Disorders of the thyroid gland

Thyroid hormone synthesis

The thyroid gland stores its hormones in a lumen surrounded by follicular (thyrocytes) cells as a semi-solid suspension (colloid). When circulating thyroid hormone levels fall, TRH is released from the hypothalamus and acts on the adenohypophysis (anterior pituitary gland). This results in the release of TSH into the systemic circulation.

At the basolateral surface of the thyrocytes, TSH binds to TSH receptors, resulting in the activation of guanine nucleotide binding proteins (G-proteins). The G-protein stimulates the production of cyclic adenosine monophosphate (cAMP), which causes hyperplasia of the thyroid follicular cells and increased production of thyroglobulin. Thyroglobulin is released at the apical part of the cell into the colloid.

The iodide that is used in the hormone synthesis is transported across the cell and into the follicular lumen by sodium-iodide symporters and iodide-chloride (pendrin) transport pumps that are located at the basolateral and apical part of the cells, respectively. Iodide is oxidized to iodine at the apical surface of the cell by thyroperoxidase (TPO). Iodine atoms are then used to convert the tyrosine moiety of thyroglobulin into monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT and DIT molecules subsequently react to form T3 and T4, which are still bound to thyroglobulin.

The gland contains enough thyroid hormones to sustain the body for about 3 months, in the event that no further hormone synthesis occurs. Within the cell, T3 and T4 are cleaved from thyroglobulin by lysosomal enzymes prior to their release. Once the hormones are secreted into the bloodstream, they bind to transport proteins (albumin [Alb], thyroxine binding globulin [TBG], and thyroxine binding prealbumin [TBPA]) that carry them to numerous target sites. The transport proteins help to maintain a tight range of free (unbound) thyroid hormones within the circulation. Additionally, they will dissociate from the bound thyroid hormone once the serum levels begin to decline.

Thyroid hormones influence the activity of the metabolic, cardiovascular, respiratory, neurological, and countless other systems throughout the body. As a result, disorders of the thyroid gland not only have local impact, but also results in deleterious events at distant sites as well. The goal of this article is to discuss the different types of thyroid disorders. 

Excessive thyroid hormone

Excess thyroid hormones result in stimulation of the aforementioned organ systems; thus pushing the patient into a hypermetabolic state. In the purest sense, this is referred to as a state of thyrotoxicosis; as the elevated serum thyroid hormones are having a toxic effect on the entire body. The mechanism behind thyrotoxicosis may be related either to a hyperactive thyroid gland (hyperthyroidism) or a self-stimulating thyroid nodule (toxic nodular goitre). Since hyperthyroidism is the most common cause of thyrotoxicosis, the words are often used interchangeably.  

Graves disease

Hyperthyroidism – also known as Graves disease – is an autoimmune disorder of the thyroid gland. It is 10 times more likely to be encountered in women than in men; and is more common in the 20 – 40 year old age groups. Various genetic abnormalities have been implicated in Graves disease. However, the key pathological component is the presence of thyroid stimulating antibody (TSAb).

TSAb has an affinity for the TSH receptors. They act as agonists for these receptors, thus reproducing the effects of TSH. Consequently, the thyroid gland becomes diffusely enlarged and the cells begin to secrete large quantities of T3 and T4. Additionally, the elevated thyroid hormone levels will activate the negative feedback mechanism, reducing the amount of TSH being released. Therefore, the patients serological panel will reveal low TSH, elevated T4, and normal or elevated T3.

Classically, patients with Graves disease present with the typical features of thyrotoxicosis, an enlarged neck mass, and prominent ocular findings. By order of systems, the features of thyrotoxicosis include, but are not limited to:

• At the cellular level, thyroid hormones increase the quantity and surface area of mitochondria. It also increases the movement of ions across the cell membrane. Both factors will translate to an increase in the basal metabolic rate of the organism. The increased metabolic rate corresponds to an increase in the consumption of energy stores. Therefore, patients will note a significant increase in their appetite.
• There is a paradoxical weight loss in spite of the increased appetite resulting from the hyperactive catabolic metabolism. Additionally, the increased metabolic rate also results in the classic heat intolerance and excessive sweating that these patients also experience.
• Thyroid hormones can also stimulate the sympathetic nervous system by binding to, and antagonizing, adrenergic receptors. In doing so, they generate a sympathomimetic effect in the absence of elevated serum catecholamines. Anxiety attacks, insomnia, nervousness, mood lability, hyperactivity, palpitations, and sweating are all symptoms of an overactive sympathetic system consistent with thyrotoxicosis. This feature of Graves disease becomes more worrying when there is an acute surge in serum catecholamines following a stressful event. During these episodes (referred to as a thyroid storm) the symptoms become more pronounced and life-threatening. 
• The increased metabolic rate also requires more oxygen to be delivered to the cells. Therefore, there is stimulation of the cardiomyocytes – driven by the increased sympathetic activity – that leads to increased chronotropy and inotropy. Unfortunately, unregulated chronotropic and inotropic stimulation of the heart leads to dysrhythmias such as tachycardia and atrial fibrillation. Therefore, patients may complain of frequent palpitations, or syncopal episodes. Chronic complications of untreated hyperthyroidism include enlargement of the heart and subsequent congestive cardiac failure. 

• Osteoclasts express T3 receptors on their cell surfaces. Binding of T3 to these receptors results in increased bone resorption. Unopposed activation of the osteoclasts will result in excessive demineralization of the bone; resulting in early onset osteoporosis. If left untreated, patients will present with pathological fractures. However, this is less commonly encountered as a result of more aggressive management of thyrotoxicosis.

Other prominent features of Graves include cutaneous manifestations, such as onycholysis and pretibial myxoedema. However, Graves ophthalmopathy remains the chief pathognomonic feature of the disease. Sympathetic activation of Müller’s muscle results in prolonged elevation of the upper eyelid; which produces the classical lid retraction and lid lag observed during clinical exams.

Furthermore, TSH receptors in the retro-orbital space become overexpressed and stimulated by TSAb. Hypertrophy of the retro-orbital tissue, along with:

• thymocyte invasion,
• extraocular muscle inflammation
• extracellular matrix build-up
• and increased adiposity,

result in increased intraorbital pressure, causing the eyeballs to protrude (exophthalmos). In advanced cases, the extraocular muscles may be compromised, resulting in diplopia. The optic nerve can also be damaged, thus threatening the patient’s vision.

Toxic nodular goitre

As opposed to the diffusely enlarged thyroid gland, there are pathological states where there is a solitary (or multiple) nodular enlargements within the gland. In some instances, these nodules may be hyperactive and produce features of thyrotoxicosis. Toxic nodular goitre – otherwise called Plummer disease – is a less common cause of hyperthyroidism that is more prevalent in older individuals.

It is characterized by either a solitary or multiple hyperactive nodules that operate without being stimulated by TSH or stimulatory antibodies. The hormonal increase in these patients occurs slowly over time, and can result in very mild symptoms. A significant increase in the thyroid hormone levels can be anticipated if these patients should increase their iodide intake.

It should also be noted that some of these patients with significantly elevated thyroid hormone levels may not present in the same manner that younger patients suffering from hyperthyroidism do. Since patients with toxic nodular goitres are older, their physiologic reserves are lower than younger patients. Therefore their response to increased thyroid hormones may be blighted. This condition is described as apathetic hyperthyroidism and it may only be discovered after serological investigations are carried out.

Thyroid adenoma

Less commonly, patients may have a solitary, benign, monoclonal follicular adenoma of the thyroid that is producing excess thyroid hormone. The tumor usually exceeds 2.5 cm in size and causes suppression of TSH secretion. Therefore, the gland will show up as the only “hot spot” on radioiodine scanning and the rest of the gland will appear “cold” since there is not enough TSH to stimulate the rest of the gland. These patients will present with similar complaints to those with the aforementioned conditions.

Insufficient thyroid hormone

While increased thyroid hormone levels have negative effect throughout the entire organism, low thyroid hormone levels also lead to unfavourable circumstances. Anything from poor iodine intake, to autoantibodies against the thyrocytes or enzymes used in the synthesis pathway can cause suppression of thyroid hormone production.

Recall that when thyroid hormone levels fall, there is an increase in the release of TSH. Consequently, the thyroid gland is also likely to be enlarged during this disease process. Hypothyroidism is often a primary disorder (occurring at the level of the thyroid gland). However, neoplasms of the pituitary gland or masses that impinge on the hypothalamus can result in secondary or tertiary hypothyroidism, respectively.

Primary hypothyroidism may present as a congenital abnormality (i.e. cretinism) or as an acquired condition in older children or adults (i.e. myxoedema). There is also an autoimmune form of hypothyroidism (Hashimoto’s thyroiditis) that essentially exists at the opposite end of the spectrum from Graves disease. The most common cause of non-autoimmune hypothyroidism is inadequate dietary supply of iodine.

The clinical features of hypothyroidism result from a significantly depressed basal metabolic rate. Patients may complain of:

• mental lethargy
• difficulty concentrating
• excessive tiredness
• cold intolerance
• weight gain
• shortness of breath
• diminished exercise capacity

Women may also experience disruption of their menstrual cycle with suppressed thyroid function.

Cretinism

Although the prevalence of cretinism is on the decline, it is still important to be familiar with this form of hypothyroidism that begins during early childhood. Traditionally, cretinism was more commonly encountered in areas where dietary iodine levels were low. However, there are also genetic abnormalities that can disrupt the thyroid hormone synthesis pathway, or release that can lead to infantile hypothyroidism.

Since thyroid hormones play an important role in stimulating osteoblastic and osteoclastic activity, their absence results in poor bone development (e.g. development of the skull, long bones of the limbs). As a result, these infants are of short stature. Additionally, the development of the central nervous system is also hampered by low thyroid hormone levels. Therefore the children born with cretinism are suffering from significant intellectual disability. The degree of intellectual disability is also worsened if the mother also has hypothyroidism. In these circumstances, there aren’t enough maternal thyroid hormones to cross the placenta and facilitate adequate brain development. However, if the mother acquires a hypothyroid state after the fetal thyroid is developed (around the 20th week of gestation) then the severity of the congenital hypothyroidism would be significantly diminished. Other signs of cretinism include, but are not limited to:

• Coarse facial features
• A hoarse cry
• Protruding tongue
• Umbilical hernias

Identification of these features are important so that exogenous thyroxine therapy can be initiated. The goal of therapy is to restore thyroid hormone concentrations to normal ranges so that the adverse events which began in utero will not worsen.

Myxoedema

Although the term myxoedema was meant to describe cases of complete thyroid failure, it is often used in reference to hypothyroidism presenting in older children or adults. Milder forms of hypothyroidism in older individuals may also result from insufficient dietary intake of iodine. There are also specific inflammatory conditions (de Quervain thyroiditis, also known as subacute granulomatous thyroiditis) that may also produce marked hypothyroidism. 

Chronic untreated hypothyroidism may be complicated by other unrelated medical conditions (i.e. infection, trauma, myocardial infarction, medications, etc.), leading to myxoedema coma or crisis. Although this rarely happens, it is an important, life-threatening event that every clinician should be able to recognize.

Like thyrotoxicosis, myxoedema crisis is a multi-systemic illness that causes:

• Negative chronotropy and inotropy at the level of the heart, leading to bradycardia, reduced cardiac output, and eventually hypotension and its sequelae.
• Altered mental status of varying degrees as the reduced oxygen concentration in the brain results in decreased brain function.
• Hypoventilation following CNS suppression, muscle weakness, and mechanical obstruction of the airway (due to macroglossia) may also occur.
• Reduced kidney function due to the decreased cardiac output may also lead to electrolyte disturbances that can further complicate the scenario.
• Reduced sympathetic response decrease the autonomic activation of the gastrointestinal tract. Therefore, patients experience malabsorption syndromes due to reduced peristaltic activity and paralytic ileus. 

Therapy should be initiated upon clinical suspicion of the diagnosis, as waiting for a laboratory confirmation to initiate therapy will be detrimental to the patient.

Hashimoto thyroiditis

At the opposite end of the autoimmune spectrum, Hashimoto thyroiditis is characterised by progressive thyroid failure, following destruction of the follicular epithelium of the gland. This form of hypothyroidism occurs in areas of the world where dietary iodine intake is sufficient. It is also more commonly encountered in female patients and can be seen in both paediatric and adult populations. However, it is more common in the 45 – 65 year old age groups.

This disease is characterized by chronic lymphocytic infiltration of the thyroid gland. Thyroid autoantigens are misidentified as foreign entities by the thymocytes (T-lymphocytes). Subsequently, antibodies are produced against key components in the thyroid hormone synthesis pathway (i.e. anti-TG, anti-TPO, etc.). As time progresses, the anti-thyroid antibodies will destroy the follicular epithelium, thus releasing the previously synthesized thyroid hormones into the capillary beds of the gland. Hence, it is not uncommon for patients with Hashimoto thyroiditis to experience a transient period of thyrotoxicosis, before hypothyroid features take precedence. Patients classically present with painless, diffuse, and symmetrical enlargement of the gland that is associated with signs and symptoms of hypothyroidism.

Thyroid cancer

With the exception of the nodular goitre, most benign causes of thyroid enlargement usually result in the entire gland (diffuse) to hypertrophy. A discrete, solitary thyroid mass with clinically normal surrounding thyroid tissue is likely to raise suspicion about thyroid malignancy. However, there are other non-cancerous causes of a discrete thyroid mass, such as:

• Thyroid cyst
• Dominant thyroid nodule in a multinodular goitre
• Focal inflammation within the gland
• Follicular adenoma

Patients are ten times more likely to have a benign thyroid mass than they are to have a thyroid carcinoma. While nodular thyroid disease is more common in women, it should be noted that these nodules are more likely to be malignant when found in male patients. Just to be safe, all thyroid masses should be investigated in order to rule out the possibility of a malignancy. To better understand the pathophysiology and classification of thyroid cancers, it is important to review the histology of the thyroid gland.

Carcinoma of the thyroid gland most often arise locally; and is seldom a manifestation of metastatic spread from another source. If it does occur, the primary source is typically from the breast or kidneys. Primary thyroid carcinoma accounts for 3.4% of new cancer cases in the United States each year. These malignancies can be subdivided histologically into differentiated (papillary, Hürthle cell, and follicular) and undifferentiated (medullary, and anaplastic) thyroid cancers.

All the cell lines within the gland can give rise to a malignant lesion. The endodermal cell lines give rise to papillary, follicular, and possibly anaplastic thyroid cancers. On the other hand, the neuroendocrine cell lines can produce a medullary carcinoma of the thyroid. Additionally, there are resident lymphoid cell lines within the gland that also gives rise to the lymphoma type thyroid cancer.

While there are known genetic mutations that predispose individuals to developing thyroid cancer, there are also environmental factors that should also be considered in its etiology. Both iatrogenic and accidental ionizing radiation exposure increases the risk of developing thyroid cancer. However, this risk factor is more commonly associated with papillary thyroid cancer. Only papillary, medullary, follicular, and anaplastic malignancies will be discussed here.

Papillary thyroid carcinoma

Of the four types of thyroid cancer, papillary thyroid cancer is the most common, most differentiated, and carries the best prognosis (90% at 10 year survival). There is a 2.5:1 ratio of females to males having this type of thyroid cancer; and it usually occurs in the 25 – 50 year old age groups.

The diagnosis can be made using cytological aspirates from a fine needle aspiration biopsy. The pathognomonic cytological features include pale, empty nuclei that are referred to as Orphan Annie-eyed nuclei, with nuclear grooving and pseudo-inclusion (cytoplasmic invaginations of intranuclear inclusions). It’s also not uncommon to encounter calcified concentric entities within the cytoplasm known as psammoma bodies. Histologically, the tumor is characterized by a fibrovascular stalk encased in layers of cuboidal epithelium. However, the papillary architecture may not always be seen; hence the diagnosis can be made with just the cytological findings. If there is metastasis of a papillary carcinoma, it occurs via the lymphatic system.

Follicular thyroid carcinoma

The second most common type of thyroid malignancy is the follicular cancer. Although it is not linked to hypothyroidism, the prevalence of this form of thyroid cancer is higher in areas with low dietary iodine intake. Females are three times more likely to develop follicular thyroid cancer than are males; and the patients are usually between their 5th to 7th decades of life.

Grossly, it is difficult to differentiate between papillary and follicular lesions as follicular lesions may also appear as well demarcated, solitary nodules. On the other hand, they may also be widely infiltrative.

Histological analysis of the mass is necessary for diagnosing this cancer as there are marked similarities between the follicular adenoma and carcinoma. Both adenoma and carcinoma may have uniform cells with almost normally appearing architecture or sheets of cells that do not resemble typical follicular cells. Hypereosinophilic, granulated Hürthle cells may also be present in both subtypes of follicular lesions. The presence of either capsular or vascular invasion by the neoplasm indicates that the lesion is malignant. Metastasis occurs via the bloodstream (hematogenous spread). The prognosis for follicular carcinoma is less than that of papillary carcinoma (70 - 85% at 10 years).

Medullary thyroid carcinoma

Associated with a poor prognosis (55% at 5 years), medullary thyroid carcinoma originates from the parafollicular C cells of the thyroid. While majority of these cases occur from de novo mutations, 20% of cases are linked to familial endocrine neoplasia (i.e. multiple endocrine neoplasms [MEN] 2A and 2B, and non-MEN medullary thyroid cancer).

Elevation of serum calcitonin facilitates diagnosis and follow-up of the lesion. However, it is not uncommon for these tumors to produce other hormones (i.e. ACTH, VIP, 5-HT) , which may be associated with other paraneoplastic syndromes.

The key difference between sporadic and familial medullary carcinoma is that the former occurs as a solitary, unilateral nodule; while the latter arises as bilateral multicentric lesions. Additionally, familiar types are also characterized by hyperplastic C-cells; which some believe is a precursor to developing the carcinoma.

With increased size, the lesions are also characterized by bleeding, necrosis, and capsular invasion. Histological assessment reveals a spectrum of polygonal to spindle-like cells in follicles, nests or traversing trabeculae. Amyloid deposits can also be identified in the thyroid stroma. This tumor has aggressive local spread in addition to dispersing via lymphatic and hematogenous routes.

Anaplastic thyroid carcinoma

The most dismal type of thyroid cancer for someone to acquire is fortunately the rarest form. Anaplastic thyroid cancer accounts for less than 5% of all cases of thyroid malignancies. Only 25% of patients survive to 1 year following their diagnosis. The average age of diagnosis is 65 years and some patients also have a history of one of the differentiated subtypes of thyroid cancer.

Histologically, the lesion has haphazardly distributed pleomorphic giant cells, sarcomatous spindle cells or a mixture of both. The tumor is characterized by rapid local spread with destruction to nearby neurovascular structures, as well as aggressive hematogenous and lymphatic dissemination.