What is hypothyroidism?

What is Hypothyroidism?

Hypothyroidism is a condition of low thyroid hormone production due to an underactive thyroid gland, resulting in decreased levels of thyroxine (T4) and triiodothyronine (T3) that leads to metabolic slowing throughout the body. 1, 2

Definition and Pathophysiology

Hypothyroidism represents thyroid hormone deficiency that causes widespread metabolic dysfunction. 3, 4 The condition is diagnosed biochemically when thyroid-stimulating hormone (TSH) levels are elevated above the normal reference range (typically >4.5 mIU/L), with or without decreased free T4 levels. 1

• Overt primary hypothyroidism is defined as elevated TSH with free T4 below the normal reference range, indicating significant thyroid gland failure. 4, 5
• Subclinical hypothyroidism presents with elevated TSH but normal free T4 levels, representing early or mild thyroid dysfunction. 1

Epidemiology and Risk Factors

Hypothyroidism affects 0.3% to 12% of the population worldwide, with prevalence varying based on iodine intake, and is significantly more common in women and older adults. 4, 5

• In the United States, approximately 1 in 300 persons has hypothyroidism, with prevalence increasing substantially with age. 6
• Up to 5% of the general population may have undiagnosed hypothyroidism. 5
• Women are disproportionately affected compared to men across all age groups. 4, 6

Etiology

In areas with adequate dietary iodine (such as the developed world), Hashimoto thyroiditis (chronic autoimmune thyroiditis) is the most common cause, accounting for up to 85% of cases. 1, 4

Other important causes include: 1

• Iatrogenic causes: Thyroidectomy, radioiodine therapy, external neck irradiation
• Medications: Amiodarone, lithium, immune checkpoint inhibitors, and other drugs
• Iodine disorders: Both deficiency and excess can cause hypothyroidism
• Worldwide: Environmental iodine deficiency remains the leading cause of all thyroid disorders globally 5

Clinical Presentation

Symptoms of hypothyroidism are nonspecific and result from decreased metabolic rate, making diagnosis challenging as they may overlap with other conditions or go unnoticed. 2, 3

The most common symptoms include: 1, 3, 4

• Fatigue and lethargy (present in 68-83% of patients)
• Weight gain (occurring in 24-59% of patients) due to decreased fat-burning rate
• Cold intolerance resulting from reduced heat production by the body
• Constipation from slowed gastrointestinal motility
• Dry skin (xeroderma)
• Cognitive impairment (45-48% of patients) including memory loss and difficulty concentrating
• Menstrual irregularities (approximately 23%) such as oligomenorrhea and menorrhagia

Clinical presentation can differ significantly with age, sex, and other patient factors, and symptoms may be particularly subtle in older persons. 3, 6

Consequences of Untreated Hypothyroidism

Untreated or inadequately treated hypothyroidism leads to serious complications affecting multiple organ systems and can be fatal in severe cases. 2, 3, 4

Cardiovascular Complications

• Hypothyroidism contributes to hypertension, dyslipidemia, heart failure, and increased cardiovascular mortality. 4, 6
• The condition causes cardiac dysfunction including delayed relaxation and abnormal cardiac output. 7
• Hypothyroidism can increase the risk for cardiovascular events through multiple mechanisms. 4

Metabolic and Endocrine Effects

• Insulin resistance and hyperglycemia can develop in patients with diabetes. 4
• Female reproductive dysfunction including disrupted ovulation, infertility, and increased miscarriage risk. 4

Severe Complications

• Myxedema coma represents severe decompensated hypothyroidism with hypothermia, hypotension, and altered mental status, requiring intensive care treatment and carrying up to 30% mortality. 4
• In infants: Untreated congenital hypothyroidism causes mental retardation and delayed developmental milestones. 2

Diagnosis

The best laboratory assessment of thyroid function is serum TSH measurement, which has sensitivity above 98% and specificity greater than 92%. 7

• Overt primary hypothyroidism: Elevated TSH with low free T4 4, 5
• Subclinical hypothyroidism: Elevated TSH with normal free T4 1
• Screening is not recommended for asymptomatic individuals, but targeted testing is appropriate for high-risk patients (such as those with type 1 diabetes). 4

Treatment

The standard treatment is lifelong thyroid hormone replacement therapy with levothyroxine (synthetic T4), which is one of the world's most widely prescribed medications. 2, 3, 4, 5

Treatment Goals

• Normalize TSH levels to the reference range (typically 0.4-4.5 mIU/L) 5
• Alleviate symptoms and prevent complications 6
• Most patients require lifelong therapy 2, 6

Dosing Considerations

• Standard starting dose: Approximately 1.6 µg/kg/day in adults with overt hypothyroidism 7, 5
• Lower starting doses (25-50 mcg/day) should be used for patients >70 years or those with cardiac disease to avoid cardiac complications 7, 8
• Dose titration is performed based on TSH levels measured 6-8 weeks after initiation or dose changes 7, 4

Monitoring

• TSH should be monitored 6-8 weeks after initiating or changing levothyroxine dose 4
• Annual monitoring is appropriate once TSH levels are stable at goal 4
• Both overtreatment and undertreatment are associated with cardiovascular health risks 4

Important Clinical Considerations

Nearly one-third of patients with treated hypothyroidism continue to exhibit symptoms despite achieving biochemical treatment targets, highlighting the need for individualized management approaches. 5

With appropriate treatment, symptoms can be effectively managed, and most people with hypothyroidism can lead normal, healthy lives. 2 Lifestyle modifications including healthy diet and regular exercise can help manage symptoms and improve quality of life. 2