Biology:Radiation-induced thyroiditis

Radiation-induced thyroiditis is a form of painful, acute thyroiditis resulting from radioactive therapy to treat hyperthyroidism or from radiation to treat head and neck cancer or lymphoma. It affects 1% of those who have received radioactive iodine (I-131) therapy for Graves' Disease, typically presenting between 5 and 10 days after the procedure. Stored T₃ and T₄ are released as rapid destruction of thyroid tissue occurs which results in pain, tenderness, and exacerbation of hyperthyroidism.

Epidemiology

→ Incidence of radiation-induced thyroiditis:

- Since radiation-induced thyroiditis mostly ranges from mild to asymptomatic, the true incidence rate remains underestimated:

• Radioactive iodine therapy (RAI) represents one of the main management means of many thyroid carcinomas and hyperthyroidism diseases

• The exposure to RAI during the management of hyperthyroidism accounts for approximately 1% of patients undergoing this therapy who may eventually develop radiation-induced thyroiditis. When it occurs, the condition typically develops within a short period, usually between 5 and 10 days after treatment.
• Other studies reports that the incidence of radiation induced thyroiditis may reach 5% of patient undergoing this therapy for Grave’s disease.

→ risk factors :

- Developing radiation induced thyroiditis depends on 2 main categories of factors :

• radiation- related factors:
  • In the case of RAI for treatment of GD, higher doses of RAI, usually above 15mCI ( about 200Gy), have been reported to induce thyroid dysfunction. In contrast, lower doses are less likely to induce the disease.
  • Higher doses of external irradiation used for the treatment of non-thyroid diseases are also associated with an increased risk  of developing radiation-induced thyroiditis
  • The impact of the environmental exposure to radiation released from nuclear agents and accidents increases the susceptibility of developing RIT
• patient related factors :
  • Elderly patients are more prone to severe clinical courses of radiation induced thyroiditis
  • Patients with underlying cardiovascular diseases exposed to RAI are at risk of developing severe complications of radiation induced thyroiditis

Aetiologies\causes

The thyroid gland is highly sensitive to irradiation; the changes can be seen regardless of the dose exposed to. Depending on the type and amount of changes that are experienced in the thyroid gland, there may be an increased risk for developing some disorders that can vary in their level of severity.

Radiation-induced thyroid dysfunction arises from  a combination of vascular, parenchymal, and immune-mediated mechanisms.

→ Vascular injury :

• Usually, the damage to the small intrathyroidal vessels represents one of the long-term causes of exposure to the irradiations. Over time, the endothelial injury leads to thrombosis, vascular sclerosis, and progressive luminal narrowing.
• Furthermore, the radiation can speed up the atherosclerosis in large arteries such as the carotid artery.
• Eventually, they can cause hypoperfusion and a decrease in blood supply to the thyroid, leading to ischemia and necrosis.

→ Capsular and Stromal Fibrosis:

• Beyond vascular injury, radiation can induce a stiffness and fibrosis of the internal supporting structure of the thyroid. This structural remodelling impairs the ability of the gland to swell and compensate effectively after surgery.

→ Parenchymal cell injury:

• In some cases, radiation may induce a direct cytotoxic effect on the DNA strands leading to chromosomal rearrangement, which further increases the risk of high mortality carcinogenic diseases.
• Moreover, the acute dysfunction of the thyroid follicles can be as a result of inflammation and apoptosis occurring after multiple episodes of oxidative stress from release of reactive oxygen species (ROS) .

→Immune-Mediated Mechanisms:

• In rare cases, radiation may trigger an autoimmune process with antibody production ( anti-thyroid peroxidase and anti-thyroglobulin antibodies) , which will eventually contribute to the chronicity of the inflammation of thyroid cells leading to hypothyroidism. However, this mechanism is not fully understood

Histopathological Changes

Under microscopy, we can notice some histological features of radiation-induced thyroid injury.

• Early changes within 3-6 weeks following high dose exposure for instance due to some catastrophic accident demonstrates shrinking in the follicular size lined by a layer of cuboidal cells.
• High dose administered therapeutically: causes severe damage including follicular death , acute vessel inflammation ,clot formation , and haemorrhage, followed later by an influx  lymphocytic cells and vascular sclerosis

• In contrast, Lower doses tend to produce distinctly different histological pattern such influx of immune cells, focal overgrowth of follicles, stromal fibrosis, with a higher likelihood of developing tumours

Diagnosis

The diagnosis of radiotherapy-induced immune thyroiditis is based on a synthesis of clinical assessment, lab tests, and imaging evaluations.

Laboratory Tests:

• Thyroid Function Tests (TFTs):

Initial Thyrotoxicosis: TSH is low and FT4 is high or normal.

Subsequent Hypothyroidism: Elevated TSH and low FT4.

Monitoring: Before starting immunotherapy or radiotherapy, baseline TFTs should be taken. During treatment, they should be monitored every 4–6 weeks, and after that, as needed.

• Thyroid Autoantibodies:

Thyroid peroxidase (TPO) and thyroglobulin antibodies may be present in up to 45% and 33% of cases, respectively; however, their absence does not preclude the diagnosis.

Imaging :

• Thyroid Ultrasound: May show heterogeneous echotexture, hypoattenuation, or reduced vascularity, consistent with thyroiditis. These findings are non-specific but support the diagnosis in the appropriate clinical context.

• Nuclear Medicine Scans: Radioactive iodine uptake or technetium-99m pertechnetate scans typically show low or absent uptake, distinguishing thyroiditis from Graves' disease, which shows increased uptake.

Differential diagnosis

• Graves' Disease is characterized by the presence of thyroid-stimulating immunoglobulins (TSI) and elevated radioactive iodine uptake.

• Hashimoto's Thyroiditis: A long-term autoimmune thyroiditis that causes hypothyroidism to develop more slowly and higher levels of autoantibody positivity.

• Subacute (De Quervain’s) Thyroiditis: Typically presents with neck pain and a viral prodrome, which are absent in radiotherapy immune thyroiditis.

Management strategies

Thyrotoxicosis Phase:

• Asymptomatic or mild symptoms: No specific treatment is required. It is advised to keep an eye on TFTs regularly to see if there is a progression to hypothyroidism.

• Symptomatic patients: beta-blockers can be used to help with palpitations, tremors, and other adrenergic symptoms. Antithyroid medications (e.g., methimazole) are contraindicated unless Graves' disease is verified.

• In cases of severe or prolonged thyrotoxicosis, corticosteroids may be considered; however, immune checkpoint inhibitors (ICIs) or radiotherapy are typically maintained unless major symptoms or complications appear.

Hypothyroidism Phase:

• Levothyroxine replacement: Lifelong thyroid hormone replacement is typically required.

• Glucocorticoid Use: Patients receiving high-dose steroids for other immune-related adverse events may require temporary adjustments in levothyroxine dosing.

Patient Education and Follow-Up :

• Counseling: Patients should be informed about the potential for thyroid dysfunction, the importance of adherence to monitoring and treatment, and the signs and symptoms of hypothyroidism and thyrotoxicosis.
• Long-Term Follow-Up: Regular TFT monitoring is essential, as hypothyroidism is usually permanent, and levothyroxine requirements may change over time.

Prognostic implications

• Cancer Outcomes: The development of thyroid immune-related adverse events, particularly overt thyrotoxicosis, is associated with improved progression-free and overall survival in cancer patients. This suggests a more robust immune response to treatment.
• Quality of Life: Early detection and management of thyroid dysfunction can mitigate symptoms and improve quality of life during cancer treatment.

References