What are the causes of hypothyroidism?

Causes of Hypothyroidism

In iodine-sufficient regions like the United States, chronic autoimmune thyroiditis (Hashimoto's disease) is the most common cause of hypothyroidism, accounting for approximately 85-90% of cases in adult women. 1

Primary Causes in Iodine-Sufficient Areas

The etiology of hypothyroidism varies significantly based on geographic iodine availability and patient demographics.

Autoimmune Thyroiditis

• Hashimoto's thyroiditis represents the predominant cause of primary hypothyroidism in regions with adequate dietary iodine, responsible for up to 85-90% of cases 1, 2, 3
• This autoimmune process involves excessively stimulated CD4+ T cells and their differentiated cells as key pathogenic mediators 4
• The presence of anti-thyroid peroxidase (anti-TPO) antibodies confirms autoimmune etiology and predicts higher progression risk to overt hypothyroidism (4.3% per year versus 2.6% in antibody-negative individuals) 1

Iatrogenic Causes

• Radioactive iodine therapy for hyperthyroidism or thyroid cancer leads to permanent hypothyroidism requiring lifelong replacement 1
• Thyroidectomy (surgical removal of thyroid tissue) results in hypothyroidism necessitating lifelong hormone replacement 1
• External-beam radiation to the head and neck area damages thyroid tissue and causes hypothyroidism 1
• Ablation therapy for previous hyperthyroidism commonly causes iatrogenic thyroid dysfunction 1

Medication-Induced Hypothyroidism

Multiple pharmacologic agents can induce thyroid dysfunction through various mechanisms 5:

• Amiodarone (iodine-containing cardiac medication) can induce thyroid dysfunction through inhibition of thyroid hormone synthesis and release 1, 5
• Immune checkpoint inhibitors (anti-PD-1/PD-L1 therapy) cause thyroid dysfunction in 5-10% of patients, with combination immunotherapy increasing risk to 20% 1, 5
• Lithium interferes with thyroid hormone synthesis and release 5
• Interferon and other cytokines induce hypothyroidism through immune mechanisms 5
• Tyrosine kinase inhibitors and drugs blocking vascular endothelial growth factor receptors are associated with thyroiditis and hypothyroidism 5, 6

The main mechanisms involved include inhibition of thyroid hormone synthesis/release, immune-mediated mechanisms, and induction of thyroiditis 5.

Worldwide Leading Cause

• Iodine deficiency remains the most common cause of hypothyroidism globally, particularly in developing nations where salt iodination is not routinely performed 1, 6
• Maternal hypothyroidism from iodine deficiency increases risk of congenital cretinism with growth failure, mental retardation, and neuropsychologic defects 1
• Salt iodination programs, while beneficial overall, may paradoxically increase the incidence of overt hypothyroidism in some populations 6

Secondary (Central) Hypothyroidism

• Pituitary or hypothalamic dysfunction causes secondary hypothyroidism through failure of adequate TSH or TRH secretion 6
• Central hypothyroidism presents with low or inappropriately normal TSH alongside low free T4 7
• The TRH test can differentiate pituitary from hypothalamic causes 6

Risk Factors

Demographic Factors

• Female sex is the strongest risk factor, with hypothyroidism being significantly more common in women than men 1, 2, 3
• Advancing age increases risk substantially, with prevalence rising in elderly populations 1
• The prevalence of hypothyroidism ranges from 0.3% to 12% worldwide depending on iodine intake 3

Medical Conditions

• Type 1 diabetes increases risk of autoimmune thyroid disease 1
• Down syndrome increases risk of thyroid dysfunction 1
• Family history of thyroid disease confers increased risk 1
• Goiter may be associated with hypothyroidism development 1

Genetic and Environmental Factors

• Genetic susceptibility plays an important role, with having a first-degree relative with hypothyroidism increasing risk 3, 4
• Environmental factors including iodine deficiency contribute to development 4
• Gender differences (existential factors) influence disease occurrence 4
• Gut and intestinal microbiota may contribute to disease development 4

Less Common Causes

• Peripheral thyroid hormone resistance can cause failure of hormone action in peripheral tissues despite normal hormone levels 6
• Pregnancy in the setting of underlying autoimmune thyroid disease increases risk 3
• Neck surgery or radiation therapy to the neck region 3

Important Clinical Considerations

• It is crucial to differentiate between primary hypothyroidism (thyroid gland failure with elevated TSH and low free T4) and secondary hypothyroidism (pituitary/hypothalamic failure with normal or low TSH and low free T4) 6
• Imaging modalities have no role in determining the underlying cause of hypothyroidism because all etiologies show uniformly decreased radioiodine uptake and cannot be distinguished by thyroid morphology 1
• Diagnosis relies on clinical history and laboratory assessment (TSH and free T4) rather than imaging 1