Autoimmune Thyroiditis

Thyroiditis is an inflammation of the thyroid gland and has multiple etiologies, including chronic (Graves’ disease and Hashimoto thyroiditis), silent or subclinical thyroiditis, transient hyperthyroidism, subacute, and acute. Laboratory testing is used to differentiate autoimmune-mediated thyroid disease from other etiologies and includes thyroid stimulating hormone (TSH) followed by free thyroxine (T4). Depending on results, antibody screening may also be necessary. Antithyroid antibody tests include thyroid peroxidase (TPO), TSH receptor antibodies (TRAb), and antithyroglobulin antibodies (Tg).

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Key Points

Autoimmune thyroid disorders (AITDs) are among the most common autoimmune disorders. Antithyroid antibodies may be helpful in the subclassification of autoimmune thyroid disease.

Antibodies by Biology, Mechanism, Type, Evidence of Tissue Damage, and Clinical Use
  TPO Antibodies TSH Receptor Antibodies (TRAb) Tg Antibodies
Biology

TPO is a transmembrane protein essential for synthesis of thyroid hormones

TSH-specific receptor controls thyroid function and cell growth

Tg is the precursor to thyroid hormones and is highly immunoreactive

Mechanism

TPO is targeted by the thyroid microsomal antibody

TRAb targets TSH receptors and competes with TSH for receptor binding

(TRAb activity is not affected by TSH levels)

Tg antibody is directed against thyroglobulin

Type

Polyclonal antibody (usually IgG1, IgG4)

3 classes (IgG antibodies)

  • Stimulating antibodies – also known as LATS or thyroid-stimulating antibodies
  • Blocking antibodies – may be etiology of hypothyroidism
  • Neutral antibodies

Test – measures both stimulating and blocking antibodies

Polyclonal antibody (IgG1 most common)

Evidence of tissue damage

No evidence for cause of tissue damage

Stimulating antibody – causes tissue damage

Blocking antibody – does not cause tissue damage

No evidence for cause of damage

Clinical use Healthy Populations

Detectable in a very small percentage

Not typically detected

Detectable in a smaller percentage

Graves Disease

Present in ~80% of individuals

Presence of antibody is diagnostic for GD, but not usually performed since TRAb is diagnostic and most sensitive

TRAb or TSI presence is pathognomonic for GD but not usually necessary for diagnosis unless clinical picture unclear; newer assays (eg, third generation) are even more accurate

Prognostic marker for relapse after treatment

Presence predicts increased risk of thyroid dysfunction in newborns born to mothers with current or treated GD

Present in 40-70% of individuals

Provides no additional information over TRAb or TPO antibodies

Hashimoto Thyroiditis

Present in >90% of individuals

Presence of antibody is pathognomonic for HT

Not recommended for monitoring

Not present

Present in 60-80% of individuals

Presence of antibody is diagnostic, but provides no additional information over TPO antibodies (less sensitive and specific than TPO)

Postpartum Thyroiditis

Presence during pregnancy predicts risk of postpartum thyroiditis

Not present

Presence may predict postpartum thyroiditis

Subclinical Hypothyroidism

May indicate increased risk of development of overt hypothyroidism

Not present

No indicated use in this disease

Thyroid Cancer

Not present

Not present

Primarily used for monitoring for thyroid cancer recurrence (post ablation or total thyroidectomy)

Tg antibodies may develop and interfere with Tg measurements

Should be assessed with each Tg measurement

GD, Graves disease; HT, Hashimoto thyroiditis; LATS, long-acting thyroid stimulating antibodies; Tg, thyroglobulin; TPO, thyroid peroxidase; TSH, thyroid stimulating hormone; TSHR, thyroid stimulating hormone receptor; TSI, thyroid stimulating immunoglobulin; TRAb, thyroid stimulating hormone receptor antibodies

Diagnosis

Indications for Testing

  • Differentiate autoimmune-mediated thyroid disease (eg, Graves disease [GD], Hashimoto thyroiditis [HT]) from other etiologies for hyper- or hypothyroidism
  • Predict risk of fetal thyroid dysfunction in mothers with history of GD
  • Establish an autoimmune cause for recurrent miscarriage

Laboratory Testing

  • Thyroid stimulating hormone (TSH) followed by free T4 – establish presence of hypo- or hyperthyroidism
    • HT – most likely if patient is hypothyroid
      • Elevated TSH and low free T4
    • GD – most likely if patient is hyperthyroid
      • Low TSH and elevated free T4
  • Antibody screening – as a follow-up when thyroid disease identified

Differential Diagnosis

Background

Epidemiology

  • Prevalence
    • Graves disease (GD) – 20-30/100,000 (Burch, 2015)
    • Hashimoto thyroiditis (HT) – 1/1,000
  • Age
    • GD – 40s-50s (peak)
    • HT – 40s (peak)
  • Sex
    • GD – M<F, 1:5
    • HT – M<F, 1:8

Classification of Autoimmune Thyroiditis

  • Acute
  • Subacute – infectious
    • Organisms usually viral
    • May include coxsackievirus, mumps virus, influenza virus, Epstein-Barr virus, adenoviruses
      • de Quervain thyroiditis – tends to follow viral epidemics with seasonal and geographical distribution
  • Transient hyperthyroidism
    • Pregnancy related – may also be linked to hyperemesis gravidarum
    • Postpartum thyroiditis – may become persistent
    • Euthyroid sick syndrome – abnormal thyroid function associated with a nonthyroidal illness
  • Silent (subclinical)
    • Excessive thyroid hormone therapy
    • Medication induced
  • Chronic – usually autoimmune
    • GD – causes hyperthyroidism
    • HT – causes hypothyroidism
      • Fibrous variant
      • Ig4-related variant
      • Juvenile variant
      • Hashitoxicosis variant

Risk Factors

  • Family history – genetic variations may predispose individuals to familial thyroid autoimmunity
  • Iodine deficiency – use of noniodized salt most common cause
  • Chronic illness or other autoimmune disease (eg, type 1 diabetes mellitus  [T1DM], celiac disease)
  • Tobacco use for HT

Clinical Presentation

  • HT
    • Slowly progressive disease
    • Constitutional – fatigue
    • Gastrointestinal – constipation
    • Skin – yellow, dry, cold
    • Endocrine – enlarged, firm thyroid gland
    • Cardiovascular – bradycardia
    • Central nervous system – memory loss, depression
  • GD
    • Symptoms of thyrotoxicosis
      • Endocrine
        • Diffuse enlargement of gland (goiter)
        • May present as thyroid storm – acute, life-threatening hypermetabolic state
      • Constitutional – weight loss, heat and cold intolerance, fatigue
      • Cardiovascular – tachycardia, high-output heart failure
      • Ophthalmologic
        • Ophthalmopathy – exophthalmos
        • Proptosis, usually bilateral
      • Skin
        • Dermopathy – nonpitting edema (rare)
  • Autoimmune polyglandular syndrome type 2

ARUP Laboratory Tests

Primary Tests

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Not routinely ordered

Acceptable testing for autoimmune thyroid disease

Prognostic marker for relapse of Graves disease (GD) or remission following drug therapy

Support GD diagnosis in difficult (euthyroid) cases

Predict risk of thyroid dysfunction in newborns of mothers with GD

Blocking antibodies specific to thyrotropin receptor (TSHR) may decrease thyroid stimulating immunoglobulin (TSI) antibody levels; net response is most likely physiologic

TSH serum levels ≥6 mU/L may cause a false-positive result

Acceptable testing for autoimmune thyroid disease

Aid in differentiation of GD from factitious thyrotoxicosis, postpartum thyroiditis, or toxic nodular goiter

Prognostic marker for relapse of GD or remission following drug therapy

Predict risk of thyroid dysfunction in newborns of mothers with GD

Evaluate for presence of euthyroid GD ophthalmopathy

Not recommended for initial thyroid disorders testing

Distinguish thyroid autoimmune disorders from nonautoimmune disease or hypothyroidism

Primary test for Hashimoto thyroiditis (HT)

Secondary testing for GD; aid in differentiation of GD from factitious thyrotoxicosis, postpartum thyroiditis, or toxic nodular goiter

Predict progression to hypothyroidism in individuals with subclinical hypothyroidism

Evaluate individuals with recurrent miscarriage, with or without infertility issues

Not recommended in the initial evaluation of autoimmune thyroid disease

Most often used to evaluate potentially unreliable thyroglobulin measurements in thyroid carcinomas

Diagnose autoimmune thyroid disease when thyroid peroxidase (TPO) antibody measurements are negative and a high clinical suspicion exists for autoimmune thyroid disease

Predict progression to hypothyroidism in individuals with subclinical hypothyroidism (eg, Hashimoto thyroiditis)

Not the preferred initial test for evaluation of autoimmune thyroid disorder; consider ordering TPO antibody

Components include thyroglobulin antibody and TPO antibody tests

Related Tests

Preferred test for screening and monitoring thyroid function

Not the preferred initial thyroid disorder screening test

Order following abnormal thyroid stimulating hormone (TSH) result to diagnose thyroid disease

Order in conjunction with TSH if pituitary (secondary) hypothyroidism is suspected

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References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®