Thyroid Diseases

1. What is the thyroid?

The thyroid is a small gland, about five centimetres in diameter, located in the neck underneath the skin and below Adam’s apple. Its shape resembles a butterfly and it is made up of two lobes, right and left, joined by a central portion called the isthmus. Each lobe is about 4cm long and 1 to 2cm wide.

2. What does the thyroid do?

This gland has a very important role since it controls the body’s metabolism, i.e. the rate at which the body uses energy. This is accomplished through the synthesis of thyroid hormones, Thyroxin (T4), mainly and Triiodothyronine (T3), which travel through the bloodstream to all parts of the body.

In addition, also the thyroid gland synthesizes calcitonin, a hormone that helps to regulate calcium levels in the blood by inhibiting bone resorption and increasing calcium excretion through the kidneys.

3. What is the role of the thyroid hormones?

Thyroid hormones are essential to life and have a major role in the regulation of body function. They have various effects on the metabolism, growth and development of the organism. They contribute to the regulation of body temperature, heart rate, blood pressure, intestinal function, weight control and mood, among other functions.

The blood carries them through the bloodstream to all body cells where they attach themselves to receptors located in the cells on which they act, triggering a response from them and influencing their metabolism.

Thyroid diseases result from changes in gland function, i.e. when hormones are produced in inadequate quantity. We may be dealing with hyperthyroidism when there is an increased gland activity, seeing as hypothyroidism is characterized by decreased thyroid function.

4. What are the end products of the thyroid gland synthesis?

The T4 (Thyroxin) is the main hormonal product of the thyroid gland. Most of the T4 is stored within the thyroid, connected to a protein called thyroglobulin. When needs grow, the thyroid synthesizes more T4 and/or releases part of which is in store into the bloodstream.

The T4 has a half-life of approximately 2-3 days and is converted to T3 in the peripheral tissues. Approximately 20% of the T3 is formed in the thyroid gland, but about 80% of it is produced by conversion from the T4 in the peripheral tissues (especially in the liver and kidney). The T3 has a half-life of approximately 1 day. Once produced, the T3 enters the core of the cells of the target tissues.

5. How are the thyroid hormones transported in the bloodstream?

Once formed and secreted, thyroid hormones bind themselves to three proteins in the bloodstream: 75% to the thyroxin-binding globulin (TBG), 15% to the transthyretin (TTR, previously known as thyroxine-binding prealbumin) and 10% to the albumin.

Changes in the carrier proteins (as occurs in pregnancy and liver disease) affect the levels of total thyroid hormones in the blood and result in abnormal numbers.

Thyroid hormones circulate in the blood as either protein-bound forms or as free forms. Usually, 0.02% of the T4 and 0.3% of the T3 are free. There is a dynamic balance in place between these two forms. Tissue activity of thyroid hormones is mainly due to the free hormone, although any bound hormone is also available for use. In most tissues, the circulating free T3 (FT3) is chiefly responsible for the biological effect and speed control of body functions.

6. How is the thyroid regulated?

The body has a complex regulatory system in the background to control the amount of T4 and T3 in the blood. When the concentration levels of thyroid hormones in the blood decline, the hypothalamus (an organ located in the brain) releases TRH (thyrotropin-releasing hormone), which in turn acts upon the hypophysis (a small gland located below the hypothalamus, the base of the brain and nearly in the centre of the head) causing the release of TSH (thyrotropin or thyroid-stimulating hormone). 

The TSH stimulates the thyroid to produce and release more thyroid hormones. When the levels of thyroid hormones are elevated, the hypothalamus and the hypophysis decrease the release of TRH and TSH respectively, in order to reduce the thyroid’s production of T3 and T4.

The hypophysis and the hypothalamus are thus a kind of sensor, sensitive to the levels of thyroid hormones in circulation. Under normal circumstances, the TSH controls the thyroid gland activity. The hypophysis responds to the need for additional thyroid hormones, secreting TSH which stimulates the production and secretion of thyroid hormones. Excessive amounts of T4 and T3 suppress the secretion of TSH.

As a result, primary hyperthyroidism is characterized by high levels of thyroid hormones and suppressed TSH, while primary hypothyroidism is characterized by inverse changes. Secondary hypothyroidism (hypothalamic or hypophysial disease) is characterized by subnormal concentrations of thyroid hormones and subnormal or inappropriately normal levels of TSH. Secondary hyperthyroidism is characterized by high levels of thyroid hormones and high or inappropriately normal levels of TSH.

7. What are thyroid diseases and how do they occur?

Thyroid diseases are the result of changes in the gland function that cause the production of hormones in inadequate quantity.

The main thyroid disorders are functional. They include hypothyroidism, in which there is an insufficient synthesis of thyroid hormones, which leads to a slowing down of the body’s functions, and hyperthyroidism when the thyroid produces too many thyroid hormones, and wherein there is an acceleration of all body functions.

Structural disorders include changes that cause the thyroid volume to increase, a situation known as goitre. The presence of nodules makes it advisable to carry out medical examinations that enable the identification of those which, being malignant, require special attention.

8. What are the signs and symptoms?

In general, Hypothyroidism shows no symptoms and it can only be diagnosed through analysis. In more pronounced cases, the warning signs are:

• Struggling to think;

• Increased sensitivity to cold;

• Fatigue;

• Tiring easily;

• Dry skin, thin and brittle hair;

• Weight gain;

• Swollen eyelids and tongue;

• Constipation;

• Irregular menstrual periods;

• In children, hypothyroidism can cause a delay in growth and normal sexual development, as well as mental retardation. That is why this disease is part of the neonatal screening since there is an effective treatment and early detection minimizes complications.

Hyperthyroidism is characterized by:

• Palpitations, nervousness, anxiety, irritability, insomnia;

• Increased heart rate (> 100 per minute);

• Trembling hands;

• Weight loss despite increased appetite;

• Excessive sweating and heat intolerance;

• Hair loss, thin skin and nail changes;

• Diarrhoea;

• Irritation and swelling around the eyes;

• Bright and fixed gaze and/or prominent eyes (bulging eyes);

• Sensitivity to light or visual changes.

9. Are there any risk factors?

Thyroid diseases are very common, but they are more frequent in women and tend to increase with age. The prevalence of hyperthyroidism in women is approximately 1.3%, increasing to about 4 to 5% in elderly women.

Graves’ disease is a variant of hyperthyroidism, resulting from an autoimmune disease, and it is more common in young women. On the contrary, toxic multinodular goiter (with hyperthyroidism) is more common in elderly women.

As for hypothyroidism, it is in 5 to 8 times more common in women than in men. Iodine deficiency, common during pregnancy and childhood, can cause thyroid disease.

10. What are the most common thyroid diseases?

The most common thyroid diseases are:

• Graves’ Disease – This is the most common cause of hyperthyroidism. Graves’ disease is a chronic autoimmune disorder in which the immune system of the affected person fails to recognize itself and starts producing antibodies that attack the thyroid, causing inflammation, damage, and the production of excessive amounts of thyroid hormones.

• Hashimoto’s Thyroiditis – This is the most common cause of hypothyroidism. Much like Graves’ disease, Hashimoto’s Thyroiditis is a chronic autoimmune disorder in which the organism’s defences fail to recognize the thyroid as part of the body and attack it as if it were a foreign entity.
  
  However, in Hashimoto’s Thyroiditis, as the thyroid is being damaged, it loses the ability to release hormones in sufficient quantity, creating the hypothyroidism.

• Thyroid Nodules – A thyroid nodule is a small lump in the thyroid gland that may be solid or a cyst filled with fluid. They are very frequent injuries and can be diagnosed through cervical palpation or by ultrasound.
  
  At least about 4% of women and 1% of men will have at least one thyroid nodule throughout their life; most of them are benign. However, on some occasions, thyroid nodules can be cancerous. The differential diagnosis of these can only be performed through fine-needle aspiration biopsy and cytology.

• Thyroiditis – These form a group of clinical conditions characterized by the inflammation of the thyroid and may be associated with both hypothyroidism and hyperthyroidism. They often cause pain in the neck, but it may not happen.
  
  Its main causes are: autoimmune, infection, exposure to chemicals toxic to the thyroid, or other unknown reasons. Depending on the cause, it may be acute, transient or chronic.

• Thyroid Cancer — Thyroid Cancer is very uncommon, affecting 1 in 1,000 people. There are basically four types of thyroid cancer:

• Papillary Thyroid Cancer — Comprises about 60-70% of all thyroid cancers. This type of cancer is more common in women than in men, especially in young people;

• Follicular Thyroid Cancer — Responsible for approximately 15% of all cases. It is the most aggressive form, which usually affects women in old age.

• Anaplastic Thyroid Cancer — Also, primarily affects women in old age. It represents 5% of thyroid cancers. It is a very aggressive form of cancer and treatment is difficult.

• Medullary Thyroid Cancer (MTC) — It is a neuroendocrine tumour of the parafollicular cells, or C cells and represents 4% of thyroid carcinomas. One of the features of these tumours is the production of calcitonin. MTC can be found along with other endocrine carcinomas in a syndrome called Multiple Endocrine Neoplasia (MEN).

11. How common is Hypothyroidism?

Hypothyroidism is relatively common, affecting 2-3% in the general population. The average age at diagnosis is approximately 55 years old. Hypothyroidism is much more common in women; the ratio of female to male subjects is 10:1. Postpartum hypothyroidism, a transitional hypothyroid phase after pregnancy, is found in 5-10% of women.

12. What is subclinical hypothyroidism?

Subclinical hypothyroidism is a mild and more frequent form of hypothyroidism, usually with few to no symptoms. Up to 10-20% of women over 50 have subclinical hypothyroidism. There is an association with hypercholesterolemia and subtle cardiac abnormalities. From the biochemical point of view, the total thyroxin (total T4) and free T4 levels are normal, whereas the TSH levels are slightly elevated.

When treated with thyroxin, patients start to feel better, and the cardiac and lipid abnormalities disappear. Anti-thyroid antibodies, one of the indicators of thyroid autoimmune disease, may help predict which patients will progress to clinical hypothyroidism; it is recommended that patients with minimally elevated levels of TSH are subjected to testing. 

13. What can cause hypothyroidism?

Hypothyroidism can be caused by several disorders. The two most common causes are chronic lymphocytic thyroiditis (Hashimoto’s disease), an autoimmune form of thyroid destruction, and radioiodine induced hypothyroidism, after treatment of Grave’s disease (autoimmune hyperthyroidism). Postpartum thyroiditis occurs in approximately 10% of women; two-thirds of which undergo a transitional hypothyroid phase (6-12 months) which requires treatment.

Other less common causes of hypothyroidism include subacute thyroiditis, external irradiation of the neck, medications (anti-thyroid drugs, amiodarone, interferon), infiltrative diseases, central hypothyroidism (hypophysial/hypothalamic), birth defects and endemic goitre (iodine deficiency).

14. What are the best tests to confirm a hypothyroidism diagnosis?

There are several thyroid function tests available to doctors, including TSH, Total T4, Total T3, Free T4 and Free T3 determinations.

In an outpatient setting, only one test is generally necessary: TSH evaluation. TSH, synthesized and secreted by the anterior pituitary, is the most sensitive indicator of thyroid functioning. Essentially, one can say: if the TSH is normal, the patient is euthyroid; if the TSH is elevated, the patient has primary thyroid insufficiency.

The physician should have some caution when interpreting total T4 levels. Many conditions not related to thyroid disease lead to the emergence of low or high levels of total T4, as more than 99% of the T4 is attached to proteins, and total T4 levels depend on the number of proteins carrying thyroid hormones which are subject to a large variation.

15. How is hypothyroidism treated?

Hypothyroidism is treated through administrating thyroid hormone in the form of Levothyroxin (LT4), to provide the organism with the number of hormones that it has become unable to produce. Other thyroid hormone preparations include triiodothyronine (LT3) which is reserved for special cases, due to its potency and its short half-life.

16. Follow-up

Most cases of hypothyroidism are final, there is no cure.

However, as long as the treatment is well done, the patient will not have any symptoms. The proper dosage of LT4 (Levothyroxin) can vary over time within the same person, which requires continuous monitoring so that the dosage can be adjusted. Young and otherwise healthy patients can start the medication with total doses of LT4 replacement (1.6 µg/kg). Elderly patients and those with known or suspected heart disease should start medication in low doses of LT4, which will gradually increase every 2-3 months until the TSH is normal.

17. Which thyroid disorders are most often associated with hyperthyroidism?

It is important to establish the difference between primary and secondary forms of hyperthyroidism. Primary hyperthyroidism is due to the hyperactivity of the thyroid gland and comprises the vast majority of cases. Secondary hyperthyroidism is a less common problem, which, on rare occasions, may result from a pituitary tumour secreting a thyroid-stimulating hormone, or excessive thyroid hormone supplementation.

Three forms of primary hyperthyroidism account for the vast majority of cases:

• Graves’ disease

• Toxic multinodular goiter

• Solitary Toxic Nodule

18. How is primary hyperthyroidism diagnosed?

Since primary hyperthyroidism results from the hypersecretion of thyroid hormones, thyroxin (T4) and/or triiodothyronine (T3) levels are high. Moreover, suppression of the pituitary leads to a low or undetectable level of TSH in the blood.

Subsequently, other tests may be required to know and differentiate the causes: determination of antibodies, thyroid scintigraphy or ultrasound.

With thyroid scintigraphy and in the case of Graves’ disease, the distribution of the tracer is uniform throughout the gland, whereas in the multinodular goitre the distribution is heterogeneous and almost completely restricted to a node in patients with toxic solitary nodule.

19. How is hyperthyroidism treated?

There are three types of treatment and your doctor can explain the risks and benefits of each one. The goal is to stop the excessive production of thyroid hormones.

1. Antithyroid Drugs:
   In Portugal, there are drugs that can decrease the production of thyroid hormones. Some patients may achieve remission with prolonged treatment (12-18 months), although others can only reach temporary control. There may be some side effects (skin reactions, liver abnormalities, reduced white blood cells) and its intake should be monitored and controlled by an endocrinologist.
   
   
2. Radioactive Iodine:
   This results in a final resolution of hyperthyroidism. It is administered orally (usually in capsules) and destroys the thyroid cells as it infiltrates them. Its maximum effect is observed 3-6 months after the administration. Occasionally hyperthyroidism remains and a second dose is required.
   
   More often it results in hypothyroidism (less active gland) and a thyroid hormone replacement is necessary. It is difficult to calculate the exact dose of iodine necessary to achieve a normal thyroid function. This method has been used for a long time and does not have any major complications.
   
   
3. Surgical Treatment:
   In some cases, it is necessary to surgically remove part of the toxic nodule or the entire gland (Graves’ disease or toxic multinodular goiter). If it is completely removed, hypothyroidism arises and it is necessary to take a thyroid hormone for the rest of your life.

20. What are some of the characteristics of antithyroid drugs? 

Most types of hyperthyroidism, including Graves’ disease, can be effectively treated with antithyroid drugs of the thyonamide group. These drugs inhibit the synthesis of thyroid hormones. Approximately 20-50% of patients achieve remission with these drugs.

Severe side effects are rare, but granulocytopenia, skin rashes and liver toxicity are possible. In order to reduce these complications, it is important to monitor liver function tests periodically and alert the patient to seek medical attention if they present new skin rashes or any sign of infection.

Moreover, we think it is necessary to perform a complete blood count with differential white cell count, every 2-4 weeks, during the administration of antithyroid drugs. A gradual decline in the number of white blood cells may indicate the beginning of granulocytopenia.

21. How important are radioactive iodine and surgery in the treatment of hyperthyroidism?

The most common treatment of Graves’ disease is radioactive iodine. The desired outcome of this therapy is hypothyroidism, due to the complete destruction of the gland, which usually occurs within 2-3 months. It is important to monitor thyroid function tests and provide additional L-thyroxine since the gland is completely destroyed, hypothyroidism comes to light.

Radioactive iodine is generally well-tolerated, but there may be severe signs and symptoms of thyrotoxicosis 1-2 weeks after therapy. Surgery is not usually indicated for Graves’ disease, but it may be appropriate in the presence of a thyroid nodule if the physician suspects that it is a carcinoma.

22. What is subacute thyroiditis?

Subacute thyroiditis is an inflammation of the thyroid gland which often occurs in association with upper respiratory tract infections. Patients typically have a painful gland of increased size. In the natural history of this disorder, an early stage of hyperthyroidism, due to the release of thyroid hormones from the damaged thyrocytes, is followed by a hypothyroidism phase.

Finally, by a return to euthyroid and the restoration of normal glandular function. Not all patients manifest this phase. The disease usually completes its course in 2-3 months. The symptomatic treatment of the hyperthyroidism and hypothyroidism phases is advisable.

23. What is the natural history of subacute thyroiditis?

Subacute thyroiditis is likely of viral origin. Although clinical recovery usually occurs, serum thyroglobulin levels remain high, and intrathyroid iodine content remains low for several months. Patients are also more susceptible to iodine-induced hypothyroidism, subsequently. These findings suggest the persistence of subclinical abnormalities after an episode of subacute thyroiditis.

24. What is postpartum thyroiditis?

Postpartum thyroiditis disorder is often seen in women (about 5-10%) after delivery. Its cause is unknown. Its course, like subacute thyroiditis, consists of three phases: an initial stage of hyperthyroidism, followed by an intermediate stage of hypothyroidism and, subsequently, euthyroid. This disorder is usually resolved within 1 year or less after delivery. However, as in the case of subacute thyroiditis, recurrent episodes can result in permanent hypothyroidism.

Postpartum thyroiditis is common, occurring in about 5-10% of women during the postpartum period. It may present itself as depression and should be differentiated from postpartum depression. Many other signs and symptoms wrongly attributed the birth and care of the baby may be related to abnormalities in thyroid function.

25. How common is postpartum thyroiditis?

After delivery, 5-10% of women develop biochemical evidence of thyroid dysfunction. About one-third of affected women develop symptoms (usually hypothyroidism) and is treated with L-thyroxine for a period of 6 to 12 months.

26. What are the differences between subacute thyroiditis and postpartum thyroiditis?

Patients with subacute thyroiditis exhibit pain in the thyroid region, high erythrocyte sedimentation rate and a transient increase in thyroid antibodies. Most of it is positive for the HLA-B35 antigen and histological examination shows the presence of giant cells and granulomas in the thyroid.

In the post-partum condition, there is no pain, the erythrocyte sedimentation rate is normal, and thyroid antibodies are positive both before and after the episode. The prevalence of HLA-DR3 and HLA-DR5 antigens is increased and histological examination shows lymphocytic infiltration of the thyroid gland.

27. Why do some women develop postpartum thyroiditis?

It is believed that women who develop postpartum thyroiditis are carriers of underlying asymptomatic autoimmune thyroiditis. During pregnancy, the maternal immune system is partially suppressed, and there is a dramatic increase in thyroid antibodies after birth.

Although it is not believed that anti-microsomal antibodies are cytotoxic, they are currently the most reliable marker of susceptibility to postpartum illness.

28. In patients carrying postpartum thyroiditis, does the thyroid function return to normal, like in subacute thyroiditis?

Not always. Approximately 20% of women suffer permanently from hypothyroidism, and an equal amount shows slight persistent abnormalities.

29. Which lab tests are essential for thyroid disorders?

It depends on the type of disorder.

The most sensitive thyroid dysfunction test is TSH. Because of the existent log/linear relationship between TSH and FT4, we should not expect an abnormal FT4, unless the TSH is >10 mIU/L or <0.05 mIU/L.

Anti-TPO antibodies are the most sensitive indicator for autoimmune thyroid. The T3 is used in some cases when it is necessary to determine the etiology of hyperthyroidism [the ratio of T3/T4 is high (>20:1) in the case of Graves’ hyperthyroidism].

TSH and anti-TPO antibodies are important in the evaluation of thyroid dysfunction during preconception and pregnancy. Thyroglobulin is used as a tumour marker for thyroid cancer.