism ensues, despite excess thyroid hormones in the circulation. In contrast to this, a far rarer condition has been described when the pituitary gland does not sense the circulating thyroid hormones, inhibiting the feedback mechanism so that the pituitary gland continues to secrete an excess amount of TSH, which, in turn, stimulates the thyroid gland, producing an excess amount of T3 and T4. This is called selective pituitary resistance and can produce hyperthyroidism.^19,20 The defect lies in a mutation of the thyroid receptor gene. About 300 families with these disorders have been identified but the population prevalence is difficult to tell.

Special situations

Thyroid disease in special situations includes thyroid disease in pregnant women, the elderly, children, those in whom there is an imbalance in iodine uptake, those exposed to radiation, and where there has been an overconsumption of thyroid preparations (thyrotoxicosis factitia).

Pregnancy and thyroid disease Thyroid disease is common in women2 and thyroid disorders are often encountered in reproductive dysfunction, pregnancy and in the post-partum period21 (Table 2). Changes in thyroid function tests occur in pregnancy, due to a rise in circulating thyroid binding globulin, causing a rise in total, but not free, thyroid hormone levels. In addition, hypermetabolic symptoms of normal pregnancy may resemble the clinical picture of thyrotoxicosis. Early pregnancy is characterised by an increase in maternal thyroid hormone secretion stimulated by human chorionic gonadotropin (HCG). Pathological conditions of excess HCG secretion, such as gestational trophoblastic disease and hyperemesis gravidarum, may present as thyrotoxicosis in pregnancy. Graves' disease is by far the most important cause of hyperthyroidism in pregnancy. Graves' disease and Hashimoto's thyroiditis tend to improve late in pregnancy, often with relapse in the post-partum period. A high titre of thyroid stimulating immunoglobulin in the mother can produce foetal goitre and/or hyperthyroidism (foetal Graves' disease), whereas blocking immunoglobulin can make the foetus hypothyroid.

Table 2: Thyroid diseases in relation to pregnancy A. Mother 1. Transient hyperthyroidism of pregnancy   2. Graves' disease   3. Postpartum thyroiditis B. Foetus/neonate 1. Foetal/neonatal hypothyroidism   . Foetal/neonatal hyperthyroidism   3. Foetal/neonatal goitre

Thyroid disease in the elderly Thyroid disease in the elderly is a very common problem. Both structural and functional changes have been noted in older people.²² Thyroid nodules are reported to be more prevalent in the elderly. This is considered to be due to an age-associated wear and tear phenomenon.²³ The diagnosis of thyroid disease is complicated by normal age-associated changes.²⁴ Thyrotoxicosis generally presents with the classic signs and symptoms in young people. However, in elderly patients, the classic symptoms may be absent.²⁵ Thyrotoxicosis in patients over the age of 60 accounts for 10 to 15 per cent of all thyrotoxic patients. The commonest cause of thyrotoxicosis in the elderly is Graves' disease followed by toxic multi-nodular goitre. In our clinic survey, we found an equal prevalence of the two conditions.²⁶ Recognising the diagnosis is the main difficulty; treatment is fairly straightforward.
Hypothyroidism is frequently difficult to diagnose in the elderly because many of the symptoms of hypothyroidism can easily be confused with the symptoms of ageing. When hypothyroidism is looked for in large population studies of elderly patients, the incidence varies from 1 per cent to as high as 17 per cent, with women being more commonly affected than men.^2,27
Thyroid nodules do occur with increasing frequency in the elderly, but most of them are not malignant. Well-differentiated cancers occur and their course is frequently less predictable than in younger patients. The incidence of lymphoma of the thyroid and undifferentiated cancers increases with age.

Iodine and thyroid diseases Iodine is a requisite substrate for the synthesis of thyroid hormones. The minimum daily requirement of iodine is 50 micrograms. There is an autoregulatory mechanism within the thyroid gland which protects us from the consequences of iodine deficiency and excess (see Panel 3). Environmental iodine deficiency continues to be a significant public problem world-wide.³⁰ The implementation of iodination programmes prevents endemic cretinism and reduces the frequency of the other pathological consequences of iodine deficiency.³¹
Iodine excess results principally from the use of iodine-containing medicinal preparations or radiographic contrast media (Table 3). The pathological consequences of iodine excess will ensue only when thyroid autoregulation is defective or absent.

Table 3: Common iodine containing preparations A. Topical Betadine 10mg/ml   Tincture of iodine 20mg/ml   Iodosorb powder 0.9% B. Oral SSKI 47mg/drop   Amiodarone 75mg/200 mg tablet   Lugol's solution 130mg/ml C. Radiographic Iopanoate (Telepaque) 335mg/500 mg tablet   Diatrizoate (Urografin-325) 325mg/ml   Iothalamate (Conray-420) 420mg/ml

Panel 3: Consequences of iodine imbalance in the body Deficiency Endemic goitre Hypothyroidism Cretinism Increased incidences of neuromotor disabilities Increased infant mortality Excess Hypothyroidism (defective autoregulation) Hyperthyroidism (absent autoregulation) Autoimmune thyroid disease Foetal/neonatal goitre with or without hypothyroidism

Particular attention should be drawn to the cardiac drug amiodarone. It has a very high iodine content. Storage in adipose tissue is a particular problem in clinical practice as its release may be prolonged for months after stopping.³² Amiodarone can cause hypothyroidism or hyperthyroidism which may result in a diagnostic dilemma.
Apart from iodine being the cornerstone of the treatment of endemic goitre and cretinism, iodine has an important role as adjunctive therapy for hyperthyroidism. It produces a prompt slowing of thyroid hormone secretion by inhibiting the proteolytic degradation of thyroglobulin into its constituent amino acids. This effect is exploited in the treatment of thyrotoxic crisis and severe thyrocardiac disease. Iodine also reduces the vascularity of the thyroid gland, and is used in the pre-operative preparation of thyroidectomy.

Thyroid disorders after radiation exposure Not unjustifiably, there are concerns about thyroid disease after radiation, be it therapeutic or accidental. A high prevalence of thyroid diseases among children in Belarus, Ukraine, Gomel, Zhitumir, Kiev and Western Bryansk has been reported following the disaster at the nuclear power station at Chernobyl.^33,34 Thyroid cancer, as well as other thyroid diseases such as follicular adenoma, goitre, chronic thyroiditis and thyroid cyst were encountered in four children. Likewise, following the Nagasaki atomic bomb exposure, an increased incidence of thyroid cancer and AITD was reported.³⁵
A radiation dose to the thyroid that exceeds approximately 26Gy frequently produces hypothyroidism. Direct or incidental thyroid irradiation multiplies the risk for well-differentiated papillary and follicular thyroid cancer by a factor of between 15 and 53.³⁶ Thyroid cancer risk is highest following radiation at a younger age, decreases with increasing age at treatment or exposure and increases with the follow-up duration. The potentially prolonged latent period between radiation exposure, and the development of thyroid dysfunction, thyroid nodularity and thyroid cancer means that individuals who have received neck or pituitary radiation require careful periodic clinical and laboratory evaluation.

Thyroid crisis Thyrotoxic crisis is an acute exacerbation of thyrotoxicosis that may lead to irreversible cardiovascular collapse and death. It can occur in Graves' disease, toxic multinodular goitre or toxic adenoma. Common precipitating factors are infection, radio-iodine therapy, thyroid surgery and major non-thyroid surgery. In the modern era, it is becoming rare, largely due to the careful pre-operative preparation of thyrotoxic patients. The diagnosis of thyrotoxic crisis is based on maintaining a high index of clinical suspicion.²⁵
The opposite end of this spectrum is myxoedema coma, the endpoint of chronic thyroid hormone deficiency, exhibiting widespread organ dysfunction. This condition is most often seen in elderly women and can result from autoimmune thyroid disease, post radio-iodine hypothyroidism, or, rarely, from hypothalamo-pituitary disorders. As in thyrotoxic crisis it has very significant mortality and aggressive treatment is required.

Thyrotoxicosis factitia In thyrotoxicosis factitia, as the name implies, thyrotoxicosis arises from factitious ingestion of excessive quantities of thyroid hormone. This usually occurs in subjects with a background of mental illness and who have ready access to thyroid preparations, for example, people in the medical profession and relatives of patients with hypothyroidism.³⁷ The patient usually denies it. A combination of factors are important to make the correct diagnosis. They are:

• Thyrotoxicosis without a palpable goitre
• Raised T4 but not T3 (unless the patient is taking T3 which is rarely prescribed now)
• Absence of infiltrative ophthalmopathy
• Decreased radioactive iodine uptake
• Low thyroglobulin
• Absent thyroglobulin antibodies

Low thyroglobulin is a very important indicator that the thyroid gland is not the source of the thyrotoxicosis.³⁸

Endocrine association

It is also important to recognise the association of thyroid disorders with various endocrinopathies because one can affect the recognition, presentation and management of the other and thus can influence the outcome. For example, an uncontrolled thyroid state can upset the glycaemic control in diabetes mellitus, whereas poorly controlled diabetes mellitus can be responsible for abnormal thyroid functions (sick euthyroid syndrome). We have recently reported two cases of type 1 diabetes mellitus where diabetic ketoacidosis was precipitated by a previously undetected thyrotoxicosis.³⁹ Some changes in thyroid function are seen in diabetic ketoacidosis as a matter of course, ie, low thyroxine, suppression of hypothalamo-pituitary thyroid axis.⁴⁰
Thyroid diseases may be associated with diseases of other endocrine glands in two ways: autoimmune endocrinopathy and multiple endocrine neoplasia. Almost all these diseases have a genetic basis.

Autoimmune polyendocrinopathy Autoimmune hypothyroidism can be associated with Addison's disease, hypoparathyroidism and candidiasis (the type 1 variety) or with type 1 diabetes mellitus and Addison's disease (the type 2 variety) in various combinations. Graves' disease can also be associated with the type 2 variety.

Multiple endocrine neoplasia Medullary thyroid carcinoma is associated with phaeochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2. This is important to recognise as diagnosis of one prompts a search for the other.

Dr Bhattacharyya is specialist registrar in endocrinology at Hope hospital, Salford and Dr Wiles is a consultant physician and endocrinologist at North Manchester General hospital

References