Hypothyroidism is a condition in which the thyroid gland is underactive, resulting in a deficiency of the thyroid hormones triiodothyronine (T3) and thyroxine (T4). In rare cases, hormone production may be sufficient, but thyroid hormones may have insufficient peripheral effects. Hypothyroidism may be congenital or acquired. If congenital, it is usually the result of thyroid dysplasia or aplasia. The etiology of acquired hypothyroidism is typically autoimmune (Hashimoto thyroiditis) or iatrogenic. The pathophysiology in hypothyroidism is characterized mainly by a reduction of the basal metabolic rate and generalized myxedema. Typical clinical findings include fatigue, cold intolerance, weight gain, and periorbital edema. More severe manifestations include myxedematous heart disease and myxedema coma, which may be fatal if left untreated. Children with congenital hypothyroidism often have umbilical hernias and, without early treatment, develop congenital iodine deficiency syndrome (intellectual disability, stunted growth). Accordingly, for hypothyroidism 24–48 hours after birth is required by law in most states. In adults, the diagnosis is established based on serum thyroid-stimulating hormone (TSH) and free T4 levels (FT4). Therapy for both acquired and congenital hypothyroidism consists of lifelong treatment with levothyroxine (L-thyroxine) and regular check-ups to monitor disease activity.
- Incidence: ∼ 1:2,300 newborns in the US (up to 1:2,000 worldwide) are affected by congenital hypothyroidism 
Prevalence: more common in women
- Women: up to 12:1,000
- Men: up to 4:1,000 
Epidemiological data refers to the US, unless otherwise specified.
- Sporadic (∼ 85% of cases) 
- Hereditary (∼ 15% of cases)
Primary hypothyroidism: insufficient thyroid hormone production
- Hashimoto thyroiditis
- Postpartum thyroiditis (subacute lymphocytic thyroiditis) 
- subacute granulomatous thyroiditis) (: often subsequent to a flu-like illness 
- Iatrogenic: e.g., post thyroidectomy, radioiodine therapy, antithyroid medication (e.g., amiodarone, lithium)
- Nutritional (insufficient intake of iodine): the most common cause of hypothyroidism worldwide, particularly in iodine-deficient regions
- Riedel thyroiditis: occurs in IgG4-related systemic disease
- Wolff-Chaikoff effect
- Secondary hypothyroidism: pituitary disorders (e.g., pituitary adenoma) → TSH deficiency
- Tertiary hypothyroidism: hypothalamic disorders → TRH deficiency
- Primary hypothyroidism: peripheral (thyroid) disorders → T3/T4 are not produced (↓ levels) → compensatory ↑ TSH
- Secondary hypothyroidism: pituitary disorders → ↓ TSH levels → ↓ T3/T4 levels
- Tertiary hypothyroidism: hypothalamic disorders → ↓ TRH levels → ↓ TSH levels → ↓ T3/T4 levels
Effects of hypothyroidism 
- Generalized decrease in the basal metabolic rate → decreased oxygen and substrate consumption, leading to:
- Decreased sympathetic activity leads to:
- Decreased transcription of sarcolemmal genes (e.g., calcium ATPases) → decreased cardiac output, myopathy
- Hyperprolactinemia: ↑ production is stimulated by TRH → suppression of LH, FSH, GnRH, and testosterone and stimulation of breast tissue growth
- Myxedema: due to accumulation of glycosaminoglycans and hyaluronic acid within the reticular layer of the dermis
General signs and symptoms
Symptoms related to decreased metabolic rate
- Fatigue, decreased physical activity
- Cold intolerance
- Decreased sweating
- Hair loss, brittle nails, and cold, dry skin
- Weight gain (despite poor appetite)
- Hypothyroid myopathy; , myalgia, stiffness, cramps
- Woltman sign: a delayed relaxation of the deep tendon reflexes, which is commonly seen in patients with hypothyroidism, but can also be associated with advanced age, pregnancy, and diabetes mellitus.
- Entrapment syndromes (e.g., carpal tunnel syndrome)
- Symptoms related to generalized myxedema
- Symptoms of hyperprolactinemia
- Further symptoms
- Congenital iodine deficiency syndrome: a complication of congenital hypothyroidism that manifests leads to an impaired development of the brain and skeleton, resulting in skeletal abnormalities (e.g., short stature and delayed fontanelle closure) and intellectual disabilities 
Most children with congenital hypothyroidism do not have symptoms at the time of birth because the placenta supplies the fetus with maternal thyroid hormone. For this reason, neonatal screening is vital even if children are asymptomatic. Irreversible intellectual disabilities can be avoided through early initiation of adequate therapy!
To remember there characteristic manifestations of congenital iodine deficiency syndrome, think of the “7 P's”: Pot-bellied, Pale, Puffy-faced, Protruding umbilicus, Protuberant tongue, Poor brain development, and Prolonged neonatal jaundice.
Basic diagnostic strategy
The initial step is to determine TSH levels, which may be followed by measurement of FT4 levels to confirm or rule out the suspected diagnosis.
Overview of changes in hormone levels
|Central hormones||Peripheral hormones|
|Overt hypothyroidism||Primary hypothyroidism|| || |
|Secondary hypothyroidism|| |
| || |
Further diagnostic considerations 
A combination of the follwoing three diagnostic tools can be useful to distinguish between different conditions affecting the thyroid, such as differentiating exogenous from endogenous hyperthyroidism.
- thyroglobulin) and (thyroid peroxidase): detectable in most patients with autoimmune hypothyroidism (
TSH receptor) (
- Thyrotropin-binding inhibitory immunoglobulin assay (TBII assay)
- Radioactive iodine uptake test
- Ultrasound of the thyroid gland: : e.g., to assess size, structure, or blood flow
Ruling out other conditions that can mimic hypothyroidism can be helpful in the diagnosis.
- Associated conditions
Euthyroid sick syndrome (ESS)
- Synonyms: sick euthyroid syndrome (SES), non-thyroidal illness syndrome (NTI)
- Etiology: occurs in severe illness or severe physical stress (most common in intensive care patients)
- Normal thyroid function → no symptoms of hyperthyroidism or hypothyroidism
- Cytokines (e.g., interleukin 6) cause various changes in levels of circulating TSH and thyroid hormones.
- Clinical features: specific to underlying nonthyroidal illness
Thyroid hormone resistance 
- Definition: insufficient end-organ sensitivity to thyroid hormones
- Etiology: deficits in thyroid hormone metabolism, transport, or receptor interaction as a result of genetic mutations
- Clinical features: Symptoms of both hypothyroidism and hyperthyroidism are possible.
- Laboratory: Persistently elevated FT4 and FT3 and absent TSH suppression is typical.
- Therapy: No causative therapy is available.
|Differential diagnoses of hypothyroidism|
|Hashimoto thyroiditis ||Postpartum thyroiditis ||Subacute granulomatous thyroiditis (De Quervain)||Congenital hypothyroidism ||Riedel thyroiditis |
|Causes|| || || || |
|Clinical course|| || || || || |
|Goiter||Structure|| || || || || |
|Pain|| || || || || |
|Iodine uptake on scintigraphy|| || || || || |
|Pathology findings|| || || |
The differential diagnoses listed here are not exhaustive.
L-thyroxine replacement 
- Lifelong replacement
- Prompt initiation
- Side effects
- Follow-ups with laboratory controls of thyroid function (TSH) at regular intervals; adjustment of dosage if necessary
|TSH levels||Thyroid metabolism||T4-dosage|
- Children with congenital hypothyroidism: Normalization of thyroid hormone levels within 2–3 weeks is vital to prevent brain damage and developmental disorders. 
- Pregnant women with preexisting hypothyroidism: Levothyroxine dose must be increased but should be reduced to prepregnancy levels after delivery.
- Anorexic patients: Synthetic thyroid hormones are sometimes misused to achieve weight loss.
- Elderly patients or patients with preexisting cardiovascular conditions: Initiate levothyroxine with a lower dose and gradually increase the dose.
- L-thyroxine replacement in subclinical hypothyroidism if:
In pregnant women with hypothyroidism, L-thyroxine dose should be increased due to increased demand. Hypothyroidism adversely affects the development of the fetal nervous system.
Myxedema coma 
Myxedema coma is an extremely rare condition caused by the decompensation of an existing thyroid hormone deficiency and can be triggered by infections, surgery, and trauma. Myxedema coma is a potentially life-threatening condition and, if left untreated, is fatal in ∼ 40% of cases. 
- Clinical presentation
- Diagnosis 
Upon clinical suspicion of myxedema coma, treatment must be initiated without waiting for laboratory results.
- Primary thyroid lymphoma 
- Increased cardiovascular risk
- Carpal tunnel syndrome 
We list the most important complications. The selection is not exhaustive.