• Clinical science

Hypothyroidism (Thyroid hypofunction)


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, it is not the production of hormones, but rather the peripheral effects of thyroid hormones that are insufficient. Hypothyroidism may be acquired or congenital. If congenital, it is usually the result of thyroid dysplasia or aplasia. The etiology of acquired hypothyroidism is commonly autoimmune (Hashimoto's thyroiditis) or iatrogenic. The pathophysiology in hypothyroidism is characterized mainly by a reduction of the basal metabolic rate as well as generalized myxedema. These two principles are reflected in the typical clinical findings, which include fatigue, cold intolerance, weight gain, and periorbital edema. More severe manifestations may 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 cretinism (intellectual disability, stunted growth). Accordingly, neonatal screening for hypothyroidism between 24 and 48 hours after birth is required by law in most states. In adults, the diagnosis is established based on serum TSH and FT4 levels. Therapy of both acquired and congenital hypothyroidism consists of lifelong treatment with levothyroxine (L-thyroxine) and regular check-ups to monitor disease activity.



Epidemiological data refers to the US, unless otherwise specified.


Congenital hypothyroidism

Acquired hypothyroidism



Hypothalamic-pituitary-thyroid axis

The hypothalamus, anterior pituitary gland, and thyroid gland, together with their respective hormones, comprise a self-regulatory circuit referred to as the hypothalamic-pituitary-thyroid axis.

Effects of hypothyroidism


Clinical features

General signs and symptoms

As changes in thyroid metabolism have very complex and far-reaching consequences, not all of the symptoms have been directly or unambiguously connected to one of the principal pathophysiological phenomena.

Older patients may not display typical symptoms of hypothyroidism. Instead, they may appear to suffer from dementia or depression!

Congenital hypothyroidism

Children with congenital hypothyroidism may also display general signs and symptoms of hypothyroidism in addition to those typical in the newborn infant (see below).

  • Postpartum
    • Umbilical hernia
    • Prolonged newborn jaundice
    • Hypotonia
    • Decreased activity, poor feeding, and adipsia
    • Hoarse cry, macroglossia
  • Cretinism; : impaired development; of the brain and skeleton, resulting in skeletal abnormalities; and intellectual disabilities

Most children with congenital hypothyroidism do not display symptoms at the time of birth, as the placenta supplies the fetus with maternal thyroid hormoneneonatal screening is vital even if children are asymptomatic! Irreversible intellectual disabilities can be avoided through early initiation of adequate therapy!

Mnemonic for the manifestations of cretinism/congenital hypothyroidism: 6 P's for Pot-bellied, Pale, Puffy-faced, Protruding umbilicus, Protuberant tongue, and Poor brain development.



Congenital hypothyroidism

Neonatal screening; (required by law): measurement of TSH levels 24–48 hours after birthTSH

Acquired hypothyroidism

Overview of changes in hormone levels

Central hormones Peripheral hormones
Overt hypothyroidism Primary hypothyroidism
Secondary hypothyroidism

Subclinical hypothyroidism

  • Normal FT3 and FT4 levels

Basic diagnostic strategy

The initial step is to determine TSH levels, which may be followed by FT4 levels to confirm or rule out the suspected diagnosis.

  1. TSH levels
  2. FT4 levels
  3. FT3 levels

Further diagnostic considerations

  • Antibody testing
    • Tg Ab (thyroglobulin) and TPO Ab (thyroid peroxidase): detectable in most patients with autoimmune hypothyroidism
    • TRAb (TSH receptor)
      • Thyrotropin-binding inhibitory immunoglobulin assay (TBII assay)
        • Can detect the presence of antibodies against the TSH receptor, but cannot determine the type of the antibodies (blocking, neutral, or stimulating)
        • However, if a patient displays symptoms of hypothyroidism and antibodies are detected via the assay, it is highly likely that these are blocking antibodies.
  • Radioactive iodine uptake test
    • Measures the proportion of exogenous iodine that is taken up by the thyroid (normally 10–35%)
    • Decreased uptake is indicative of hypothyroidism.
  • Associated conditions

Normal TSH levels very likely rule out both the possibility of hypothyroidism and hyperthyroidism and are therefore the decisive parameter in screening for both conditions!

Differential diagnoses

Sick euthyroid syndrome (SES) (euthyroid sick syndrome (ESS), non-thyroidal illness syndrome (NTI))

  • Occurs in severe illness or under severe physical stress (especially in intensive care patients)
  • Pathophysiology
  • Laboratory
    • n/↓ TSH, ↓ FT3
    • FT4 levels may be normal or, in prolonged courses of illness, low.
  • Treatment: usually not recommended as thyroid function is normal; insufficient evidence that thyroid hormone substitution is beneficial to the patient

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: commonly persistently elevated FT4 and FT3, absent TSH suppression
  • Therapy: no causative therapy available


The differential diagnoses listed here are not exhaustive.


L-thyroxine replacement

  • L-thyroxine: synthetic form of T4 → peripherally converted to T3 (biologically active) and rT3 (biologically inactive)
  • General principles: lifelong replacement ; prompt initiation; gradual increase in elderly patients or those with preexisting cardiovascular conditions
  • L-thyroxine interactions
  • Follow-ups with laboratory controls of thyroid function (TSH) at regular intervals; adjustment of dosage if necessary
TSH Thyroid metabolism T4-dosage
decreased increase
normal maintain
increased reduce

Special considerations



Myxedema coma

This extremely rare condition is caused by 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 up to ∼ 40% of cases.

  • Clinical presentation
  • Treatment
    • IV combination of T4 and T3 (possibly plus IV hydrocortisone )
    • Patient should be treated and monitored in an ICU.

Further complications


We list the most important complications. The selection is not exhaustive.