• Clinical science

Hypothyroidism (Thyroid hypofunction)

Summary

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, neonatal screening or 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.

Epidemiology

  • Congenital hypothyroidism: ∼ 1/2300 newborns in the US (1/2000 to 1/4000 worldwide) [1]
  • Acquired hypothyroidism: ∼ 3.7% in the US population (1–3% worldwide)

References:[2][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Congenital hypothyroidism

Acquired hypothyroidism

References:[6][2][4][7][8]

Pathophysiology

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 [9]

References:[6][10]

Clinical features

General signs and symptoms

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

Congenital hypothyroidism

Children with congenital hypothyroidism may have general signs and symptoms of hypothyroidism in addition to those typical in neonates (see below).

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!

7 P's for the manifestations of congenital iodine deficiency syndrome: Pot-bellied, Pale, Puffy-faced, Protruding umbilicus, Protuberant tongue, Poor brain development, and Prolonged neonatal jaundice.

References:[6][2][12][13][11][14]

Diagnostics

Congenital hypothyroidism

Neonatal screening to measure TSH levels 24–48 hours after birth is required by law. Increased TSH levels indicate congenital hypothyroidism.

Acquired hypothyroidism

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
  • ↓ Free T4 (FT4) and ↓ free T3 (FT3) levels
Secondary hypothyroidism
Tertiary hypothyroidism

Subclinical hypothyroidism

  • Mildly TSH
  • Normal FT3 and FT4 levels
Euthyroid sick
syndrome


TSH is also altered in hyperthyroidism. However, in hyperthyroidism FT3 and FT4 would be increased.

Further diagnostic considerations

Normal TSH levels very likely rule out primary hypothyroidism and hyperthyroidism and are therefore the decisive parameter in screening for both conditions!
References:[6][16][17][18][19]

Differential diagnoses

Euthyroid sick syndrome (ESS)

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 [5] Postpartum thyroiditis [20] Subacute granulomatous thyroiditis (De Quervain)[21] Congenital hypothyroidism [1] Riedel thyroiditis [22]
Epidemiology
  • Most common cause of hypothyroidism in the US
  • > (7:1)
  • Within 1 year of delivery in 5:100 of women
  • Incidence: 12:100,000 per year
  • > (3:1)
  • Incidence: 1.6:100,000 per year
  • > (4:1)
Causes
  • Autoimmune thyroiditis
  • Autoimmune thyroiditis
  • Variant of subacute lymphocytic thyroiditis
  • Viral and mycobacterial infections causing damage to follicular cells
  • Autoimmune thyroiditis
Clinical course
  • Classic triphasic course: hyperthyroid → hypothyroid → recovery
  • Asymptomatic at birth → hypothyroidism
  • Hypothyroidism in 30% of patients
  • Most patients without hypothyroidism remain euthyroid; very few present with hyperthyroidism.
Goiter Structure
  • Early-stage: rubbery and symmetrically enlarged
  • Late-stage: normal-sized or small if extensive fibrosis has occurred
  • Diffuse and firm
  • Diffuse and firm
  • Diffuse or nodular
  • Slowly growing and stone-hard
Pain
  • Painless
  • Painless
  • Painful
  • Painless
  • Painless
Antibodies
  • Absent
Iodine uptake on scintigraphy
  • Patchy and irregular
  • Reduced
  • Reduced
  • Absent or patchy
  • Normal or reduced
Pathology findings
  • Depend on cause
  • Dense and white fibrotic tissue

References:[23][24]

The differential diagnoses listed here are not exhaustive.

Treatment

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
  • 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

  • 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.
  • 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:
    • TSH ≥ 10 mU/L
    • TSH 7.0–9.9 mU/L in asymptomatic patients < 70 years
    • TSH above the upper limit of normal to 6.9 mU/L in symptomatic patients < 70 years

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!

References:[4][18][25][26][27]

Complications

Myxedema coma

Myxedema coma is an extremely rare condition 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 ∼ 40% of cases.

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

Further complications

References:[28][29][30][31][32][33]

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