Hyperthyroidism

Department of Diabetes & Endocrinology

Nelson R Mandela School of Medicine
University of KwaZulu-Natal

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Key References

1. Hyperthyroidism: Lancet 2003; 362: 459 to 468

2. Graves’ disease: N Engl J Med 2016; 375: 1552-65

3. Radioiodine: N Engl J Med 2011; 364: 542

4. Graves’ orbitopathy: N Engl J Med 2009; 360: 994

Anatomy of the thyroid gland
Thyroid Physiology

TRH
-

TSH

T4 T3
Follicles: the Functional Units of the
Thyroid Gland
Thyroid Hormone Synthesis

Iodine + tyrosine T4 - Thyroglobulin

Hydrolysis
Iodine
H2 O 2
Thyroid peroxidase

Iodide pump

Iodide T4, T3
Thyroid Hormone Physiology

T4 – Thyroid binding globulin

T4 5’ deiodinase enzyme
Free T4 Free T3

Upregulates or DNA T3 receptor

downregulates
DNA transcription
& protein synthesis

Cytoplasm Nucleus
Thyrotoxicosis: Aetiology

• Hyperthyroidism (excess thyroid hormone

production)
• Graves’ disease
• Toxic multinodular goitre
• Toxic adenoma
• Iodine-induced hyperthyroidism
• Trophoblastic tumour
• Increased TSH secretion

• No excess thyroid hormone production

• Thyroiditis: autoimmune and non-immune
• Exogenous thyroid hormone
• Ectopic thyroid tissue
Thyrotoxicosis: Aetiology

Graves’ disease

Toxic multi-nodular goitre > 90% of

all cases
Toxic adenoma

Hashimoto’s thyroiditis
Thyrotoxicosis: Symptoms

• General
 Weight loss
 Malaise & weakness
 Increased sweating
 Heat intolerance
 Alopecia
 Onycholysis (Plummer’s nails)

• Cardiovascular
 Palpitations
 Dyspnoea
 Poor effort tolerance
Thyrotoxicosis: Symptoms
• Neurologic
 Tremor, restlessness
 Poor concentration
 Anxiety
 Emotional lability
 Insomnia
 Muscle weakness, diplopia

• Alimentary
 Increased appetite (Anorexia in elderly)
 Diarrhoea, abdominal cramps
 Dysphagia

• Reproductive
 Infertility, oligo - amenorrhoea
Thyrotoxicosis: Signs

Thyroid

 No goitre may be evident

 Smooth, diffuse, bi-lobe goitre with bruit (Graves’)
 Single nodule
 Multiple nodules (Toxic MNG)
 Tender, firm goitre (Thyroiditis / Hashimoto’s)
 Retrosternal extension (Pemberton’s sign)
 Tracheal / mediastinal compression
 Horner’s syndrome
Palpation of the thyroid
Diffuse goitre
Thyrotoxicosis: Signs

General

 Warm, sweaty hands

 Palmar erythema
 Alopecia
 Thyroid acropachy (clubbing) - Graves’ disease
 Pre-tibial myxoedema - Graves’ disease
 Evidence of weight loss
 Cervical lymphadenopathy - Graves’ disease
Pre-tibial myxoedema

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Thyroid acropachy
Thyrotoxicosis: Signs

Cardiovascular

 Tachycardia
 Arrhythmias – invariably supraventricular
 Increased pulse volume
 Systolic hypertension
 Loud heart sounds
 Forceful apical impulse
 Ejection systolic murmurs (basal)
 Cardiac failure
 Means-Lehrman scratch
Thyrotoxicosis: Signs
Eyes

 Lid-retraction
 Lid-lag
 Exophthalmos
- Only in Graves’ disease
- Swelling of extra-ocular muscles
- Infiltration of the orbit
- Chemosis
 Ophthalmoparesis
- NB to exclude myasthenia gravis
Thyroid Eye disease

Pictures with patient consent; copying not permitted without permission

Thyroid Eye disease

Pictures with patient consent; copying not permitted without permission

Thyrotoxicosis: Signs

Neurologic

 Tremor
 Proximal myopathy
Thyrotoxicosis: Investigations

1. Thyroid hormone levels

2. Thyroid antibodies

3. Thyroid ultrasound

4. Isotope thyroid scanning

Thyroid hormone levels

TSH
 Suppressed - one of the first indications of
thyrotoxicosis
 Elevated, rarely in TSH secreting pituitary
adenoma

Free T4
 Elevated
 Occasionally normal (in “T3 toxicosis”)

Free T3
 Elevated
Thyroid antibodies

TSH receptor antibody

 Aetiology of Graves’ disease

 > 80% of subjects with Graves’ disease are +
 IgG class
 Competes with TSH for the receptor
 Crosses the placenta, stimulates fetal thyroid
TSH receptor Antibody

TSH TSH

X
TSHr Ab

T4, T3 + + T4, T3

Normal Graves’ disease

Thyroid antibodies

Anti-microsomal & anti-thyroglobulin

 Found in the general population

 Prevalence increases with age
 Found in high titre in Hashimoto’s thyroiditis
 Correlate with presence of thyroid lymphocytic
infiltration
 Do not confer disease with passive transfer
(eg across the placenta)
Prevalence of Thyroid antibodies in USA
35
Anti-TPO Ab’s in NHANES
30 Male
Female
25

% 20

15

10

0
13-19 20-29 30-39 40-49 50-59 60-69 70-79 >80 Age in years

Sieiro Netto L, et al. Am J Reprod Immunol. 2004;52:312-316. Lazarus JH. Minerva Endocrinol. 2005 Jun;30(2):71-87.
Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499. Hak AE, et al. Ann Intern Med. 2000;132:270-278.
Thyroid ultrasound

Useful to determine size and consistency of the

gland

Useful in differentiating solid and cystic nodules

Doppler flow increased in hyperplastic glands

Thyroid ultrasound
Thyroid isotope scan

Two isotopes commonly used:

 Technetium 99

 131 Iodine

Both accumulate in the thyroid and are detectable

by emission of radiation – detected by scanning at
various time intervals after injection of the isotope

Pattern and extent of radiation emission provide

useful information on thyroid function and patterns
of activity
Thyroid isotope scan

Patterns of isotope emission in thyrotoxic states

Increased uptake and emission

 Graves’ disease
 Toxic multinodular goitre
 Toxic adenoma
 Trophoblastic disease
 TSH-secreting tumour

Decreased or absent uptake and emission

 Thyroiditis
 Exogenous or ectopic thyroid hormone
 Iodide-induced
Thyroid isotope scan: Technetium 99m
Thyrotoxicosis: Specific types

Graves’ disease

 Common disorder
 Predominantly young females (F:M=10:1)
 Incidence: 1 per 1000 per year
 Genetic associations: HLA
 Precipitant of clinical disease unknown
 Related to presence of TSH r Ab
 Anti-microsomal and anti-thyroglobulin antibodies
often also detected (>60%)
Graves’ disease
Specific characteristics

 Smooth diffuse non-tender goitre with bruit

 Thyroid acropachy
 Thyroid dermopathy (pre-tibial myxoedema)
*
 Infiltrative ophthalmopathy
 Often have severe thyrotoxicosis
 May have associated autoimmune disease:
- Vitiligo, myasthenia gravis, Type 1 diabetes

* Pathognomonic of Graves’ disease

Graves’ disease

Vitiligo

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Toxic multinodular goitre

Specific features:

 Affects older persons

 Gender involvement approximately equal
 Develops in pre-existent euthyroid nodular goitre
 Autonomy of one or more nodules
 Less severe thyrotoxicosis
 Nodular goitre on palpation and ultrasound
 Isotope scan shows areas of increased and decreased
uptake in sporadic fashion
 Antibodies negative
Multinodular goitre
Toxic adenoma

Specific features:

 Affects persons in 30-40 year age group

 Slow growth of nodule over many years
 Toxicity develops when size > 2.5 cm
 Milder thyrotoxicity than in Graves’ disease
 Single nodule on palpation and ultrasound
 Single “hot” nodule on isotope scan, with decreased
uptake in the remainder (unaffected) gland
 Antibodies negative
Thyroiditis

Specific features:

 Any age affected

 May be immune (Hashimoto’s / post-partum) or non-
immune (post-infectious)
 Mild thyrotoxicosis
 Pain over the gland, often referred to the jaw
 Decreased isotope uptake
 Antibodies variable (depends on type)
 Often self-limiting
 May progress to hypothyroidism
Hashimoto’s Thyroiditis
Thyrotoxicosis: Treatment

Treatment options

1. Symptomatic
2. Anti-thyroid drug therapy
3. Surgery
4. Radioactive Iodine
Symptomatic therapy
Beta-blockers:

 Propranolol or atenolol
 Control heart rate and tremor
 Limited effect on reducing conversion of T4 to T3
 Remember contra-indications:
- ASTHMA and COPD
- Cardiac failure
- Peripheral vascular disease
- Myasthenia gravis
- Heart block
Anti-thyroid drugs
Carbimazole (Neomercazole®)

 Inhibits formation of thyroid hormones

 Possible immuno-modulatory effect
 Indications:
- Young person (< 40 years) with Graves’ disease
- Thyrotoxicosis in pregnancy
- Preparation for surgery
- Cardiac failure
- Thyroid crises
 Adverse effects:
- Skin rash
- Neutropaenia, thrombocytopaenia
- Arthralgia, hepatitis, cholestasis
Radioactive Iodine
131 Iodine

 Taken up by thyroid, local emission of radiation

 Radiation slowly destroys thyroid tissue
 > 80% development of hypothyroidism
 Dose: 5 – 15 milli-Curies (mCi)
 Indications:
- Graves’ disease
- Toxic multinodular goitre
- Small (< 6cm) toxic adenoma

 Contra-indications:
- PREGNANCY & LACTATION
- Severe ophthalmopathy
Radioactive Iodine

Points to note

 Graves’ infiltrative ophthalmopathy may increase

after 131 Iodine – this is ameliorated by concomitant
use of corticosteroids (prednisone)
 Onset of activity is slow (6 weeks)
 Anti-thyroid drugs may be used whilst awaiting
response
 Doses may be repeated after at least a 6 month
period
Surgery: Sub-total thyroidectomy

Indications:
- Large goitre with compression
- Patient preference
- Pregnancy (mid-trimester)
- Failed medical therapy

Preparation:
- Subject must be euthyroid (carbimazole, Lugol’s
Iodine, beta blocker)

Adverse effects:
- Hypothyroidism
- Hypoparathyroidism
- Recurrent laryngeal nerve injury
Selection of Therapy

Graves’ disease
 Young person (< 20 years) – medical therapy
 Older person – 131 Iodine (or trial medical therapy)
 Surgery – patient preference, large goitre
 Failed medical therapy - 131 Iodine

Toxic multinodular goitre

 131 Iodine or surgery

Toxic adenoma
 131 Iodine (< 6 cm); surgery (> 6 cm)

Thyroiditis
 Symptomatic or large dose 131 Iodine (Hashimoto’s)
Thyroid Crisis / Thyroid Storm

 Exaggeration of thyrotoxic state; medical emergency

 Due to very high levels of thyroid hormones

 Scoring system introduced to standardise the diagnosis

(Burch and Wartofsky: Endocrinol Metab Clin

North Am 1993; 22(2): 263-277)

• A score of ≥ 45 is diagnostic
• A score of 25 to 44 suggests impending thyroid
storm
Thyroid Crisis / Thyroid Storm
Parameter Scoring points

Temperature (0C)
37.2 to 37.7 5
37.8 to 38.0 10
38.1 to 38.8 15
38.9 to 39.4 20
39.5 to 39.9 25
≥ 40.0 30
CNS Effects
Absent 0
Agitation 10
Delirium, psychosis, extreme lethargy 20
Seizures or coma 30
GIT Effects
Absent 0
Diarrhoea, nausea/vomiting, pain 10
Unexplained jaundice 20
Thyroid Crisis / Thyroid Storm
Parameter Scoring points

Pulse rate (bpm)

90 to 109 5
110 to 119 10
120 to 129 15
≥130 25
Heart Failure
Absent 0
Mild (pedal oedema) 5
Moderate (basal crackles) 10
Severe (pulmonary oedema) 15
Atrial Fibrillation
Absent 0
Present 10
Precipitant
Absent 0
Present 10
Thyroid Crisis / Thyroid Storm
Management:

• ICU placement; supportive therapy

• Carbimazole 25 mg 6 hourly po
• Lugol’s Iodine 4-8 drops 6 hourly po
• Propranolol 80 to 120 mg 6 hourly po
• Hydrocortisone 100 mg 8 hourly ivi
• Atrial fibrillation treated if present (digoxin / amiodarone)
• Alternatives:
 Lithium carbonate 300 mg 8 hourly po
 Potassium perchlorate 1 g daily po
 Cholestyramine 4 g 6 hourly po
 Plasmapheresis
Graves’ orbitopathy

Uncommon component of Graves’ disease

Risk factors for development:

• Cigarette smoking – strong association

• Uncontrolled and severe hyperthyroidism
• Radioactive Iodine
• Hypothyroidism

Pathogenesis:

• Largely unknown
• Cross reactivity of thyroid and orbital antigens
Graves’ orbitopathy
Clinical assessment:

1. Assess activity *:
• Spontaneous retrobulbar pain
• Pain on attempted up– or down-gaze
• Redness of the eyelids
• Redness of the conjunctiva
• Swelling of the eyelids
• Inflammation of the caruncle and / or plica
• Conjunctival oedema

≥ 3 out of 7 = ACTIVE eye disease

* Clinical Activity Score

Graves’ orbitopathy

2. Assess severity

MILD Minor impact on daily life

Lid retraction < 2mm
Exophthalmos < 3 mm
Transient or no diplopia
Corneal dryness responds to topical

MODERATE Lid retraction ≥ 2 mm

Exophthalmos ≥ 3mm
Moderate to severe soft tissue swell
Constant diplopia
Impact justifies use of immune
suppression
Graves’ orbitopathy

2. Assess severity (cont)

SEVERE (SIGHT-THREATENING):

Dysthyroid optic neuropathy and / or corneal

breakdown

REQUIRES IMMEDIATE REFERRAL

Graves’ orbitopathy

Indications for referral:

• Unexplained deterioration in vision

• Change in colour vision in one or both eyes
• History of the eye “popping” out (subluxation)
• Corneal breakdown
• Optic disc swelling
• Poor response to 1-2 months of treatment
• Cosmetic concern
All patients with Graves’ orbitopathy
• Restore euthyroidism
• Urge cessation of smoking
• Refer all except mildest cases

MILD MODERATE SEVERE

Local measures ACTIVE INACTIVE iv Steroids

Observation
iv Steroids
(± radiation) Poor response
in 2 weeks

Decompressive
surgery

Still active

iv Steroids
(± radiation)

Rehabilitative surgery if needed when inactive

Graves’ orbitopathy
Steroid therapy:

• Methylprednisolone 500 mg once weekly x 12

• Limit total dose to 8 g
• Risk of liver necrosis if dose exceeded
• Oral prednisone less effective
• Bisphosphonates recommended

Orbital Radiation:

• 10 Gy total dose adequate

• Care < 35 years
• Contraindicated with diabetic retinopathy and
severe hypertension
• Oral prednisone recommended with radiation