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, 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.

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
  • Hashimoto thyroiditis
    • The most common cause of hypothyroidism in iodine-sufficient regions ^[5]
    • Associated with other autoimmune diseases (e.g., vitiligo, pernicious anemia, type 1 diabetes mellitus, and systemic lupus erythematosus)
  • Postpartum thyroiditis (subacute lymphocytic thyroiditis) ^[5]
  • De Quervain thyroiditis (subacute granulomatous thyroiditis) ^[5]
  • Iatrogenic (e.g., post thyroidectomy, radioiodine therapy, antithyroid medication such as amiodarone and lithium)
  • Nutritional (insufficient intake of iodine); : the most common cause of hypothyroidism worldwide, particularly in iodine-deficient regions
  • Riedel thyroiditis
  • Wolff-Chaikoff effect
• Secondary hypothyroidism: pituitary disorders (e.g., pituitary adenoma) → TSH deficiency
• Tertiary hypothyroidism: hypothalamic disorders → thyrotropin-releasing hormone (TRH) deficiency (very rare)

References:^{[6][2][4][7][8]}

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 hypothalamic-pituitary axis.
• Hypothyroidism
  • Primary hypothyroidism: peripheral (thyroid) disorders → T3/T4 are not produced (decreased levels) → compensatory increase of TSH
  • Secondary hypothyroidism: pituitary disorders → decreased TSH levels → decreased T3/T4 levels
  • Tertiary hypothyroidism: hypothalamic disorders → decreased TRH levels → decreased TSH levels → decreased T3/T4 levels

Effects of hypothyroidism ^[9]

• Generalized decrease in the basal metabolic rate → decreased oxygen and substrate consumption, leading to:
  • CNS: apathy, slowed cognition
  • Skin and appendages: skin dryness, alopecia
  • Lipid profile: ↑ low-density lipoproteins, ↑ triglycerides
• Decreased sympathetic activity leads to:
  • Decreased sweating
  • Constipation
  • Bradycardia
• Decreased transcription of sarcolemmal genes (e.g., calcium ATPases) → decreased cardiac output, myopathy
• Hyperprolactinemia: prolactin production is stimulated by TRH → increased prolactin suppresses LH, FSH, GnRH, and testosterone secretion; also stimulates breast tissue growth
• Accumulation of glycosaminoglycans and hyaluronic acid within the reticular layer of the dermis → myxedema
  • Complex protein mucopolysaccharides bind water → nonpitting edema
  • Initially, edema is pretibial, but as the condition progresses it can generalize, resulting in a range of symptoms (see “Clinical features” below).

References:^[6][10]

General signs and symptoms

• Symptoms related to decreased metabolic rate
  • Fatigue, bradykinesia
  • Cold intolerance
  • Hair loss and cold, dry skin
  • Weight gain (despite poor appetite)
  • Constipation
  • Bradycardia
  • Myopathy; , myalgia, stiffness, cramps, delayed tendon reflex relaxation; (Woltman sign), 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, difficulty articulating words
  • 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 ^[11]
  • Goiter (in Hashimoto thyroiditis) or atrophic thyroid (in atrophic thyroiditis)

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).

• Postpartum
  • Umbilical hernia
  • Prolonged neonatal jaundice
  • Hypotonia
  • Decreased activity, poor feeding, and adipsia
  • Hoarse cry, macroglossia
• Congenital iodine deficiency syndrome; : 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!

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

References:^{[6][2][12][13][11][14]}

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	↑ TSH	↓ Free T4 (FT4) and ↓ free T3 (FT3) levels
	Secondary hypothyroidism	↓ TSH
	Tertiary hypothyroidism
Subclinical hypothyroidism		Mildly ↑ TSH	Normal FT3 and FT4 levels
Euthyroid sick syndrome		Normal TSH	Normal FT4 and ↓ FT3 levels (low T3 syndrome) ↓ FT3 and ↓ FT4 levels (low T3 low T4 syndrome)

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

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 antibodies against the TSH receptor, but cannot determine the type of antibody (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 indicates hypothyroidism.
• Associated conditions
  • Hypercholesterolemia; (increased LDL; ), hyperlipidemia, hypoglycemia
  • Increased creatine kinase
  • Mild anemia ^[15]
  • In rare cases: hyponatremia

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]}

Euthyroid sick syndrome (ESS)

• Synonyms: sick euthyroid syndrome (SES), non-thyroidal illness syndrome (NTI)
• Occurs in severe illness or severe physical stress (most common in intensive care patients)
• Pathophysiology
  • 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.
    • Altered deiodinase enzyme activity
      • ↓ Conversion of T4 to T3
      • ↑ Conversion of T4 to reverse T3 (rT3)
      • ↓ Thyroid binding globulin
• Clinical features: specific to underlying nonthyroidal illness
• Laboratory
  • Low T3 syndrome: decrease in both total and FT3 levels; normal FT4 and TSH, and increased reverse T3
  • FT4 levels may be low in prolonged courses of illness (low T3 low T4 syndrome); indicates a poor prognosis
• Treatment
  • Treat underlying illness
  • Thyroid hormone replacement is usually not recommended because thyroid function is normal; there isn't conclusive evidence that thyroid hormone substitution is beneficial to patients with 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: 1:2300 newborns ♀ > ♂ (2:1)	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	Thyroid dysgenesis Iodine deficiency	Autoimmune thyroiditis
Clinical course		Asymptomatic or transient hyperthyroidism → hypothyroidism	Classic triphasic course: hyperthyroid → hypothyroid → recovery	Transient hyperthyroidism → hypothyroidism	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		Anti-TPO and TgAb	Anti-TPO	Absent	TgAb	Anti-TPO
Iodine uptake on scintigraphy		Patchy and irregular	Reduced	Reduced	Absent or patchy	Normal or reduced
Pathology findings		Lymphocytic infiltration with germinal centers and oncocytic-metaplastic cells (Hurthle cells)	Lymphocytic infiltration	Multinucleated giant cells and granuloma formation	Depend on cause	Dense and white fibrotic tissue

References:^[23][24]

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
• L-thyroxine interactions
  • Increased dosage necessary
    • Estrogen
    • SERM
    • Bile acid-binding 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 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]}