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.

Congenital hypothyroidism

• Sporadic (∼ 85% of cases)
  • Thyroid hypoplasia or dysplasia
  • Thyroid aplasia (athyroidism)
• Hereditary (∼15% of cases)
  • Defects in thyroid hormone synthesis
  • Peripheral resistance to thyroid hormones

Acquired hypothyroidism

• Primary hypothyroidism: insufficient thyroid hormone production
  • Autoimmune etiology (Hashimoto's thyroiditis)
    • Often associated with other autoimmune diseases (e.g., vitiligo, pernicious anemia, type 1 diabetes mellitus, and SLE)
  • Lymphocytic thyroiditis (or postpartum thyroiditis)
  • Subacute granulomatous thyroiditis (or de Quervain thyroiditis)
  • Iatrogenic (e.g., surgery, radioiodine therapy, medication )
  • Nutritional (insufficient intake of iodine)
• Secondary hypothyroidism: pituitary disorders → thyroid-stimulating hormone (TSH) deficiency
• Tertiary hypothyroidism: hypothalamic disorders → thyrotropin-releasing hormone (TRH) deficiency (very rare)

References:^{[4][1][3][5][6]}

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.

• Physiological: See “thyroid gland” in general endocrinology.
• Hypothyroidism
  • Primary: peripheral (thyroid) disorders → T₃/T₄ are not produced (↓ levels) → compensatory increase of TSH
  • Secondary: pituitary disorders → ↓ TSH levels → ↓ T₃/T₄ levels
  • Tertiary: hypothalamic disorders → ↓ TRH levels → ↓ TSH levels → ↓ T₃/T₄ levels

Effects of hypothyroidism

• Generalized decrease of the basal metabolic rate: oxygen and substrate consumption decreased throughout the body
• Generalized myxedema: caused by increased deposition of glycosaminoglycans (and thus fluid) in the dermis and mucous membranes (e.g., of the pharynx)
• Hyperprolactinemia: prolactin production is stimulated by TRH → ↑ prolactin suppresses LH, FSH, and testosterone secretion; also stimulates breast tissue growth

References:^[4][7]

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.

• Symptoms related to decreased metabolic rate
  • Fatigue, bradykinesia
  • Cold intolerance
  • Cold, dry skin, and hair loss
  • Weight gain (despite poor appetite)
  • Constipation
  • Myopathy; , myalgia, stiffness, cramps, delayed tendon reflex relaxation; , entrapment syndromes (e.g., carpal tunnel syndrome)
• Symptoms related to generalized myxedema
  • Doughy skin texture, puffy appearance
  • Myxedematous heart disease (dilated cardiomyopathy, bradycardia, dyspnea)
  • Myxedema coma (see “Complications” below)
  • Hoarse voice, clumsy speech
  • Pretibial and periorbital edema
• Symptoms of hyperprolactinemia
  • Abnormal menstrual cycle (esp. secondary amenorrhea; or menorrhagia)
  • Galactorrhea
  • Decreased libido, erectile dysfunction, delayed ejaculation and infertility in men
• Further symptoms
  • Impaired cognition (concentration, memory), depression
  • Hypertension
  • Goiter (in Hashimoto's thyroiditis) or atrophic thyroid (in atrophic thyroiditis)

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 hormone → neonatal 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.

References:^{[4][1][8][9][10][11]}

Congenital hypothyroidism

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

Acquired hypothyroidism

Overview of changes in hormone levels

		Central hormones	Peripheral hormones
Overt hypothyroidism	Primary hypothyroidism	↑ TSH	↓ FT4 → thyroid hormone synthesis deficiency
	Secondary hypothyroidism	↓ TSH
Subclinical hypothyroidism		↑ TSH	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
   • Normal: hypothyroidism highly unlikely
   • High: indicative of primary hypothyroidism, subclinical hypothyroidism, or other thyroid disorders
   • Low: indicative of secondary hypothyroidism or other thyroid disorders
2. FT4 levels
   • Low, TSH abnormal: primary (↑ TSH) or secondary (↓ TSH) hypothyroidism
   • Normal, ↑ TSH: subclinical hypothyroidism
3. FT3 levels
   • Low, FT4 and TSH normal: low T3 syndrome
   • Low, ↓ FT4, TSH normal: low T₃ low T₄ syndrome

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
  • Hypercholesterolemia (↑ LDL); , hyperlipidemia, hypoglycemia
  • Mild anemia
  • In rare cases: hyponatremia

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!
References:^{[4][12][13][14][15]}

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
  • Increased dosage necessary: estrogen, SERM ; bile acidbinding resins, omeprazole, calcium carbonate ; phenytoin, carbamazepine ; propranolol
  • Reduced dosage necessary: glucocorticoids
• 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.
• L-thyroxine replacement in subclinical hypothyroidism
  • If TSH > 10 mU/L
  • For patients with atherosclerotic cardiovascular disease
  • Pregnancy or pregnancy planned in the near future

References:^{[3][14][18][19][20]}