Update on the Diagnosis and Management of Thyroid Diseases

Update on the Diagnosis and Management of Thyroid Diseases

Kristien BoelaertReader in Endocrinology

Consultant EndocrinologistUniversity of Birminghamk.boelaert@bham.ac.uk

Thyroid Diseases

Hyperthyroidism

Hypothyroidism

Thyroid enlargement

Hyperthyroidism

Thyrotoxicosis: disorder of excess circulating TH Hyperthyroidism: increased synthesis and secretion of TH

Prevalence

Incidence

UK: 2%♀ and 0.2% ♂ US: 1.3%

2.1-22/100,000 ♂ 23-99/100,000 ♀

Whickham Survey Tunbridge et al. 1977 Clin Endocrinol 7: 481Golden et al. 2009, JCEM 94: 1853 Wilson et al. 2006 JCEM 91: 4809De Leo et al 2016, Lancet 388: 906 McGrogan et al. 2008, Clin Endocrinol 69: 687

Hyperthyroidism

Graves’ hyperthyroidism

Toxic nodular goitre (single or multinodular)

Thyroiditis (silent, subacute, postpartum)

Exogenous iodine

Factitious thyrotoxcosis

Drugs: amiodarone, lemtrada, immunological treatments

TSH secreting pituitary adenoma

Neonatal hyperthyroidism

Aetiology of hyperthyroidism

Most prevalent autoimmune disorder in the UK

60-80% of cases of thyrotoxicosis in UK

Pathogenetic antibodies to TSH receptor on thyroid follicular cells (Long Acting Thyroid Stimulators) Twin concordance studies: 80% genetic – 20% environmental susceptibility

Genetic regions: HLA region, CTLA4 and PTPN22 – encoding proteins involved in immune regulation

Environmental factors: infection (Yersinia enterocolitica), smoking, childbirth, stress, iodine

Brand et al. 2009, Hum Mol Genet 18: 1704 Wang et al. 2010, JCEM 95: 4012Asvold et al. 2007, Arch In Med 167: 4012 Franklyn & Boelaert 2012, Lancet 379: 1155

Graves’ Disease

System Symptoms Signs

CNS Fatigue, anxiety hyperactivity

Hair Hair loss

Eyes (GD) Soreness, grittiness Stare, lid retraction, exophthalmos, ophthalmoplegia

Thyroid Neck swelling goitre

Muscles Weakness, tremor Fine tremor, muscle wasting

Skin Heat intolerance Warm, moist skin

Cardiovascular Palpitation, SOB Tachycardia, arrhythmia

Gastro-intestinal Appetite, weight loss Weight loss

Peripheral nervous system Hyper-reflexia

Reproductive system Oligomenorrhoea, ↓ fertility

Franklyn & Boelaert 2012, Lancet 379: 1155

Clinical Presentation

Extra-thyroidal manifestations

Feature Prevalence (%)

Hyperthyroidism and diffuse goitre 95

Thyroid ophthalmopathy 50

Pretibial myxoedema 5

Acropachy 1

Thyroid eye disease without hyperthyroidism (Euthyroid Graves’ disease)

5

De Leo et al. 2016, Lancet 388: 906 Girgis 2011 Ther Adv Endocrinol Metab 2: 135

Symptoms according to age

0

10

20

30

40

50

60

18-32 y

33-44y

45-60y

over 61 y

Nu

mb

er

of

pati

en

ts (

%)

0-2 symptoms 3-4 symptoms 5 or more symptoms

P < 0.001

Boelaert et al. 2010, JCEM 95: 2715

3049 subjects with hyperthyroidism

Diagnosis of hyperthyroidismSymptoms and signs of hyperthyroidism

Serum TSH

Reduced Normal/Raised

fT4 (± fT3) Thyrotoxicosis excluded (unless RTH or TSH-oma)

Normal Raised

Subclinical hyperthyroidism

Thyrotoxicosis

• Identify extrathyroidal manifestations• Presence/character of goitre

Determine Aetiology

Franklyn & Boelaert 2012, Lancet 379: 1155

Clinical features of Graves’

Check TSH-receptor Abs: +ve in 98% of Graves’

TPO Abs reflect generalized autoimmunity (+ve in 75%)

Isotope scanning (Tc/Iodine) if TSH-RAb negative

Thyroid US: limited value

Determining the cause of hyperthyroidism

NICE guidelines 2019: Draft Recommendations

Treatment of hyperthyroidism

• Antithyroid drugs to block hormone synthesis

• Radioiodine (131I) therapy

• Surgical removal of thyroid

Carbimazole (methimazole) and propylthiouracil

In addition to β-blockers

Short-term preparation of patients for definitive treatment

Induction of remission in Graves’ disease (12-18 months)

Poor remission rates (up to 50%)

Significant side-effects

Allahabadia et al. 2000, JCEM 85: 1038 Franklyn & Boelaert 2012, Lancet 379: 1155De Leo et al 2016, Lancet 388: 906

Antithyroid drugs

Severity Carbimazole PropylthiouracilMajor side-effects (rare)

Agranulocytosis (0.2-0.5%)Cholestatic hepatitis TeratogenicityAplastic anaemia Thrombocytopaenia

Agranulocytosis (0.2-0.5%)Toxic hepatitis and fulminantliver failureANCA-positive vasculitis Aplasticanaemia Thrombocytopaenia

Common minor side-effects (1-5%)

Urticaria, rash, arthralgia, fever, transient neutropenia

Urticaria, rash, arthralgia, fever, transient neutropenia

Uncommon minorside-effects (<1%)

Nausea and vomiting, abnormalities of taste and smell, arthritis

Nausea and vomiting, abnormalities of taste and smell, arthritis

Franklyn & Boelaert (2012) Lancet 379,1155 De Leo et al 2016, Lancet 388: 906

Side-effects of antithyroid drugs

0

10

20

30

40

50

60

70

80

90

185 MBq

370 MBq

600 MBq

Ou

tco

me

acco

rdin

g to

do

se

regi

men

(%

)

Cure Hypothyroidism

***

***

***

***

**

**

1278 patients treated with 131I for hyperthyroidism

Single fixed dose of 131I

Boelaert et al. 2009, Clin End 70: 129

Outcomes following radioiodine

Cause of death Overall Whilst on Thionamide Rx

Following 131INot hypothyroid

Following 131IHypothyroid

SMR SMR P SMR P SMR P

All causesMalesFemales

1.151.261.11

1.301.361.27

0.0060.100.07

1.241.341.21

0.020.110.06

1.021.1

0.95

0.850.570.60

Comorbidity absentComorbidity present

0.951.52

1.031.68

0.84<0.001

1.091.48

0.480.002

0.811.43

0.080.01

Sinus RhythmAtrial fibrillation

1.071.59

1.181.74

0.180.006

1.171.53

0.110.02

0.921.51

0.430.08

Circulatory deaths 1.20 1.37 0.05 1.19 0.22 1.12 0.45

Boelaert et al. 2013, JCEM 98: 1869

Hyperthyroidism and mortality

Used infrequently

Pre-treatment with antithyroid drugs

Indications:

Large goitre/compression (especially if suspicion of co-existing thyroid cancer) Pregnancy (serious side-effects of drugs) Pronounced ophthalmopathy Patient preference

Franklyn & Boelaert 2012, Lancet 379: 1155 De Leo et al. 2016, Lancet 388: 906

Surgical treatment of hyperthyroidism

Clinical Case 68 y old female patient

Hypertension controlled on lisinopril

Sister had MI aged 62 years

Found to have abnormal TFT on routine testing

Asymptomatic

O/E: P76/min regular, BP 138/76 mm Hg, euthyroid, no palpable goitre/nodules

Time point TSH (mIU/L) [0.3-4.5] fT4 (pmol/L) [10-22] fT3 (pmol/L) [3.2-6.7]

3 months ago <0.02 18.2

Today <0.02 18.6 6.3

A: Thyroid US

B: TSHR-Ab

C: Radio-Isotope scan

D: 24h Holter

E: DEXA scan

F: No further tests required

Which test do you request next?

What would I do?

B: TSHR-Ab

Subclinical hyperthyroidism - Epidemiology Below normal serum thyrotropin – fT4 and fT3 within population reference

range

Prevalence 0.3-12% depending on iodine status

Mild/Grade 1: TSH = 0.1-0.4 mIU/L (~75%)

Severe/Grade 2: TSH < 0.1 mIU/L

Exogenous (~ 20% of patients on L-T4) or endogenous

Endogenous: causes similar to overt hyperthyroidism

T3 normal or high normal in endogenous Shyper

? Disparate long term consequences endogenous vs exogenous SHyper

Biondi & Cooper. NEJM 2018, 378: 2411

Boelaert. 2013 Nat Rev Endocrinol, 9: 194

? Only present in individuals with co-morbidities

Increased risk of incident atrial fibrillation

? Higher risk of AF with more TSH suppression

Absolute risks increase with age

Cardiovascular effects of SHyper

22212019181716151413121110

12

11

10

9

8

7

6

5

4

3

2

serum free T4 concentration (pmol/L)

Pre

vale

nce

of A

F(%

)

Gammage et al. 2007 Arch Int Med, 167: 928

5860 patients aged > 65 years

AF and fT4 in reference range

19 Cohort studies, N = 79,368 participants

Yang et al. 2018 J Bone Miner Metab, 36: 209

Shyper and fracture risk

Factor TSH < 0.1 mIU/L TSH 0.1-0.5 mIU/L

Age ≥ 65y Yes Consider treatment

Age < 65 y with co-morbiditiesCardiac Risk Factors/Heart DiseaseOsteoporosisMenopausalHyperthyroid symptoms

YesYesYesYes

Consider treatmentConsider treatment

NoConsider treatment

Age < 65 y asymptomatic Consider treatment Observe

Treatment Guidelines

Biondi et al. 2015 ETA guidelines on subclinical hyperthyroidism, Eur Thyroid J 4: 14

Ross et al. 2016 ATA Guidelines, Thyroid 26 : 1343-1421

Hypothyroidism

Prevalence 40/1000 females

Prevalence increases with age

Aetiology:

Autoimmune – Hashimoto’s thyroiditis (TPO and Tgantibodies - genetic predisposition)

After treatment for hyperthyroidism

Subacute/silent thyroiditis

Iodine deficiency

Congenital (thyroid agenesis/enzyme defects)

Hypothyroidism

Symptoms and signs of hypothyroidism

Cardiovascular

Bradycardia

Heart failure

Pericardial effusion

Gastrointestinal

Weight gain

Constipation

Skin

Myxoedema

Vitiligo

Neurological

Depression

Psychosis

Carpal tunnel syndrome

Treatment of hypothyroidism

2014: 3rd most prescribed medication in UK

29 million tablets of levothyroxine prescribed

Most common endocrine condition

Goal of therapy is to restore patients to euthyroid state and to normalise serum T4 and TSH concentrations

Ongoing symptoms despite replacement

Approximately 10% of people on T4 have continuing symptoms

Screen for associated auto-immune disorders

T3 or T3+T4 combination treatment not recommended

“Natural thyroid” – Armour not endorsed by national/international professional societies

Identification of subgroup with common deiodinase 2 gene variation - ? Benefit from T3+T4

Jonklaas et al. ATA guidelines 2014 Thyroid, 24: 1670

Okosieme et al. BTA guidelines 2016 Clin Endo, 84: 799

Dayan C et al 2018 Thyroid research, 11:1Panicker et al. 2009 JCEM, 94: 1623

Clinical Case 71 y old woman

Fatigue and mild depression and MI 4 years ago

PMH: Hypertension (Lisinopril)

FHx: sister with hypothyroidism

O/E: Wt = 159 lb (72 kg); BMI = 26.4 kg/m2; no palpable thyroid enlargement

Normal FBC, renal function, Ca and ESR

TPO Abs: 276 IU/ml [<35]

Time point TSH (mIU/L) [0.4-4.5] fT4 pmol/L [10-22]

3 months ago 6.9 18.0

Today 6.8 18.0

What is the best management plan?

A: Start levothyroxine 50 mcg daily

B: Start levothyroxine 112 mcg (1.6 mcg/kg)

C: Repeat TFT after 6 months

D: Re-check anti TPOAbs and start levothyroxine if higher than before

E: Discharge patient

What would I do?

A: Start levothyroxine 50 mcg daily

Subclinical Hypothyroidism - Epidemiology

Raised serum thyrotropin – fT4 within population reference range

Incidence 3-15%

Mild: Normal reference range < TSH < 10 mIU/L (75% of patients)

Severe: TSH > 10 mIU/L

Exogenous (~ 20% of patients on L-T4) or endogenous

Risk of progression 2-6%

Increased risk in: Women Higher serum TSH Higher levels of thyroid auto-antibodies Low-normal fT4

R Peeters 2017 NEJM, 376: 2556

SHypo - Progression

Normalisation of thyrotropin in 46% when TSH <7.0 mIU/L

Higher rates of progression with higher TSH and positive TPO

Meyerovitch et al. Arch Intern Med 2007, 167: 1533

Somwaru et al. 2012 JCEM , 97: 1962

Huber et al. 2002 Clin Endo, 87: 3221

Upper serum TSH concentrations

Surks and Hollowell 2007 JCEM, 92: 4575

Age and physiological changes to TSH

SHypo - Symptoms

Colorado Health Fair Study

Range: asymptomatic-multitude of symptoms

Canaris et al. Arch Intern Med 2000, 160: 526

Fewer symptoms in older people

? Better physical function if SHypo

Simonsick et al. Arch Intern Med 2009, 169: 2591Bano et al. Sci Rep 2016, 6: 38912

SHypo – CHD events and mortality

Rodondi et al. JAMA 2010, 304: 1365

SHypo – Effect of treatment on symptoms

TRUST-trial

737 adults aged ≥ 65 years

TSH: 4.6-19.9 IU/L

Randomised to receive levothyroxine or placebo with dose adjustment

No difference in Hypothyroid Symptom or Tiredness Score

No difference in secondary outcomes (BMI, BP, handgrip strength, waist circumference)

Stott et al. NEJM 2017, 376: 2534

Relatively mild Shypo

27% of subjects had no hypothyroid symptoms at baseline

SHypo – Treatment Guidelines Repeat TFT and check TPOAbs

Annual TFT if TPOAb positive

R Peeters. NEJM 2017, 376: 2556; Pearce S et al. ETA Guidelines Eur Thyroid J 2013, 2: 215Garber et al. ATA Guidelines Thyroid 2012, 22: 1200; Jonklaas et al. ATA Guidelines Thyroid2014, 24: 1670

TSH < 10 mIU/L TSH ≥ 10 mIU/L

7 ≤ TSH > 10 mIU/L4.5 < TSH > 7 mIU/L ≤ 70y > 70y

Treatment not recommended

Consider 6 month levothyroxine trial if

symptoms

Repeat TFT after 6 monthsTSH nl: discharge

TSH < 10: as aboveTSH ≥ 10 treat if < 70 y

Treatment recommended,

especially if symptoms, TPOAb

pos, cardiac risk factors

Consider 6 month levothyroxine trial if

symptoms regardless of age, or <70, cardiac risk factors,

TPOAb pos

Treatment not recommended

Treatment not recommended

Consider 6 month levothyroxine trial if

symptoms regardless of age, or TPOAb pos, or low

fT4 rising TSH

Repeat TFT after 6 monthsTSH nl: discharge

TSH < 10: as indicated on leftTSH ≥ 10 as above

Thyroid enlargement

Thyroid nodules: epidemiology

Definition: “Discrete lesions within the thyroid gland, radiologically distinct from surrounding parenchyma”

May be discovered on palpation, imaging, incidentally Most common in women (4:1) and in older populations Increased in areas of low iodine intake

Cooper DS et al. 2009 Revised ATA Guidelines Thyroid 2009, 19: 1167-1214Popoveniuc & Jonklaas Med Clin North Am 2012, 96: 329-349

Significance of thyroid nodules

May cause thyroid dysfunction

May cause compression

Need to exclude thyroid cancer

Prevalence of malignancy is 4 – 6.5%

Independent of nodule size

Malignancy risk in incidentalomas remains controversial

Risk of PET-positive thyroid nodule: 27%

Features suggestive of malignancy

History Examination Imaging

Family Hx of MEN, MTC, PTC Firm nodule Suspicious US features

History of head and neck irradiation

Nodule fixed to adjacent structures

Lymphadenopathy

History of Hodgkin and non-Hodgkin lymphoma

Growth of nodules, especially during therapy to suppress TSH

Age < 20 Abnormal cervical lymph nodes

Age > 70 Vocal cord paralysis

Male gender

Symptoms of compression: hoarseness, dysphagia, dyspnoea, cough, dysphonia

Popoveniuc & Jonklaas Med Clin North Am 2012, 96: 329-349Hegedus 2004 NEJM;351:1764-1771

UK Thyroid Cancer Incidence

Cancer Research UK, 2013

< 1% of all cancers

Incidence in UK = 3.2 per 100,000

Male:female = 1:3 (1:13 in Japan)

2013: 3,241 new cases – 373 deaths

52 y old male patient

Hx of increasing lower back and neck pain

PMH: Hypertension

FHx: Mother: hypothyroidism

Sister: ca colon aged 58 y

Rx: Bendroflumethazide

O/E: P 72/’ BP 132/68

- Normal systems examination

- Reduced neck movement due to pain

MRI neck

Clinical Case

Neck MRI

Neck examination: palpable 1 x 1.5 cm R sided thyroid nodule, thyroid gland not enlarged, no abnormal neck nodes

TSH: 4.2 mU/l

What would you do next?

A: Reassure patient

B: Check serum thyroglobulin

C: Request thyroid ultrasound

D: Request thyroid isotope scan

E: Check serum calcitonin

C: Request thyroid ultrasound

What would I do?

Clinical Case

Neck examination: palpable 1 x 1.5 cm R sided thyroid nodule, thyroid gland not enlarged

TSH: 4.2 mIU/l

Thyroid ultrasonography

Extremely sensitive for diagnosis of thyroid nodules

Specific for thyroid ca diagnosis (papillary)

Aids decision making to select nodules for FNA

Increases yield of diagnostic FNA

Patients with possible thyroid cancer should undergo ultrasonographicevaluation of neck by experienced operator

British Thyroid Association, RCP 2014 Revised guidelines for the management of thyroid cancerClin Endo (2014) 81: 1-122

Ultrasound features

Benign nodule Malignant nodule: Papillary/medullary

Follicular lesion

Spongiform/honeycomb Solid and hypoechoic Hyperechoic/homogeneous/halo benign

Purely cystic Irregular margin Hypoechogencity/loss of halo suspicious

Egg shell calcification Intranodular vasularity

Iso/hyper echoic (hypoechoichalo)

Absence of halo

Peripheral vascularity Taller than wide

Microcalcifications

British Thyroid Association, RCP 2014 Revised guidelines for the management of thyroid cancerClin Endo (2014) 81: 1-122

Scoring system:U1-U5

U1: NormalU2: BenignU3: IndeterminateU4: SuspiciousU5: Malignant

British Thyroid Association, RCP 2014 Revised guidelines for the management of thyroid cancerClin Endo (2014) 81: 1-122

THY classification

Classification Cytology Action

Thy 1 Non-diagnostic US +/- repeat FNA

Thy 2 Non-neoplastic Correlate with clinical and US findings

Thy 3a Neoplasm possible (atypical features)

Further US +/- FNAMDT discussion if Thy3a on repeat sample

Thy 3f Follicular neoplasm Diagnostic hemi-thyroidectomy

Thy 4 Suspicious of malignancy Diagnostic hemi-thyroidectomy

Thy 5 Diagnostic of malignancy Therapy appropriate to tumour type: usually surgery

British Thyroid Association, RCP 2014 Revised guidelines for the management of thyroid cancerClin Endo (2014) 81: 1-122

Take home messages

Treatment of overt hyperthyroidism is to block/ablate thyroid gland (drugs – 131-I)

Treatment of subclinical hyperthyroidism in selected patients considering patients’ age and long term risk

Treatment of overt hypothyroidism with levothyroxine monotherapy

Consider treatment of subclinical hypothyroidism based on degree of TSH rise and risk

Management of thyroid nodules based on combination of clinical suspicion, US and cytology