Dr Gabriela Brenta

Department of Milstein Hospital, Buenos Aires, Argentina

THYROIDITIS Thyroiditis - definition

Thyroiditis is characterized by the presence of inflammation in the

Can be painful or indolent

Thyroid dysfunction and goiter may or may not be present

THYROIDITIS Types of thyroiditis Classification according to clinical presentation

PAINFUL • Acute • Subacute • Radiation • Trauma

PAINLESS • Hashimoto • Post-partum • Silent • Drug-induced • Riedel

THYROIDITIS Types of thyroiditis Classification according to clinical course

acute subacute chronic

INFECTIOUS SUPPURATIVE: GRANULOMATOUS Suppurative • Infectious unspecific (or De Quervain) Non suppurative • Infectious specific (TBC, syphillis, NON INFECTIOUS actinomicosis) Traumatic LYMPHOCYTIC OR PAINLESS NON SUPPURATIVE: Actinic (sporadic or post- • Fibrous (or Riedel) Chemical: induced by partum) • Lymphocytic (or drugs Hashimoto’s)

THYROIDITIS Chronic thyroiditis

Suppurative: • Infectious unspecific • Infectious specific (TBC, syphillis, actinomicosis)

• Non suppurative: • Fibrous (or Riedel) •Lymphocytic (or Hashimoto)

THYROIDITIS Dr Hakaru Hashimoto described thyroiditis in 1912, hence it’s name

THYROIDITIS Lymphocytic or Hashimoto’s thyroiditis

Part of the spectrum of autoimmune thyroid diseases (AITDs)

Characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes

More frequent in women (estrogen + X chromosome, fetal microchimerism) from age 30 onwards

Most frequent cause of primary

THYROIDITIS Lymphocytic or Hashimoto’s thyroiditis

Background factors: increased iodine intake, selenium deficit, stress, toxins, drugs, infection smoking (decreases incidence)

Incidence in US: 3.5 per 1000/year in women and 0.8 per 1000/year in men

Prevalence of detectable TGAb and TPOAb levels were 10 and 12% of the healthy population1

Associated with development of B cell lymphoma

1Vanderpump F. British Medical Bulletin 2011 Sept1;99(1):39-51.

THYROIDITIS Clinical manifestations of Hashimoto’s thyroiditis

Asymptomatic (euthyroid or subclinical hypothyroidism)

Clinical hypothyroidism: 10-20% (5% annual risk)

Hyperthyroidism: 5% (Hashi-Graves). Alternating hypo- and

Diffuse goiter. In 1/3 of cases uni- or multinodular. Painless, firm consistency, irregular surface or lobulated and of variable size

Atrophic thyroiditis: late evolution, TPOAb positive, no goiter and with hypothyroidism

THYROIDITIS Pathophysiology of Hashimoto’s thyroiditis

Peripheral tolerance is guaranteed by regulatory B and T cells

Autoimmunity (loss of tolerance) could be due to an imbalance between effector and regulatory cells in favour of a pro-inflammatory response

Bliddal S, et al. 1000Research 2017;6(F1000 Faculty Rev):1776.

THYROIDITIS Potential mechanisms of thyroid autoimmunity

Infiltration of Thyroid hematopoietic expression Molecular mononuclear cells of HLA mimicry class II (mainly lymphocytes), into the interstitium among the thyroid follicles occurs, Bystander leading to thyroid cell activation lysis

THYROIDITIS Hashimoto’s thyroiditis disease mechanism

Hashimoto’s thyroiditis results when the effects of cumulative weaknesses line up to allow autoimmune destruction to occur

Weetman AP. Eur Thyroid J 2013 Jan;1(4):243-50.

THYROIDITIS Diagnosis

Thyroid Thyroid antibodies ultrasonography

THYROIDITIS Antibodies in Hashimoto’s thyroiditis

Thyroid peroxidase antibody (TPOab) positive in 90-100% of cases

50-60% TPOab positive patients are thyroglobulin antibody (TGab) negative

TGab positive: 80-90%

Relatives of patients with Hashimoto’s: 30-50% are TPOab positive

THYROIDITIS Ultrasonography (US) in Hashimoto’s thyroiditis

• 20% of individuals with higher •• TheThe presencepresence ofof Hashimoto’sHashimoto’s TSH values and lymphocytic thyroiditisthyroiditis onon USUS increasesincreases thethe riskrisk infiltration of the gland have ofof thethe diseasedisease movingmoving fromfrom hypoechogenicity without subclinicalsubclinical toto clinicalclinical detectable thyroid antibodies hypothyroidismhypothyroidism

Pedersen OM, et al. Thyroid 2000 Mar;10(3): 251-9. RosárioRosário PW, PW, et et al. al. Thyroid Thyroid 2009 2009 Jan;19(1):9-12. Jan;19(1):9-12.

THYROIDITIS Ultrasonography in Hashimoto’s thyroiditis

Ultrasound image of a patient with Hashimoto’s thyroiditis, showing a heterogeneous pattern to the gland and hypervascularization

THYROIDITIS Clinico-pathological spectrum of Hashimoto’s thyroiditis

Hashimoto’s thyroiditis variants: Primary forms

Painless Fibrous IgG4-related thyroiditis Classic form Juvenile form variant variant (sporadic or post-partum)

Caturegli P, et al. Autoimmun Rev 2014 Apr-May;13(4-5):391-7.

THYROIDITIS Clinico-pathological spectrum of Hashimoto’s thyroiditis

Hashimoto’s thyroiditis can be part of the “Polyglandular autoimmune syndromes” (PAS)

PAS Type 1: Juvenile, also PAS Types 2-4 known as autoimmune Adults, polyendocrinopathy-candidiasis- ectodermal dystrophy (APECED) Polygenetic inheritance or Whitaker syndrome AITD 70-75% Monogenic T1D 50-60% Mucocutaneous candidiasis is Autoimmune Addison disease associated with glandular failure 40-50%

Kahaly GJ, et al. J Endocrinol Invest 2018 Jan;41(1):91-98.

THYROIDITIS Classic form of Hashimoto’s thyroiditis

• Few thyroid follicles • Interstitial infiltration of hematopoietic mononuclear cells, mainly composed of lymphocytes • Lymphoid follicles • Fibrosis • Hürthle cells

Caturegli P, et al. Autoimmun Rev 2014 Apr-May;13(4-5):391-7.

THYROIDITIS Fibrous variant of Hashimoto’s thyroiditis

• Enlarged, hard gland • Thyroid capsule contains the fibrosis • Pseudonodular • Represents 10% of Hashimoto variants • In the elderly, it may explain idiopathic myxedema with a small gland

Caturegli P, et al. Autoimmun Rev 2014 Apr-May;13(4-5):391-7.

THYROIDITIS IgG4-related variant of Hashimoto’s thyroiditis

• First described by Li et al. in Japan in 2009.* • Pronounced lympho-plasmacytic infiltrate • Plasmatic cells produce IgG4 • Fibrosis

*Li Y, et al. Pathol Int 2009;59:636-41. Caturegli P, et al. Autoimmun Rev 2014 Apr-May;13(4-5):391-7; Watanabe T. Scand J Rheumatol 2013;42(4):325-30.

THYROIDITIS Differences among the Hashimoto forms

Classic Fibrous IgG4-related Juvenile Hashi-toxicosis Post-partum

Peak age 40-60 60-70 40-50 10-18 40-60 20-40 (years) at onset F:M ratio 12:1 10:1 3:1 6:1 5:1 N/A

Thyroid Normal in Hypo- Hypothyroidism Normal/ Hyper-thyroidism Hyper-or function at most patients thyroidism subclinical hypothyroidism presentation hypothyroidism Sonographic Hypoecho- Hypoecho- Pronounced Hypo- Hypo- Hypo- findings genicity genicity with hypo- echogenicity echogenicity echogenicity nodularity echogenicity 24h RAI Variable Decreased Unknown Variable Increased Decreased uptake Fibrosis Yes Severe Yes No No No

Caturegli P, et al. Autoimmun Rev 2014 Apr-May;13(4-5):391-7.

THYROIDITIS Post-partum thyroiditis occurs in 5-10% of pregnancies

Risk is higher in those with: • Autoimmune disease: DM1 (25%) • TPOab+ (50%) • Personal or family history of thyroid autoimmune disease • Previous post-partum thyroiditis (70%)

Stagnaro-Green A. J Clin Endocrinol Metab, 2012 Feb;97(2):334-42.

THYROIDITIS Chronic thyroiditis

Suppurative: Bilateral • Infectious unspecific compromise of the thyroid • Infectious specific (TBC, gland syphillis, actinomicosis) Mildly painful, • Non suppurative: slow progression • Fibrous (or Riedel) • Lymphocytic (or May be Hashimoto’s) euthyroid

THYROIDITIS Chronic thyroiditis

Suppurative: • Infectious unspecific • Infectious specific (TBC, syphillis, actinomicosis)

• Non suppurative: • Fibrous (or Riedel) • Lymphocytic (or Hashimoto’s)

THYROIDITIS Fibrous or Riedel thyroiditis

Very infrequent, incidence 1.06/100,000 prevalence 0.05% of thyroidectomies (Mayo Clinic data)

Occurs in women 30-50 years 5-10x more often than in males

Fibrosis is widely invasive

Most cases are isolated (70%), can be systemic

Associated with other autoimmnune disorders

Has been related to IgG4

Kottahachchi D, Topliss DJ. Eur Thyroid J 2016;5:231-9; Fatourechi MM, et al. Thyroid 2011;7:765-72.

THYROIDITIS

GRANULOMATOUS (or De Quervain)

LYMPHOCYTIC OR PAINLESS (sporadic or post-partum)

THYROIDITIS Classical evolution of thyroiditis

Hypo- Hyper- Euthy- Recovery: thyroid roid thyroid Euthyroidism phase phase phase

THYROIDITIS Granulomatous (or De Quervain) thyroiditis

Frequency 5‒6% Female gender (7:1) 30–60 years

Limited to 1‒3 Summer/early Associated with months Autumn HLA B35 (ad integrum restitution)

Viral: enterovirus, VEB, influenza, coxackie, adenovirus, Malaria, Q fever echovirus, CMV. Post- vaccine VHB. Kramer AB, et al. Thyroid 2004;14:544-7; Ohsako N, et al. J Clin Endocrinol Metab 1995;80:3653-6.

THYROIDITIS Granulomatous (or De Quervain)

Clinical presentation:

Subacute pain in the front of the neck

Preceded by upper respiratory tract infection 2-8 weeks prior Fever (30%), astenia, myalgia

arthralgias, anorexia

• Thyroid gland enlargement: uni- or bilateral (64%) or migratory • Symptomatic thyrotoxicosis (60%)

THYROIDITIS Granulomatous (or De Quervain)

Laboratory test findings:

Erythrocyte sedimentation (>50 mm/h)/ high PCR

Leucocytosis

TPOab and TG ab negative

Thyroid function:

• Hyperthyroid phase: Elevation of thyroglobulin, T3 and T4. TSH suppressed • Hypothyroid phase: Low free T4 and high TSH

Images: US: Thyroid volume increased, focally or diffusely hypoechoic. Not hypervascularized

Radioiodine (RAI) uptake and scintigraphy: reduced uptake

THYROIDITIS Granulomatous (or De Quervain)

Treatment

• Nonsteroidal anti-inflammatory drugs • Methylprednisone 151 to 40 mg/day for 2–4 weeks • A longer period of treatment2 is related to fewer relapses (40 vs 20 days) • Improvement is expected in 24–48hs. (if not, look for a differential diagnosis) • Propanolol 40 to 120 mg/day or atenolol 25 to 50 mg/day while thyrotoxic, while hypothyroid 1Sato J, et al. Endocrine 2017 Jan;55(1):209-214; 2Arao T, et al. J UOEH. 2015 Jun 1;37(2):103-10.

THYROIDITIS Acute thyroiditis

INFECTIOUS Bacterial~85% Suppurative • mycobacterium and Non suppurative syphilis NON INFECTIOUS Traumatic Actinic Chemical: induced by Others: drugs mycotic, parasitic~15%

THYROIDITIS Infectious thyroiditis

Fistulae from piriform sinus (in children) 90% in left thyroid lobe

Fistulae from 4th branchial arch sinus or from a thyroglossal persistent duct

Hematogenous: pharingitis, parotiditis, mastoiditis, otitis, endocarditis, retropharingeal abscess, airway infections, odontological, etc.

THYROIDITIS Infectious thyroiditis

Severe cervical pain of abrupt onset, unilateral High fever, In case of with maxilar Odinophagia, Thyroid recurrence The abcess auricular or chills disphagia, dysfunction suspect can drain (bacteremia) occipital adenopathies disphony exceptional piriform sinus spontaneously irradiation, fistulae aggravated with hyperextension

THYROIDITIS Infectious thyroiditis

Laboratory: Leucocitosis, high erythrocyte sedimentation rate

Discount HIV

FNAB of the abscess and bacterial culture

THYROIDITIS Infectious thyroiditis

Barium- CT/MRI neck and contrasted US confirms if mediastinum esophagus study Gallium there is one or may alert of air in or laringoscopy scintigraphy more abscess the neck (fístulase and diverticulum)

THYROIDITIS Infectious thyroiditis treatment

Aspirate abscess and prescribe antibiotics

May not require surgery

Avoid steroids

THYROIDITIS Acute thyroiditis

INFECTIOUS Suppurative Non suppurative NON INFECTIOUS Traumatic Actinic Chemical: induced by drugs

THYROIDITIS Immune-related drug-induced thyroiditis

Immune- Immune Tyrosine modulators checkpoint Lithium Amiodarone kinase inhibitors (INF alpha/ inhibitors beta, IL-2) (ICIs)

Ferrari S, et al. Rev Endocr Metab Disord. 2018 Sep 21:doi: 10.1007/s11154-018-9463-2; Iyer PC, et al. Thyroid 2018 Oct;28(10):1243-1251.

THYROIDITIS Conclusions

If thyroiditis is suspected, check for pain

If no history of trauma or radiation, discard subacute or acute thyroiditis depending upon clinical presentation A low iodine uptake might be useful for diagnosis

In the absence of pain, drugs or the patient being post- partum, check thyroid function, thyroid antibodies and iodine uptake to confirm etiology

THYROIDITIS Conclusions

Treatment includes:

Acute: ATB and eventually drainage

Subacute: NSAID, glucocorticoids and beta-blockers

Chronic: Levothyroxine, eventually beta-blockers, surgery and tamoxifen (Riedel)

THYROIDITIS