Hypothyroidism
Classification and external resources
Thyroxine (T4) normally produced in 20:1 ratio to triiodothyronine (T3)
ICD-10 | E 03.9
ICD-9 | 244.9
DiseasesDB | 6558
eMedicine | med/1145
MeSH | D007037

Hypothyroidism /ʔ h[unsupported input]p ʔ ʔ ʔ[unsupported input][unsupported input]d ʔ z[unsupported input]/ is a state in which the thyroid gland does not make enough thyroid hormone.

Iodine deficiency is often cited as the most common cause of hypothyroidism worldwide but it can be caused by many other factors. It can result from the lack of a thyroid gland or from iodine-131 treatment, and can also be associated with increased stress. Severe hypothyroidism in infants can result in cretinism.

A 2011 study concluded that about 8% of women over 50 and men over 65 in the UK suffer from an under-active thyroid and that as many as 100,000 of these people could benefit from treatment they are currently not receiving.[1]

## Classification[edit]

Hypothyroidism is often classified by association with the indicated organ dysfunction (see below):[2][3]

Type | Origin |
--- | --- | ---
Primary | Thyroid gland | The most common forms include Hashimoto's thyroiditis (an autoimmune disease) and radioiodine therapy for hyperthyroidism.
Secondary | Pituitary gland | Occurs if the pituitary gland does not create enough thyroid-stimulating hormone (TSH) to induce the thyroid gland to produce enough thyroxine and triiodothyronine. Although not every case of secondary hypothyroidism has a clear-cut cause, it is usually caused by damage to the pituitary gland, as by a tumor, radiation, or surgery.[4] Secondary hypothyroidism accounts for less than 5%[5] or 10%[6] of hypothyroidism cases.
Tertiary | Hypothalamus | Results when the hypothalamus fails to produce sufficient thyrotropin-releasing hormone (TRH). TRH prompts the pituitary gland to produce thyroid-stimulating hormone (TSH). Hence may also be termed hypothalamic-pituitary-axis hypothyroidism. It accounts for less than 5% of hypothyroidism cases.[5]

## Signs and symptoms[edit]

Early hypothyroidism is often asymptomatic and can have very mild symptoms. Subclinical hypothyroidism is a state of normal thyroid hormone levels, thyroxine (T4) and triiodothyronine (T3), with mild elevation of thyrotropin, thyroid-stimulating hormone (TSH). With higher TSH levels and low free T4 levels, symptoms become more readily apparent in clinical (or overt) hypothyroidism.

Hypothyroidism can be associated with the following symptoms:[7][8][9]

### Early[edit]

- Cold intolerance, increased sensitivity to cold
- Constipation
- Weight gain and water retention[10][11][12]
- Bradycardia (low heart rate ? fewer than sixty beats per minute)
- Fatigue
- Decreased sweating
- Muscle cramps and joint pain
- Dry, itchy skin
- Thin, brittle fingernails
- Rapid thoughts
- Depression
- Poor muscle tone (muscle hypotonia)
- Female infertility; any kind of problems with menstrual cycles
- Hyperprolactinemia and galactorrhea
- Elevated serum cholesterol

### Late[edit]

- Goiter
- Slow speech and a hoarse, breaking voice ? deepening of the voice can also be noticed, caused by Reinke's Edema.
- Dry puffy skin, especially on the face
- Thinning of the outer third of the eyebrows (sign of Hertoghe)
- Abnormal menstrual cycles
- Low basal body temperature
- Thyroid-related depression

### Uncommon[edit]

- Impaired memory[13]
- Impaired cognitive function (brain fog) and inattentiveness.[14]
- A slow heart rate with ECG changes including low voltage signals. Diminished cardiac output and decreased contractility
- Reactive (or post-prandial) hypoglycemia[15]
- Sluggish reflexes
- Hair loss
- Anemia caused by impaired haemoglobin synthesis (decreased EPO levels), impaired intestinal iron and folate absorption or B12 deficiency[16] from pernicious anemia
- Difficulty swallowing
- Shortness of breath with a shallow and slow respiratory pattern
- Increased need for sleep
- Irritability and mood instability
- Yellowing of the skin due to impaired conversion of beta-carotene[17] to vitamin A (carotoderma)
- Impaired renal function with decreased glomerular filtration rate
- Acute psychosis (myxedema madness) (a rare presentation of hypothyroidism)
- Decreased libido in men[18] due to impairment of testicular testosterone synthesis
- Decreased sense of taste and smell (anosmia)
- Puffy face, hands and feet (late, less common symptoms)
- Gynecomastia
- Deafness[19]
- Enlarged tongue[20]

### Subclinical hypothyroidism[edit]

Subclinical hypothyroidism occurs when thyrotropin (TSH) levels are elevated but thyroxine (T4) and triiodothyronine (T3) levels are normal.[21] In primary hypothyroidism, TSH levels are high and T4 and T3 levels are low. TSH usually increases when T4 and T3 levels drop. TSH prompts the thyroid gland to make more hormone. In subclinical hypothyroidism, TSH is elevated but below the limit representing overt hypothyroidism. The levels of the active hormones will be within the laboratory reference ranges.

## Pregnancy and fertility[edit]

Main article: Thyroid disease in pregnancy

During pregnancy there is a substantially increased need of thyroid hormones and substantial risk that a previously unnoticed, subclinical or latent hypothyroidism will turn into overt hypothyroidism.

Subclinical hypothyroidism in early pregnancy, compared with normal thyroid function, has been estimated to increase the risk of pre-eclampsia with an odds ratio (OR) of 1.7 and the risk of perinatal mortality with an OR of 2.7.[22]

Even mild or subclinical hypothyroidism is known to adversely affect fertility.

## Epidemiology[edit]

0.3% of the general American population have overt hypothyroidism, and 4.3% have subclinical hypothyroidism.[23] A 1995 survey in the UK found the mean incidence (with 95% confidence intervals) of spontaneous hypothyroidism in women was 3.5/1000 survivors/year (2.8-4.5) rising to 4.1/1000 survivors/year (3.3-5.0) for all causes of hypothyroidism and in men was 0.6/1000 survivors/year (0.3-1.2).[24]

Estimates of subclinical hypothyroidism range between 3?8%, increasing with age; incidence is more common in women than in men.[25]

## Causes[edit]

Iodine deficiency is the most common cause of hypothyroidism worldwide.[26] In iodine-replete individuals hypothyroidism is frequently caused by Hashimoto's thyroiditis, or otherwise as a result of either an absent thyroid gland or a deficiency in stimulating hormones from the hypothalamus or pituitary.

Factors such as iodine deficiency or exposure to iodine-131 from nuclear fallout, which is absorbed by the thyroid gland like regular iodide and destroys its cells, can increase the risk.

Congenital hypothyroidism is very rare accounting for approximately 0.2% and can have several causes such as thyroid aplasia or defects in the hormone metabolism. Thyroid hormone insensitivity (most often T3 receptor defect) also falls into this category although in this condition the levels of thyroid hormones may be normal or even markedly elevated.

Hypothyroidism can result from postpartum thyroiditis, a condition that affects about 5% of all women within a year of giving birth.[citation needed] The first phase is typically hyperthyroidism; the thyroid then either returns to normal, or a woman develops hypothyroidism. Of those women who experience hypothyroidism associated with postpartum thyroiditis, one in five will develop permanent hypothyroidism requiring lifelong treatment.

Hypothyroidism can result from de Quervain's thyroiditis, which, in turn, is often caused by having a bad flu that enters and destroys part, or all, the thyroid.[27]

Hypothyroidism can also result from sporadic inheritance, sometimes autosomal recessive.[citation needed]

Temporary hypothyroidism can be due to the Wolff-Chaikoff effect. A very high intake of iodine can be used to temporarily treat hyperthyroidism, especially in an emergency situation. Although iodide is a substrate for thyroid hormones, high levels reduce iodide organification in the thyroid gland, decreasing hormone production. The antiarrhythmic agent amiodarone can cause hyper- or hypothyroidism due to its high iodine content.

Hypothyroidism can be caused by lithium-based mood stabilizers, usually used to treat bipolar disorder (previously known as manic depression).[26] In fact, lithium has occasionally been used to treat hyperthyroidism.[28] Other drugs that may produce hypothyroidism include interferon alpha, interleukin-2, and thalidomide.[26]

### Stress and hypothyroidism[edit]

Stress is known to be a significant contributor to thyroid dysfunction; this can be environmental stress as well as lesser-considered homeostatic stress such as fluctuating blood sugar levels and immune problems.[citation needed] Stress's effect on thyroid function can be indirect, through its effects on blood sugar levels (dysglycemia),[29] but it can also have more direct effects. Stress may cause hypothyroidism or reduced thyroid functioning by disrupting the HPA axis which down-regulates thyroid function,[30] reducing the conversion of T4 to T3,[31] weakening the immune system thus promoting autoimmunity,[32] causing thyroid hormone resistance,[33] and resulting in hormonal imbalances. Indeed, excess estrogen in the blood caused by chronic cortisol elevations can result in hypothyroid symptoms by decreasing levels of active T3.[34] Stress also affects thyroid functioning through the sympathetic nervous system.[35] Refugees from East Germany in a 1994 study who experienced chronic stress were found to have a very high rate of hypothyroidism or subclinical hypothyroidism, although not all refugees displayed clinical or behavioral symptoms associated with this reduced thyroid functioning.[36] TSH levels correlate positively with physiological stress.[37][38]

Adrenal insufficiency can also result in hypothyroid symptoms without affecting the thyroid itself.[39]

## Diagnosis[edit]

Main article: Thyroid function tests

The only validated test to diagnose primary hypothyroidism, is to measure thyroid-stimulating hormone (TSH) and free thyroxine (T4).[40] However, these levels can be affected by non-thyroidal illnesses.

High levels of TSH indicate that the thyroid is not producing sufficient levels of thyroid hormone (mainly as thyroxine (T4) and smaller amounts of triiodothyronine (T3)). However, measuring just TSH fails to diagnose secondary and tertiary hypothyroidism, thus leading to the following suggested blood testing if the TSH is normal and hypothyroidism is still suspected:

- Free triiodothyronine (fT3)
- Free thyroxine (fT4)
- Total T3
- Total T4

Additionally, the following measurements may be needed:

- Free T3 from 24-hour urine catch[41]
- Antithyroid antibodies ? for evidence of autoimmune diseases that may be damaging the thyroid gland
- Serum cholesterol ? which may be elevated in hypothyroidism
- Prolactin ? as a widely available test of pituitary function
- Testing for anemia, including ferritin
- Basal body temperature

## Treatment[edit]

Main article: Medical use of thyroid hormones

Hypothyroidism is treated with the levorotatory forms of thyroxine (levothyroxine) (L-T4) and triiodothyronine (liothyronine) (L-T3). Synthroid is, in the US, the most common name form of the pill Levothyroxine. Synthroid is also the most common pill prescribed by doctors that has the synthetic thyroid hormone in it. This medicine can improve symptoms of thyroid deficiency such as slow speech, lack of energy, weight gain, hair loss, dry skin, and feeling cold. It also helps to treat goiter. It is also used to treat some kinds of thyroid cancer along with surgery and other medicines. Both synthetic and animal-derived thyroid tablets are available and can be prescribed for patients in need of additional thyroid hormone. Thyroid hormone is taken daily, and doctors can monitor blood levels to help assure proper dosing. Levothyroxine is best taken 30?60 minutes before breakfast, as some food can diminish absorption. Calcium can inhibit the absorption of levothryoxine.[42] Compared to water, coffee reduces absorption of levothyroxine by about 30 percent.[43] Some patients might appear to be resistant to levothyroxine, when in fact they do not properly absorb the tablets - a problem which is solved by pulverizing the medication.[44] There are several different treatment protocols in thyroid-replacement therapy:

T4 only
  This treatment involves supplementation of levothyroxine alone, in a synthetic form. It is currently the standard treatment in mainstream medicine.[45]

T4 and T3 in combination
  This treatment protocol involves administering both synthetic L-T4 and L-T3 simultaneously in combination.[46]

Desiccated thyroid extract
  Desiccated thyroid extract is an animal-based thyroid extract, most commonly from a porcine source. It is also a combination therapy, containing natural forms of L-T4 and L-T3.[47]

### Treatment controversy[edit]

The potential benefit from substituting some T3 for T4 has been investigated, but no conclusive benefit for combination therapy has been shown.[48][49]

The 2002 Laboratory Medicine Practice Guidelines of the National Academy of Clinical Biochemistry state that during pregnancy: "The L-T4 dose should be increased (usually by 50 mcg/day) to maintain a serum TSH between 0.5 and 2.0 mIU/L and a serum FT4 in the upper third of the normal reference interval." Doctors however often assume that if your TSH is in the "normal range", sometimes defined as high as 5.5 mIu/L, it has no effect on fertility. Healthy pregnant women however have a TSH level of around 1.0 mIU/L.

### Subclinical hypothyroidism[edit]

There is a range of opinion on the biochemical and symptomatic point at which to treat with levothyroxine, the typical treatment for overt hypothyroidism. Reference ranges have been debated as well. As of 2003, the American Association of Clinical Endocrinologists (ACEE) considers 0.3?3.0?mIU/L within normal range.[50]

There is always the risk of overtreatment and hyperthyroidism. Some studies have suggested that subclinical hypothyroidism does not need to be treated. A 2007 meta-analysis by the Cochrane Collaboration found no benefit of thyroid-hormone replacement except "some parameters of lipid profiles and left-ventricular function."[51] A 2002 meta-analysis looking into whether subclinical hypothyroidism may increase the risk of cardiovascular disease, as has been previously suggested,[52] found a possible modest increase and suggested further studies be undertaken with coronary-heart disease as an end point "before current recommendations are updated."[53]

### Alternative treatments[edit]

Compounded slow-release T3 has been suggested for use in combination with T4, which proponents argue will mitigate many of the symptoms of functional hypothyroidism and improve quality of life. This is still controversial and is rejected by the conventional medical establishment.[54]

### Non-human presentation[edit]

Hypothyroidism is also a relatively common disease in domestic dogs, with some specific breeds having a definite predisposition.[55]

## See also[edit]

- Pituitary disease
- Subacute lymphocytic thyroiditis
- Thyroid hormone resistance
- Hyperthyroidism
- Adrenal insufficiency

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## Further reading[edit]

- Tchong L, Veloski C, Siraj ES (May 2009). - Hypothyroid.pdf "Hypothyroidism: management across the continuum". J Clin Outcomes Manage 16 (5): 231?5.
- Rayman, Margaret P (2000). "The importance of selenium to human health". The Lancet 356 (9225): 233?41. doi:10.1016/S0140-6736(00)02490-9.

## External links[edit]

- Hypothyroidism Booklet - American Thyroid Association

Endocrine pathology: endocrine diseases (E00–E35, 240–259)
Pancreas/ glucose metabolism |
Hypofunction | Diabetes mellitus types: type 1 type 2 MODY 1 2 3 4 5 6 complications coma angiopathy ketoacidosis nephropathy neuropathy retinopathy cardiomyopathy insulin receptor (Rabson–Mendenhall syndrome) Insulin resistance
Hyperfunction | Hypoglycemia beta cell (Hyperinsulinism) G cell (Zollinger–Ellison syndrome)
Hypothalamic/ pituitary axes |
Hypothalamus | gonadotropin Kallmann syndrome Adiposogenital dystrophy CRH (Tertiary adrenal insufficiency) vasopressin (Neurogenic diabetes insipidus) general (Hypothalamic hamartoma)
Pituitary |
Hyperpituitarism | anterior Acromegaly Hyperprolactinaemia Pituitary ACTH hypersecretion posterior (SIADH) general (Nelson's syndrome)
Hypopituitarism | anterior Kallmann syndrome Growth hormone deficiency ACTH deficiency/Secondary adrenal insufficiency GnRH insensitivity FSH insensitivity LH/hCG insensitivity posterior (Neurogenic diabetes insipidus) general Empty sella syndrome Pituitary apoplexy Sheehan's syndrome Lymphocytic hypophysitis
Thyroid |
Hypothyroidism | Iodine deficiency Cretinism Congenital hypothyroidism Myxedema Euthyroid sick syndrome
Hyperthyroidism | Hyperthyroxinemia Thyroid hormone resistance Familial dysalbuminemic hyperthyroxinemia Hashitoxicosis Thyrotoxicosis factitia Graves' disease
Thyroiditis | Acute infectious Subacute De Quervain's Subacute lymphocytic Autoimmune/chronic Hashimoto's Postpartum Riedel's
Goitre | Endemic goitre Toxic nodular goitre Toxic multinodular goiter Thyroid nodule
Parathyroid |
Hypoparathyroidism | Hypoparathyroidism Pseudohypoparathyroidism Pseudopseudohypoparathyroidism
Hyperparathyroidism | Primary Secondary Tertiary Osteitis fibrosa cystica
Adrenal |
Hyperfunction | aldosterone: Hyperaldosteronism/Primary aldosteronism Conn syndrome Bartter syndrome Glucocorticoid remediable aldosteronism AME Liddle's syndrome 17α CAH cortisol: Cushing's syndrome (Pseudo-Cushing's syndrome) sex hormones: 21α CAH 11β CAH
Hypofunction/ Adrenal insufficiency (Addison's, WF) | aldosterone: Hypoaldosteronism 21α CAH 11β CAH cortisol: CAH Lipoid 3β 11β 17α 21α sex hormones: 17α CAH
Gonads | ovarian: Polycystic ovary syndrome Premature ovarian failure testicular: enzymatic 5α-reductase deficiency 17β-hydroxysteroid dehydrogenase deficiency aromatase excess syndrome) Androgen receptor (Androgen insensitivity syndrome general: Hypogonadism (Delayed puberty) Hypergonadism Precocious puberty Hypoandrogenism Hypoestrogenism Hyperandrogenism Hyperestrogenism
Height | Dwarfism/Short stature Midget Laron syndrome Psychosocial Ateliosis Gigantism
Multiple | Autoimmune polyendocrine syndrome multiple APS1 APS2 Carcinoid syndrome Multiple endocrine neoplasia 1 2A 2B Progeria Werner syndrome Acrogeria Metageria Woodhouse-Sakati syndrome
M: END | anat/phys/devp/horm | noco (d)/cong/tumr, sysi/epon | proc, drug (A10/H1/H2/H3/H5)