43. Inflammatory, tumorous diseases as well as disorders associated with hyperplasia of the thyroid gland (+ hyperthyroidism and hypothyroidism)
Introduction
The thyroid gland consists of two lateral lobes connected by a thin isthmus, usually located below and anterior to the larynx. It develops from pharyngeal endoderm that descends from the base of the tongue to its normal position on the anterior neck. It normally weighs less than 30 g.
The gland is divided into lobules, each of which is composed by 20 to 40 thyroid follicles. These follicles are lined by cuboidal/low columnar epithelium, and the lumen of the follicles is filled with colloid. This colloid is mostly composed of thyroglobulin, the precursor protein for the active thyroid hormones T3 and T4. When stimulated by TSH the thyroid follicular cells will convert thyroglobulin in the colloid into T3 and T4, which are then released into the circulation. Thyroid hormones act on cells to increase their metabolism and to increase their sensitivity to catecholamines.
The thyroid is subject to many clinical diseases, like inflammation, hyperplasia, autoimmune disease and tumors. Due to its easily accessible anatomical location, these conditions are often easy to treat if necessary. In a worst case scenario the thyroid can be removed and thyroid hormone replacement therapy can be initiated.
Most clinically important thyroid disorders are 3-10 times more common in women. The population that is most frequently affected are young (20s) females.
Goiter
Introduction and epidemiology
Goiter, also called struma, refers to an enlargement of the thyroid gland. It is the most common clinical manifestation of thyroid disease. It can accompany hyperthyroidism (toxic goiter), hypothyroidism (hypothyroid goiter) and normothyroidism (non-toxic goiter). It can occur due to hyperplasia, thyroiditis or neoplasms.
Goiter is endemic in areas where the soil, water and food contain little iodine. Iodine deficiency is the most common cause of goiter worldwide, but not in the western countries, where autoimmune conditions like Hashimoto thyroiditis and Graves disease are more common causes.
Pathology
The enlargement of the thyroid can come from increased stimulation by TSH. In conditions that cause hypothyroidism, like iodine deficiency and Hashimoto thyroiditis, the decreased level of thyroid hormone means decreased feedback inhibition of TSH, which causes more TSH to be secreted by the pituitary. TSH then stimulates hyperplasia of the thyroid, causing it to grow. Enlargement can also come from cysts or neoplastic processes.
Classification
We classify goiters based on the morphology. A goiter can be either diffuse or nodular. Diffuse goiters are those that are diffusely and symmetrically enlarged, while nodular goiters are those that are irregularly enlarged and form nodules. Nodular goiters can be either uninodular or multinodular.
Etiology
Many things can cause goiter:
| Condition | Morphology |
|---|---|
| Graves disease | Diffuse goiter |
| Hashimoto thyroiditis | Diffuse or nodular goiter |
| Iodine deficiency | Diffuse goiter |
| Non-toxic adenoma | Uninodular goiter |
| Toxic adenoma | Uninodular goiter |
| Non-toxic multinodular goiter | Multinodular goiter |
| Toxic multinodular goiter | Multinodular goiter |
Complications
Goiters are most commonly asymptomatic, but they can compress the trachea and oesophagus, causing dyspnoea and dysphagia, respectively. Mostly the multinodular goiters cause compression symptoms. Diffuse goiters are usually around 150 g, while multinodular goiters may reach up to more than 500 g!
Hyperthyroidism and thyrotoxicosis
Introduction
Thyrotoxicosis is the state where the level of circulating free T3 and T4 is elevated, causing hypermetabolism. It is most commonly caused by hyperthyroidism, which is the state where the thyroid is overactive, but it can also be caused by ectopic hormones or destruction of the thyroid. Because of this, the two terms are often used interchangeably.
Etiology
Thyrotoxicosis can be caused by many conditions:
- Primary hyperthyroidism
- Graves disease
- Toxic adenoma
- Toxic multinodular goiter
- Destruction of the thyroid gland – causes release of stored thyroid hormone in the early phase of disease
- Hashimoto thyroiditis
- De Quervain thyroiditis
- Postpartum thyroiditis
- Drug and contrast-induced thyroiditis (amiodarone, contrast material)
- Secondary hyperthyroidism
- Gestational thyrotoxicosis – hCG stimulates TSH receptors due to their structural similarity
- Struma ovarii – an ovarian teratoma which produces thyroxine
- TSH-producing pituitary adenoma
In regions without iodine deficiency, Graves disease is the most common cause of thyrotoxicosis. In iodine deficient regions, toxic adenoma and toxic multinodular goitre are more common.
Clinical features
Thyrotoxicosis can cause many symptoms, most of which are related to the hypermetabolic state and to the overactivity of the sympathetic nervous system:
- Weight loss despite increased appetite
- Warm, moist skin
- Tachycardia or arrhythmia
- Heat intolerance
- Palmar erythema
- Nervousness
- Diarrhoea
- Hypertension with widened pulse pressure
- Palpitations
- Fine tremor
- Anxiety, restlessness
Diagnosis and evaluation
The diagnosis of (primary) hyperthyroidism is based on the levels of TSH, the most sensitive biomarker. Free T4 and T3 are measured to look for subclinical hyperthyroidism.
| TSH | Free T4 | Free T3 | |
|---|---|---|---|
| Euthyroidism | Normal | Normal | Normal |
| Subclinical hyperthyroidism | Decreased | Normal | Normal |
| Overt hyperthyroidism | Decreased | Increased | Increas |
The clinical features, including the thyroid size, consistency, nodularity, as well as the presence of eye symptoms, can help narrow the differential diagnosis. The following investigations are important in determining the etiology:
- Autoantibodies against thyroid peroxidase (anti-TPO), thyroglobulin (anti-Tg), and TSH receptor (anti-TSHR)
- Ultrasound
- Thyroid scintigraphy (nuclear imaging)
Hypothyroidism
Introduction
(Overt) hypothyroidism refers to decreased production of T3 and T4 by the thyroid gland. It’s a common condition. Chronic hypothyroidism is almost always due to Hashimoto thyroiditis.
Subclinical hypothyroidism is very common, but despite being subclinical it may be associated with adverse outcomes on cardiovascular disease. Also, most patients with subclinical hypothyroidism progress into overt hypothyroidism.
Etiology
- Primary hypothyroidism
- Thyroiditis
- Hashimoto thyroiditis
- De Quervain thyroiditis
- Postpartum thyroiditis
- Following surgical removal or radioiodine treatment
- Iodine deficiency
- Drugs
- Thyroiditis
- Secondary hypothyroidism
- TSH insufficiency
- Tertiary hypothyroidism
- TRH insufficiency
Thyroiditis, especially Hashimoto thyroiditis, is the most common cause of hypothyroidism. Secondary and tertiary hyperthyroidism are rare.
Clinical features
Hypothyroidism can also cause many symptoms, most of which are opposite of those of thyrotoxicosis:
- Weakness
- Memory problems
- Depression
- Dry skin
- Myxoedema
- Hair loss
- Constipation
- Weight gain
- Cold intolerance
- Bradycardia
- Anaemia
- Menstruation problems
- Hypercholesterolaemia -> accelerated atherosclerosis
Diagnosis and evaluation
TSH is the most important biomarker in the evaluation of hypothyroidism as it’s much more sensitive than T3 and T4. T3 and T4 are only measured to diagnose subclinical hypothyroidism, the stage before overt hypothyroidism develops.
| TSH | Free T4 | Free T3 | |
|---|---|---|---|
| Euthyroidism | Normal | Normal | Normal |
| Subclinical hypothyroidism | Increased | Normal | Normal |
| Overt hypothyroidism | Increased | Decreased | Decreased |
To find the etiology, measurement of anti-thyroid antibodies (anti-TPO and anti-Tg), ultrasound, and FNAB are used.
Treatment
The body requires normal amounts of thyroid hormones for proper function, so hypothyroidism must be treated by replacing them, most commonly by replacing T4 (thyroxine). The dose is adjusted until the laboratory values no longer show hypothyroidism.
Graves disease
Introduction and epidemiology
Graves disease, sometimes called Basedow disease, is the most common cause of hyperthyroidism. It’s caused by the immune system forming autoantibodies against the ligand-binding site on the TSH-receptor on the follicular cells, which activates the receptor, stimulating thyroid function and growth.
It most commonly affects younger adult women.
Pathology
Goiter results from the hyperplasia stimulated by the TSH receptor, but the anti-TSH antibodies also stimulate fibroblasts. They stimulate fibroblasts in the orbit, which produce fibrofatty tissue which causes the eyeballs to be pushed outwards (exophthalmos). This condition is called Graves or endocrine ophthalmopathy. The antibodies also stimulate fibroblasts in the skin, causing them to produce more glycosaminoglycans, causing thyroid dermopathy.
The name pretibial myxoedema is misleading and old, as it doesn’t always occur on the tibia and doesn’t really cause just oedema. True myxedema occurs only in hypothyroidism.
Clinical features
In addition to hyperthyroidism, Graves disease causes a triad of symptoms:
- Diffuse goiter
- Graves/endocrine ophthalmopathy (which causes exophthalmos)
- Thyroid dermopathy (pretibial myxoedema)
Inflammation of the thyroid
Thyroiditis is most frequently subacute (transient) or chronic, but acute inflammation exists as well.
Hashimoto thyroiditis
Hashimoto thyroiditis, also called chronic autoimmune hypothyroidism is an autoimmune condition characterised by CD8-mediated destruction of the thyroid parenchyme. It’s the most common cause of chronic hypothyroidism in western countries, affecting 3 – 5 per 10 000. It mostly affects middle-aged females.
It’s associated with other autoimmune diseases and with HLA-DR5.
In the early phase thyrotoxicosis develops as the destroyed cells release preformed hormones, sometimes called “hashitoxicosis”. In this phase, there’s a non-tender and painless goitre.
Later, hypothyroidism occurs in the chronic phase, as the number of cells decreases. In this phase, the thyroid may be normal or small. Hashimoto causes painless goitre.
De Quervain thyroiditis
De Quervain thyroiditis, also called subacute granulomatous thyroiditis or giant cell thyroiditis, is a transient, self-limiting viral infection of the thyroid that occurs some weeks after a viral upper respiratory tract infection. Granulomas are present in the thyroid, hence the name.
It’s a moderately frequent disorder with seasonal fluctiations. It mostly affects middle-aged females.
It follows the same development as Hashimoto thyroiditis, except that it’s self-limiting. The goitre is painful.
Postpartum thyroiditis
Postpartum thyroidits is a form of autoimmune subacute thyroiditis which affects postpartum women. It’s likely that postpastum thyroiditis is an accelerated form of Hashimoto thyroiditis which is triggered by the pregnancy, as 50% of cases were anti-TPO positive ahead of pregnancy. It occurs in 5 – 10% of deliveries.
Acute thyroiditis
Acute thyroiditis is due to bacterial infection of the thyroid, most commonly in immunodeficient persons. The prognosis is very good with treatment.
The clinical features include severely painful goitre, fever, and overlying erythema. The onset is acute. Sometimes an abscess forms.
Riedel thyroiditis
Riedel thyroiditis is a rare condition with unknown etiology. The thyroid parenchyme is replaced by fibrous tissue.
Thyroid nodules
Introduction
Discovery of a thyroid nodule, either by the patient or incidentally during physical examination, is a common presentation of thyroid neoplasms or cysts. 95% of thyroid nodules are benign.
Some thyroid tumours produce thyroid hormones, causing hyperthyroidism, in which case they’re called “toxic”.
Etiology
These are the most common causes of thyroid nodule:
- Benign thyroid nodule
- Follicular adenoma
- Toxic adenoma
- Thyroid cyst
- Malignant thyroid nodule
- Thyroid carcinoma
The most common thyroid nodule is the follicular adenoma. Follicular adenomas are derived from the follicular epithelium. They’re solitary, well-circumscribed masses that may give rise to painless uninodular goiter.
Toxic adenomas are follicular adenomas which produce thyroid hormones. These toxic adenomas have acquired a gain-of-function mutation in the TSH receptor complex, allowing the follicular cells to be stimulated even in the absence of TSH. They’re common in iodine deficient regions, but very rare in iodine sufficient regions.
Multinodular goitre (MNG) is a complication of long-standing nodular goitre which occurs when multiple nodules develop. These nodules may be toxic (toxic multinodular goitre) or non-toxic (non-toxic multinodular goitre).
Thyroid cancer
Introduction and epidemiology
Thyroid cancer is rare and generally has a good prognosis. The incidence has increased markedly in the recent decades, but the mortality remains low. Thyroid cancer is rarely hyperfunctional.
The differentiated types are the most common, and these types rarely metastasize and have a good prognosis. If they do metastasise, it’s frequently to the cervical lymph nodes. The treatment for any type of thyroid carcinoma is total thyroidectomy.
Etiology
The major risk factor predisposing to thyroid cancer is previous exposure to ionizing radiation at the area of the neck, especially during the first 2 decades of life. Therefore it’s not strange that the incidence of papillary carcinomas among children exposed to the chernobyl disaster was high. Dietary deficiency of iodine is also linked with follicular thyroid carcinoma.
Medullary carcinoma is associated with MEN2A and MEN2B.
Classification
We classify the malignant thyroid tumors according to their differentiation. Here they are in order from most to least common:
| Tumor type | Cell of origin |
|---|---|
| Differentiated | |
| Papillary carcinoma | Thyroid follicular cell (= epithelial cells) |
| Follicular carcinoma | Thyroid follicular cell |
| Poorly differentiated | |
| Medullary carcinoma | Parafollicular cell (= C cells) |
| Anaplastic carcinoma | Thyroid follicular cells |
Papillary carcinoma is the most frequent type by far as it accounts for 80% of all thyroid carcinomas. It has a very good prognosis.
Medullary carcinomas are associated with multiple endocrine neoplasia type 2a and 2b (MEN-2). It has a poor prognosis.
Anaplastic carcinoma is most frequent in elderly. It’s one of the most aggressive cancers. It has an average 6 months survival.
The tumour marker for thyroid cancer is thyroglobulin, except for medullary carcinoma, for which calcitonin is the tumour marker.
Clinical features
Thyroid carcinomas are usually discovered as nodular, painless goiters. The nodule is fixed and rapidly growing, and may cause symptoms of compression of the trachea or oesophagus.