Hashimoto's Thyroiditis

Definition

Hashimoto thyroiditis (chronic lymphocytic autoimmune thyroiditis) is a progressive, organ‑specific autoimmune disorder characterized by autoreactive T‑cell–mediated follicular destruction, autoantibody production, and a clinical spectrum from transient thyrotoxicosis to subclinical and overt hypothyroidism.

Epidemiology and clinical phenotypes in children

Incidence and demographics:

• female predominance emerges in school‑age and adolescence; incidence rises through puberty
• familial clustering common.

Presentations by age:

• Infancy: rare; may present with poor growth, feeding problems, macroglossia or prolonged jaundice when hypothyroid.
• Childhood: overt hypothyroidism with growth deceleration, weight gain, delayed bone age, cold intolerance; subclinical disease often detected incidentally.
• Adolescence: goitre, fatigue, menstrual irregularities, slowed school performance; presentation mimics adult disease but with greater potential impact on linear growth and puberty.

Phenotypic variants:

• classic chronic hypothyroid
• Hashitoxicosis (destructive transient thyrotoxicosis)
• silent/postpartum‑type thyroiditis in adolescent postpartum patients
• painless chronic forms.

Pathogenesis and molecular/immunologic mechanisms

• Adaptive immunity drivers: Loss of central/peripheral tolerance with autoreactive CD4+ Th1/Th17 responses, cytotoxic CD8+ T cells, and B‑cell autoantibody production (anti‑TPO >>> anti‑TG).
• Innate immunity and antigen presentation: Aberrant thyrocyte expression of HLA‑DR, upregulation of TLRs, dendritic cell activation, and local cytokine milieu (IFN‑γ, IL‑17) promote sustained lymphoid infiltration and germinal centre formation.
• Epitope spreading and molecular mimicry: Viral/environmental triggers can expose cryptic epitopes; cross‑reactive immune responses expand autoimmunity.
• Genetic architecture: Polygenic risk with immune regulatory loci (CTLA4, PTPN22), HLA associations, and thyroid‑specific genes (TSHR, FOXE1) modulating susceptibility and phenotype. Family clustering and co‑occurrence with other autoimmune endocrinopathies reflect shared pathways.
• B‑cell biology and pathogenic antibodies: Anti‑TPO correlates with tissue destruction and progression risk; anti‑TG less specific; functional TSHR‑blocking antibodies rare but clinically important in pregnancy or neonatal disease.
• Fibrosis and remodelling: Chronic inflammation leads to fibrosis, nodularity, and in some cases, return of normal gland architecture is unlikely once significant scarring develops.

Clinical phenotypes and differential diagnostic subtleties

Classic hypothyroid phenotype:

• Insidious fatigue
• weight gain
• cold intolerance
• constipation
• bradycardia
• menorrhagia
• mixed hypercholesterolemia
• goitre may be firm and non‑tender.

Subclinical disease

• Elevated TSH with normal fT4
• risk of progression relates to anti‑TPO titre
• TSH magnitude, age, and comorbidities.

Hashitoxicosis

• Transient thyrotoxic phase from destructive release of hormone
• low radioiodine uptake differentiates from Graves disease.

Painless/postpartum variants

• Silent thyroiditis and postpartum thyroiditis overlap clinically and immunologically
• temporal relation to childbirth and spontaneous recovery help classification.

Rapidly enlarging neck mass

• Red flag for primary thyroid lymphoma; differentiate from anaplastic carcinoma and infected thyroiditis.

Associated autoimmune syndromes

• Screen for type 1 diabetes, Addison disease, pernicious anemia, celiac disease, vitiligo, and autoimmune gastritis where indicated.

Diagnostics — advanced investigations and interpretation

Serology

• Anti‑TPO: most sensitive marker; titre correlates with progression risk.
• Anti‑TG: supportive but less specific, may confound monitoring in post‑surgical or post‑radioiodine patients.
• TSH receptor antibodies: assess when thyrotoxicosis or pregnancy context.

Thyroid function testing

• Use high‑quality fT4 assays calibrated for clinical cutoffs; consider total T4/albumin or mass‑spec fT4 if assay interference is suspected. Interpret TSH within clinical context and coexisting pituitary disease.

Ultrasound with Doppler and elastography

• Typical: diffuse hypoechogenicity, heterogeneous echotexture, micronodularity; reduced vascularity in chronic disease, increased vascularity may indicate active inflammation or coexistent Graves disease. Shear‑wave elastography can quantify fibrosis and help triage nodules for FNA.

Radionuclide imaging

• Low uptake in destructive thyroiditis/Hashitoxicosis; use selectively when uptake pattern will change management.

Fine‑needle aspiration and histopathology

• Indicated for suspicious nodules or rapidly enlarging gland; cytology shows dense lymphoid infiltrate, Hurthle cell change; excisional biopsy required when lymphoma suspected. Immunophenotyping (CD20+, B‑cell clonality), flow cytometry, and molecular studies essential to confirm primary thyroid lymphoma.

Advanced molecular testing

• Consider targeted gene panels or GWAS‑informed testing in familial clusters, early severe disease, or atypical phenotypes; interpret variants in phenotypic context.

Autoimmune workup

• Screen for coexisting autoimmune conditions based on symptoms and family history rather than universal panels.

Management — precision strategies, special situations, and emerging therapies

General LT4 replacement

• Individualise dosing. Overt hypothyroidism: start levothyroxine;
• typical paediatric replacement dose:
  • Infants: 10–15 µg/kg/day (higher end for neonates with severe deficiency).
  • Children: 4–6 µg/kg/day (dose falls with increasing age and weight); adolescents approach adult dosing (~1.4–1.6 µg/kg/day).
• Administer in morning, consistently relative to feeds; use liquid or accurately compounded formulations where dosing precision required.
• Target TSH within reference range and resolution of symptoms; avoid persistent overreplacement. Titrate at 6–8 week intervals.

Subclinical hypothyroidism

• Treat when: TSH >10 mIU/L, symptomatic, anti‑TPO positive, pregnancy/planned conception, infertility, or progressive TSH rise; individualise for older adults and frailty. Discuss risks/benefits and monitor if conservative.

Hashitoxicosis and thyrotoxic phases

• Symptomatic control with β‑blockers; antithyroid drugs are not indicated for destructive thyroiditis; reserve for coexistent Graves disease confirmed by clinical, serologic, or uptake evidence.

Pregnancy and reproductive considerations

• Proactively increase LT4 dose by ~20–30% at pregnancy confirmation in treated patients; monitor TSH/fT4 every 4 weeks in first half and at least once mid‑pregnancy. Treat subclinical disease in pregnancy when anti‑TPO positive or TSH >4 mIU/L by pregnancy‑specific ranges. Screen women with infertility and recurrent pregnancy loss for anti‑TPO. Manage TSHR‑blocking antibodies when present.

Immune checkpoint inhibitor and immunotherapy‑related thyroiditis

• Recognise early thyrotoxicosis progressing to hypothyroidism; manage symptomatically then institute LT4 when hypothyroid; multidisciplinary coordination with oncology for therapy continuation as clinically appropriate.

Adjunctive therapies and supplements

• Selenium supplementation shows modest benefit in reducing anti‑TPO titres in mild disease but not standard for all patients; assess iodine status and avoid excess. Vitamin D deficiency correction may be considered as part of autoimmune modulation.

When to consider immunomodulation

• No established disease‑modifying immunotherapy for routine use; experimental approaches (B‑cell depletion, antigen‑specific tolerance) currently investigational and reserved for clinical trials or exceptional refractory scenarios.

Nodules, surgery, and lymphoma

• Indications for surgery: compressive symptoms, suspicious or malignant cytology, cosmetic concerns, or coexistent nodular disease. Rapid enlargement or systemic symptoms require urgent FNA, flow cytometry, and haematology referral for lymphoma management (chemotherapy ± radiotherapy).

Transition of care and comorbidity management

• Address cardiovascular risk, dyslipidaemia, metabolic bone health, and neurocognitive complaints; coordinate with primary care for long‑term surveillance and pregnancy planning.

Special scenarios

• Coexisting type 1 diabetes: coordinate dosing and glucose monitoring; hypothyroidism can reduce insulin requirements
• Down syndrome: lower threshold for screening and early treatment due to higher prevalence and developmental vulnerability.
• Adolescents planning pregnancy or postpartum: manage as adult pregnancy guidelines for dose adjustments and TRAb assessment if relevant.