Hypothyroidism

Last updated: April 20, 2022

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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.

Overview of common causes of primary hypothyroidism
Hashimoto thyroiditis [2] Postpartum thyroiditis [3] Subacute granulomatous thyroiditis (De Quervain) [4] Congenital hypothyroidism [5] Riedel thyroiditis [6]
Epidemiology
  • Most common cause of hypothyroidism in the US
  • > (7:1)
  • Within 1 year of delivery in 5:100 of women
Causes
  • Viral and mycobacterial infections causing damage to follicular cells
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 patients 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
  • Inflammatory infiltrate

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.”

Effects of hypothyroidism [7][8]

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

Approach [10][11]

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]

Overview of TFT findings in the evaluation of suspected hypothyroidism [11][15]
TSH FT4 FT3
Subclinical hypothyroidism Mildly ↑ Normal Normal
Overt hypothyroidism Primary hypothyroidism

Normal or ↓

Secondary and tertiary hypothyroidism

Euthyroid sick syndrome [16]

Low T3 syndrome Normal Normal ↓ Free T3 and reverse T3
Low T3 low T4 syndrome

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.

Associated laboratory findings [11]

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

Imaging [13]

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

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]
  • 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: ↓ FT3, 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:

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]

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.
Dosage and administration of levothyroxine
Dosage
Monitoring and dose adjustments
Administration
  • Time of intake: 30–60 minutes before breakfast, taken separately from interfering drugs
  • Parenteral treatment: IV levothyroxine may be considered if enteral treatment is not possible. [10][25]
  • Refill: Maintenance of a single preparation is preferred.

Dosing in consultation with endocrinology is recommended for: [10]

  • Infants and children
  • Pregnant patients and those who are planning conception
  • Patients with cardiac disease and/or other endocrine conditions
  • Patients with structural thyroid pathology (e.g., goiter, thyroid nodules)
  • Patients for whom establishing or maintaining euthyroidism is difficult

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][31]

Some individuals may misuse synthetic thyroid hormones for weight loss. [32]

Myxedema coma [33][34]

Remember to evaluate precipitating factors, e.g., screening for infectious causes, or obtaining cardiac enzymes and an ECG to exclude myocardial infarction. [33]

Suspect myxedema coma in patients with typical symptoms and a history of hypothyroidism, and initiate treatment immediately without waiting for laboratory results! [33]

Further complications

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

Epidemiology [5]

Etiology

Clinical features

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

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

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]
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