Autoimmune Thyroid Disease - Thyroiditis

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, function, type, evidence of antibody damage, and clinical use

 

Thyroid peroxidase (TPO) antibodies

Thyroid Stimulating Hormone Receptor (TSHR) antibodies (TRAb)

Thyroglobulin (Tg) antibodies

Biology

TPO is a transmembrane protein essential for synthesis of thyroid hormones

TSHR, a TSH-specific receptor, controls thyroid function and cell growth

Tg is the precursor to thyroid hormones and is highly immunoreactive

Function

TPO is targeted by the thyroid microsomal antibody

TRAb targets TSHRs and competes with TSH for receptor binding

TRAb is not inhibited by the TSH feedback loop

Tg antibody is directed against thyroglobulin

Type

Polyclonal antibody (usually IgG1, IgG4)

3 classes (IgG antibodies)

  • Stimulating antibodies
    • Also known as long-acting-thyroid stimulating antibodies (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 antibody damage

No evidence for mediation of damage

  • TPO is a marker

Stimulating antibody

  • Mediates damage

Blocking antibody

  • Does not mediate damage

No evidence for mediation of damage

  • Tg is a marker

Clinical Use

Healthy populations
Detectable in a very small percentageNot typically detectedDetectable in a smaller percentage
Graves disease (GD)

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 thyroid-stimulating immunoglobulin (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 (HT)

Present in >90% of individuals

Presence of antibody is pathognomonic for HT

Not recommended for use in monitoring

No indicated use in this disease

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 disease postpartum

No indicated use in this disease

Presence may predict postpartum thyroiditis

Subclinical hypothyroidism

May indicate increased risk of development of overt hypothyroidism

No indicated use in this diseaseNo indicated use in this disease
Thyroid cancer
No indicated use in this diseaseNo indicated use in this disease

Most important in 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

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 followup when thyroid disease identified
    • Refer to Key Points section

Differential Diagnosis

Clinical Background

Thyroiditis is an inflammation of the thyroid gland and has multiple etiologies.

Epidemiology

  • Prevalence
    • Graves disease (GD) – 14/100,000
    • 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
    • Viral – organisms 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
    • Euthyroid sick syndrome – abnormal thyroid function associated with a nonthyroidal illness)
  • Silent (subclinical)
    • Excessive thyroid hormone therapy
    • Medication-induced
  • 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 another other autoimmune disease (eg, diabetes mellitus type 1 [DM1], celiac disease)
  • Tobacco use for HT

Clinical Presentation

  • HT
    • Slowly progressive disease
    • Constitutional – fatigue
    • Gastrointestinal – constipation
    • Skin – yellow, dry, and cold
    • Endocrine – enlarged, firm thyroid gland
    • Cardiovascular – bradycardia
    • CNS – memory loss, depression
  • GD
    • Endocrine
      • Diffuse enlargement of gland (goiter)
      • Causes 70-80% of thyrotoxicoses in iodine-sufficient areas
      • May present as thyroid storm – acute, life-threatening hypermetabolic state
    • Constitutional
      • Weight loss, heat and cold intolerance, fatigue
    • Cardiovascular
    • Ophthalmologic
      • Ophthalmopathy – exophthalmos
      • Proptosis, usually bilateral
    • Skin
      • Dermopathy – nonpitting edema (rare)
  • Autoimmune polyglandular syndrome type 2

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Assess thyroid function in evaluation of autoimmune thyroid disease

   
Thyroid Stimulating Immunoglobulin 0099430
Method: Quantitative Bioassay/Quantitative Chemiluminescent Immunoassay

Preferred testing for autoimmune thyroid disease (eg, GD) based on ARUP analytical sensitivities (versus TRAb sensitivities)

Prognostic marker for relapse of 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 TSHR may decrease TSI antibody levels; net response is most likely physiologic

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

 
Thyroid Stimulating Hormone Receptor Antibody (TRAb) 2002734
Method: Quantitative Electrochemiluminescent Immunoassay

Acceptable testing for autoimmune thyroid disease

Aids in the 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 the presence of euthyroid GD ophthalmopathy

   
Thyroid Peroxidase (TPO) Antibody 0050075
Method: Quantitative Chemiluminescent Immunoassay

Preferred test for Hashimoto thyroiditis

Secondary testing for Graves disease (GD)

Predict progression to hypothyroidism in individuals with subclinical hypothyroidism

Evaluate individuals with recurrent miscarriage, with or without infertility issues

   
Thyroglobulin Antibody 0050105
Method: Quantitative Chemiluminescent Immunoassay

Diagnose autoimmune thyroid disease when 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)

   
Thyroid Antibodies 0050645
Method: Chemiluminescent Immunoassay

Test panel composed of TPO and TG antibody tests

See individual tests for recommended uses

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay

Preferred test for screening and monitoring thyroid function

Aid in the diagnosis of primary hyperthyroidism and differential diagnosis of hypothyroidism

Monitor individuals on thyroid hormone replacement therapy

Confirm suppression during thyroxine therapy for thyroid carcinoma

Do not order more than every 3-6 months

Thyroxine, Free (Free T4) 0070138
Method: Quantitative Electrochemiluminescent Immunoassay

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

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

Assess thyroid status in pregnant women or those on estrogen supplementation, phenytoin, or salicylates

Monitor thyroid hormone replacement therapy during pregnancy and treatment of secondary hypothyroidism