Hypothyroidism

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 very rare cases, hormone production may be sufficient, but thyroid hormones may have insufficient peripheral effects. Hypothyroidism may be congenital or acquired. Congenital hypothyroidism is usually caused by thyroid dysplasia or aplasia. The etiology of acquired hypothyroidism is typically autoimmune (Hashimoto thyroiditis) or iatrogenic. The pathophysiology of hypothyroidism is characterized mainly by a reduction of the basal metabolic rate and generalized myxedema. Typical clinical features include fatigue, cold intolerance, dry skin, and constipation. More severe manifestations include myxedematous heart disease and myxedema coma, which may be fatal if left untreated. In adults, the diagnosis is established based on serum thyroid-stimulating hormone (TSH) and free T₄ levels (FT₄). Children with congenital hypothyroidism often have umbilical hernias and, without early treatment, can develop severe developmental delay. Accordingly, neonatal screening for hypothyroidism 24–48 hours after birth is required by law in most states. Therapy for both acquired and congenital hypothyroidism consists of lifelong treatment with levothyroxine and regular checkups to monitor disease activity.

Prevalence: more common in women

• Women: up to 12:1,000
• Men: up to 4:1,000 ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Primary hypothyroidism: insufficient thyroid hormone production
  • Hashimoto thyroiditis
    • The most common cause of hypothyroidism in iodine-sufficient regions ^[2]
    • Associated with HLA-DR3 and other autoimmune diseases (e.g., vitiligo, pernicious anemia, type 1 diabetes mellitus, and systemic lupus erythematosus)
  • Postpartum thyroiditis (subacute lymphocytic thyroiditis) ^[2]
  • De Quervain thyroiditis (subacute granulomatous thyroiditis): often subsequent to a flu-like illness ^[2]
  • 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
  • Thyroid dysplasia: a disorder of embryologic development characterized by abnormal development and/or location of thyroid tissue (e.g., lingual thyroid)
• Secondary hypothyroidism: pituitary disorders (e.g., pituitary adenoma) → TSH deficiency
• Tertiary hypothyroidism: hypothalamic disorders → TRH deficiency

Hypothalamic-pituitary-thyroid axis ^[7]

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.”

• 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 ^[7][8]

• 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
  • Cold intolerance
• Decreased sympathetic activity leads to:
  • Decreased sweating
  • Cold skin (due to decreased blood flow)
  • Constipation (due to decreased gastrointestinal motility)
  • Bradycardia
• Decreased transcription of sarcolemmal genes (e.g., calcium ATPases) → decreased cardiac output, myopathy
• Hyperprolactinemia: ↑ prolactin 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
  • 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).

• Symptoms related to decreased metabolic rate
  • Fatigue, decreased physical activity
  • Cold intolerance
  • Decreased sweating
  • Hair loss (Queen Anne sign), brittle nails, and cold, dry skin
  • Weight gain (despite poor appetite)
  • Constipation
  • Bradycardia
  • Hypothyroid myopathy , myalgia, stiffness, cramps
  • Woltman sign: a delayed relaxation of the deep tendon reflexes, which is commonly seen in patients with hypothyroidism, but may also be associated with advanced age, pregnancy, and diabetes mellitus.
  • Entrapment syndromes (e.g., carpal tunnel syndrome)
• Symptoms related to generalized myxedema
  • Doughy skin texture, puffy appearance
  • Myxedematous heart disease (dilated cardiomyopathy, bradycardia, dyspnea)
  • Hoarse voice, difficulty articulating words
  • Pretibial and periorbital edema
  • Myxedema coma (see “Complications” below)
• 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), somnolence, depression
  • Hypertension ^[9]
  • 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.

Approach ^[10][11]

• Initial evaluation: thyroid function tests (TFTs)
  • Obtain TSH level for all patients: ↑ TSH with classic clinical features is typically diagnostic for primary hypothyroidism.
  • Abnormal TSH: Order FT₄.
• Further investigations: May be indicated to evaluate underlying etiology based on clinical suspicion (See also “Overview of common causes of primary hypothyroidism.”)
  • Thyroid antibody testing: Consider if autoimmune thyroiditis is suspected (not routinely indicated). ^[10]
  • Imaging: Consider if structural pathology (e.g., thyroid nodules, goiters, malignancy) is suspected. ^[12][13]

Normal TSH levels generally rule out primary hypothyroidism and hyperthyroidism and are therefore the decisive parameter in screening for both conditions. ^[14]

Laboratory studies

Thyroid function tests ^[10][11]

• TSH
  • Best initial screening test; also used to diagnose and monitor primary hypothyroidism.
  • The reference range varies between laboratories and differs in pregnancy and with increasing age. ^[10]
• FT₄
  • Confirmatory test for primary hypothyroidism if TSH is elevated
  • Primary test in suspected secondary or tertiary hypothyroidism and following treatment for hyperthyroidism
• Free or total T₃: may be measured alongside FT₄, but they are not used for the diagnosis of hypothyroidism

Avoid routine TSH screening in acutely ill patients unless a thyroid disturbance is the suspected cause (e.g., myxedema coma), since other non-thyroid illnesses can interfere with serum TSH and results may be unreliable. ^[10]

TSH can be abnormal in both hyperthyroidism and hypothyroidism. Peripheral hormones (FT₄ and FT₃) are elevated in hyperthyroidism as opposed to hypothyroidism, in which levels are reduced. ^[11]

Serum thyroid antibody testing ^[10][17]

Serum thyroid antibody testing can confirm suspected autoimmune thyroid disease. Additionally, thyroid peroxidase antibody measurements may also be considered in patients with subclinical hypothyroidism or recurring miscarriages.

• Thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb): detectable in the majority of patients with autoimmune hypothyroidism
• TSH receptor antibodies (TRAbs): detectable in up to 20% of cases of autoimmune hypothyroidism ^[18]

Associated laboratory findings ^[11]

Other routine blood tests are not required for the diagnosis but may show characteristic changes.

• CBC: mild anemia
• BMP: hyponatremia (in acute hypothyroidism) , hypoglycemia (rare) ^[19][20]
• Lipid profile: hypercholesterolemia (increased LDL), hyperlipidemia
• Creatine kinase: increased in hypothyroid myopathy ^[21]

Imaging ^[13]

Imaging has no role in the primary evaluation of hypothyroidism but may be indicated if structural abnormalities are present or suspected.

• Thyroid ultrasound ^[12]
  • Useful for the assessment of thyroid vascularity, goiters, and thyroid nodules
  • Possible findings in hypothyroidism include signs of thyroiditis.
• Nuclear medicine thyroid scan ^[22]
  • May be indicated in the workup of thyroid nodules and goiters
  • In hypothyroidism, radiotracer activity is decreased.

Nonthyroidal illness syndrome (NTIS) ^[16][23]

• Description
  • A change in thyroid hormone levels (typically decreased) that occurs in severe illness or severe physical stress
  • Common in intensive care patients and associated with morbidity and mortality
  • Also known as euthyroid sick syndrome (ESS)
• Pathophysiology: multifactorial and not fully understood ^[24]
  • Thyroid gland function typically remains normal.
  • Cytokines (e.g., interleukin 6) are thought to cause various changes in levels of circulating TSH and thyroid hormones.
  • Altered deiodinase enzyme activity leads to:
    • ↓ Conversion of T₄ to T₃
    • ↑ Conversion of T₄ to reverse T₃ (rT₃) by thyroxine 5-monodeiodinase
  • Various factors, e.g., protein loss due to nephrotic syndrome, may also lead to decreased levels of thyroid-binding globulin.
• Clinical features
  • Signs and symptoms of the underlying illness
  • Typically no classic symptoms of hyper- or hypothyroidism
• Diagnostics
  • NTIS is typically diagnosed incidentally following TFT screening done in critically ill patients to rule out thyrotoxicosis or hypothyroidism as the underlying cause, e.g., patients with unexplained tachyarrhythmias or heart failure, suspected myxedema coma, or a strong family history of thyroid disease.
  • TSH is typically normal in both low T₃ syndrome and low T₃ low T₄ syndrome.
    • Low T₃ syndrome: decrease in both total and FT₃ levels, normal FT₄ and TSH, and normal or increased rT₃
    • Low T₃ low T₄ syndrome: FT₄ levels may be low in prolonged courses of illness, indicating a poor prognosis.
  • Rarely, TSH may also be slightly low, but not enough to explain the low FT₃ and/or FT₄.
  • Consult endocrinology as the interpretation of TFTs in critically ill patients is complex and can be misleading.
• Treatment
  • Continued treatment of underlying illness
  • Thyroid hormone replacement is usually not recommended. ^[25]

Suspect NTIS in critically-ill patients who have a combination of the following: ↓ FT_3, normal or ↓ FT₄, normal or ↓ TSH, and absent typical clinical features of hypothyroidism. ^[16]

Other differential diagnoses ^[26]

The following conditions can mimic one or more manifestations of hypothyroidism:

• Adrenal insufficiency
• Hypopituitarism (can also be a cause of central hypothyroidism)
• CHF and other causes of pulmonary edema
• Other causes of shock
• Sepsis and other systemic infections
• Depression
• Major neurocognitive disorders
• Encephalopathy
• Environmental hypothermia
• Other differential diagnoses of constipation

The differential diagnoses listed here are not exhaustive.

General principles ^[10][15][25]

• Hypothyroidism is treated with lifelong hormone substitution.
  • Levothyroxine: synthetic form of T₄
    • First-line choice for the treatment of hypothyroidism
    • Peripherally converted to T₃ (biologically active metabolite) and rT₃ (biologically inactive metabolite)
  • Liothyronine: synthetic form of T₃
    • Part of the treatment for myxedema coma
    • Not recommended as monotherapy or in combination with levothyroxine for the long-term treatment of hypothyroidism ^[10][27][28]
• Starting dose and monitoring requirements vary depending on factors such as age and comorbidities.
• Reassess treatment response regularly to avoid under- and overtreatment.

Indications for treatment ^[10][25]

• Overt hypothyroidism: Initiate treatment.
• Subclinical hypothyroidism: Treat select cases. ^[10][27]
  • Repeat TSH measurement after 1–3 months to confirm the diagnosis. ^[29]
  • Consider treatment in the following cases:
    • TSH ≥ 10 mIU/L
    • TSH < 10 mIU/L in addition to one of the following: positive TPOAb, cardiac risk factors, planned or current pregnancy

Ensure follow-up is in place for patients with subclinical hypothyroidism if treatment is not initiated.

Levothyroxine replacement ^[10][25]

• In primary hypothyroidism, levothyroxine is gradually titrated according to serial TSH measurements targeting a normal level, for example:
  • ↑ TSH (suggests ↓ T₄ activity): typically requires a dose increase
  • ↓ TSH (suggests ↑ T₄ activity): typically requires a dose decrease
• In secondary hypothyroidism, dosage is titrated according to FT₄ levels.

Titrate thyroid hormone substitution carefully for individuals with preexisting coronary artery disease. ^[25]

In patients with hypothyroidism who are pregnant, the levothyroxine dose must be increased in line with increased demand. Hypothyroidism adversely affects the development of the fetal nervous system. ^[11]

Long-term therapy considerations ^[10][25][32]

• Side effects: Overtreatment can lead to symptoms of thyrotoxicosis.
  • Sweating, heat intolerance, tremors
  • Tachycardia; , palpitations, arrhythmias
  • Weight loss, osteoporosis
  • See also “Exogenous thyrotoxicosis.”
• Drug interactions
  • Drugs that reduce levothyroxine absorption include PPIs, calcium salts, ferrous sulfate, and bile acid sequestrants.
  • Treatment with estrogens may necessitate a dose increase.
  • Treatment with androgens may necessitate a dose reduction.
  • Glucocorticoids interfere with thyroid hormone metabolism and the dose of levothyroxine may need to be reduced.
• Reasons for treatment failure
  • Nonadherence
  • Malabsorption due to gastrointestinal conditions: e.g., gastritis, celiac disease

Some individuals may misuse synthetic thyroid hormones for weight loss. ^[33]

Myxedema coma ^[34][35]

• Definition: : extremely rare, potentially life-threatening decompensation of preexisting thyroid hormone deficiency
• Etiology
  • Triggers include infections, severe illness or trauma, and certain drugs.
  • Prior discontinuation of thyroid supplements is a frequent contributing factor in patients with known hypothyroidism.
• Clinical presentation
  • Cardinal symptoms: impaired mental status; , hypothermia; , and myxedema
  • Hypoventilation with hypercapnia and hypoxemia
  • Hypotension (possibly shock) and bradycardia
• Diagnosis ^[36]
  • Laboratory studies
    • TFTs: ↑ TSH and ↓ T₄ and T₃
    • BMP: hypoglycemia and hyponatremia ^[19]
    • ↓ Cortisol in patients with concomitant adrenal insufficiency
    • Other possible findings: ↑ CK and LDH, abnormal clotting
  • ECG: low-voltage QRS complexes, nonspecific T-wave changes ^[34]
  • CSF analysis: slightly ↑ CSF protein ^[35]
• Treatment ^[25][26][34]
  • Immediate measures: airway management and fluid resuscitation (See “ABCDE approach.”)
  • Intravenous hormone substitution: levothyroxine PLUS liothyronine PLUS hydrocortisone ^[25]
  • Supportive treatment: passive rewarming, ventilatory support as indicated, management of precipitating factors, treatment of hypoglycemia
• Disposition: Admission to critical care is typically warranted for ventilatory support, invasive monitoring, and management of electrolytes and fluids. ^[26]
• Prognosis: Even with treatment, mortality rates of up to 60% have been described. ^[34]

Remember to evaluate precipitating factors, e.g., screening for infectious causes, or obtaining cardiac enzymes and an ECG to exclude myocardial infarction. ^[34]

Suspect myxedema coma in patients with typical symptoms and a history of hypothyroidism, and initiate treatment immediately without waiting for laboratory results! ^[34]

Further complications

• Primary thyroid lymphoma
  • Hashimoto thyroiditis is the most common cause of hypothyroidism and the only known risk factor for primary thyroid lymphoma. ^[37]
  • Almost all primary thyroid lymphomas are non-Hodgkin large B-cell lymphomas.
• Increased cardiovascular risk
• Carpal tunnel syndrome ^[38]

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

• Perform ABCDE survey.
• Secure airway and begin ventilatory support if there is respiratory failure.
• Establish IV access and send blood samples for thyroid function tests, cortisol, BMP, CK, LDH, and coagulation panel.
• Start fluid resuscitation and vasopressors as needed.
• Begin continuous cardiac and respiratory monitoring and consider invasive BP monitoring.
• Check core temperature and consider passive rewarming.
• Identify and treat hypoglycemia.
• Urgently consult endocrinology and critical care for admission.
• Administer IV hydrocortisone together with or prior to thyroid hormone replacement and continue until concomitant adrenal insufficiency is ruled out. ^[25]
• Start IV levothyroxine and IV liothyronine.
• Identify and treat precipitating factors.
• Admit to ICU.

Epidemiology ^[5]

• US: affects ∼ 1:2,300 newborns
• Worldwide: affects up to 1:2,000 newborns

Etiology

• Sporadic (∼ 85% of cases) ^[41]
  • Thyroid hypoplasia, dysplasia, or ectopy
  • Thyroid aplasia (athyroidism)
  • Transplacental transmission of maternal antithyroid antibodies
• Hereditary (∼ 15% of cases)
  • Dyshormonogenetic goiter: Defects in thyroid hormone synthesis (most commonly in thyroid peroxidase) lead to thyroid hyperplasia and goiter.
  • Peripheral resistance to thyroid hormones
• Fetal iodine deficiency syndrome: Congenital hypothyroidism caused by iodine deficiency in utero (rare in iodine-sufficient areas). ^[39]

Clinical features

Children with congenital hypothyroidism may have general signs and symptoms of hypothyroidism in addition to those seen in neonates.

• Onset
  • Usually little to no features are present at birth as maternal T4 can cross the placenta.
  • Features can develop over weeks to months if screening is not performed.
  • Features can be apparent at birth in fetal iodine deficiency syndrome.
• Possible neonatal features
  • Abdominal distention
  • Delayed passage of meconium
  • Umbilical hernia
  • Prolonged neonatal jaundice
    • Most commonly, unconjugated hyperbilirubinemia
    • Less commonly, conjugated hyperbilirubinemia
  • Hypotonia
  • Decreased activity, poor feeding, and adipsia
  • Hoarse cry, macroglossia
  • Hypothermia
  • Failure to thrive (length affected more than weight)
• Cretinism: a complication of severe, untreated congenital hypothyroidism that leads to impaired development of the brain and skeleton, resulting in skeletal abnormalities (e.g., short stature and delayed fontanelle closure) and permanent intellectual disabilities ^[42]

The 7 P's of congenital hypothyroidism are Pot-bellied, Pale, Puffy-faced, Protruding umbilicus, Protuberant tongue, Poor brain development, and Prolonged neonatal jaundice

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!

Diagnostics

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

Treatment

• Lifelong hormone replacement is necessary.
• Normalization of thyroid hormone levels within 2–3 weeks is vital to prevent brain damage and developmental disorders. ^[43]