Underactive thyroid The diagnosis and management of primary

hypothyroidism Kristien Boelaert

Senior Clinical Lecturer and Consultant Endocrinologist University of Birmingham, UK

k.boelaert@bham.ac.uk

http://images.google.co.uk/imgres?imgurl=http://postgrad.eee.bham.ac.uk/Schwirtza/index_files/unilogo4.jpg&imgrefurl=http://postgrad.eee.bham.ac.uk/Schwirtza/&usg=__nEI6zj8JA3YOwrQTHaz4ldDW9ec=&h=512&w=578&sz=46&hl=en&start=7&itbs=1&tbnid=KzmY3fxadUY7-M:&tbnh=119&tbnw=134&prev=/images?q=university+of+birmingham+uk&gbv=2&hl=en

Thyroid gland

Located in neck

Brownish-red

25-30 g

Right and left lobe

Joined by isthmus

Thyroid gland

Thyroid hormones

Control of metabolism:

energy generation and use

Regulation of growth

Important in development

Thyroid hormones

T3 is biologically active hormone

T4 produced in highest quantity

Deiodinase enzymes convert T4 to T3 in tissues

Thyroid binding proteins

T4 T3

TBG

TBPA Albumin

Free T4: 0.03%

Deiodination

TBG

TBPA Albumin

Free T3: 0.3%

Thyroid hormones are bound to proteins

Control of thyroid hormone synthesis

Hypothalamus

Pituitary

TRH

TSH

-ve +ve

+ve

Thyroid

Target Tissue

T4 T3

-ve

-ve

T3

Serum TSH

Serum free T4

Serum free T3

Tests of thyroid function

Serum TSH

Serum free T4

Serum free T3

Serum TSH

Serum free T4

Serum free T3

Hyperthyroidism Hypothyroidism

Overactive Underactive

Hypothyroidism

Hypothyroidism

Occurs in 3.8-4.6% of population

Most common endocrine disease

10 times more common in women

Incidence rising

2010: 23 million prescriptions for levothyroxine in UK – 3rd most prescribed medication

Causes of hypothyroidism

Autoimmune – Hashimoto’s thyroiditis: genetic predisposition and antibodies (anti-TPO and anti-Tg)

Iodine deficiency

Following treatment for hyperthyroidism

Subacute/silent thyroiditis: inflammation of thyroid gland

Congenital (incomplete thyroid gland development/enzyme defects)

Drugs: amiodarone, lithium

Hashimoto’s thyroiditis

Hashimoto’s thyroiditis

Normal thyroid gland

Inflammation and

goitre/swelling

Fibrosis and shrinkage

Iodine deficiency

Major cause of goitre and hypothyroidism world-wide

WHO identified in 7% of world’s population

Range from near 0% (Japan) to 80% (Andes, Zaire)

UK iodine deficiency Common in many areas

up to 1960’s

Main source of iodine is from milk and dairy products

Evidence for iodine deficiency in vegans

Daily iodine increased from 80 to 255g/day

UK Iodine status

Vanderpump et al. (2011) Lancet 377, 2007

Treatment options for hyperthyroidism

• Antithyroid drugs to block hormone synthesis

• Radioiodine (131I) therapy

• Surgical removal of thyroid

Outcome following 131I therapy

1278 patients treated with 131I for hyperthyroidism

Single fixed dose of 131I

Boelaert et al. (2009) Clin End 70, 129

Symptoms and signs of hypothyroidism

Cardiovascular

Slow heart rate

Heart failure

Gastrointestinal

Weight gain

Constipation

Skin

Myxoedema (puffiness of skin)

Hair loss

Dry skin

Neurological

Tiredness

Depression

Psychosis

Clinical features of hypothyroidism

Vitiligo

Diagnosis: symptoms

Sensitivity of individual symptoms: 2.9-24.5%

Likelihood increases with more symptoms

Absence of symptoms does not exclude diagnosis

Many symptoms are non-specific

Colorado Thyroid Prevalence Study

Canaris et al. (2000), Arch Int Med 160: 526

Biochemical diagnosis

Serum TSH

Serum free T4

Serum free T3

Normal TSH reference range: 0.4-4.5 mU/l

Use trimester-specific reference ranges in pregnancy

TSH distribution influenced by age

Upper serum TSH concentrations

Surks and Hollowell (2007) JCEM 92: 4575

Physiological changes to thyroid function with age

Biochemical diagnosis

Measure serum TFT not other bodily fluids

No evidence to support measurement of basal body temperature

Other illnesses may affect test results

Different methods may give different results

Support for harmonisation of reference ranges

RCP updated statement 2011

Treatment of hypothyroidism

Levothyroxine (T4) replacement

7 day half-life

Initiation at full dose safe except in elderly or patients with known heart disease (1.6μg/kg/day)

Take on empty stomach 30 mins before breakfast

Bedtime dosage of levothyroxine

Better biochemical control

No improvements in quality of life, blood pressure, lipid profiles

Bolk et al (2010) Arch Int Med 170: 1996

Monitoring of thyroid function

Stabilisation of TFT may take up to 4 months

Measure serum TSH 6-8 weeks after initiation/dose change

Annual TFT if on stable dose

Aim of treatment is to restore patient to euthyroid state

Symptoms usually recover

Fine-tuning may be required in individual patients

Causes of persistently raised serum TSH

Chakera et al (2011) Drug des, dev and therapy 6: 1

Drug interactions with L-T4

Chakera et al (2011) Drug des, dev and therapy 6: 1

Continued symptoms and biochemical euthyroidism

Investigate further for other causes

Think of associated autoimmune disorders

Hypothyroidism and dysphoria are common

Associated autoimmune disorders

Boelaert et al. (2010) Am J Med 123, 183.e1

Efficacy of T4 replacement

Audit of 18,944 prescribing records in general practice

Prevalence of T4 therapy 0.8% (3.6% > 60y)

Abnormal TFT in those prescribed T4

Low TSH in 20.6% (undetectable in 7%)

High TSH in 26.8%

T4 dose (g) High TSH Low TSH

150 25% 25%

Parle et al 1993 Br J Gen Pract, 43, 107

T3/T4 combination

Initial study from Lithuania: improvement in well-being

Meta-analysis of 11 RCT: no effect on bodily pain, depression, anxiety, quality of life, weight, lipid profile

Current T3 formulation does not result in normal physiological profile

Not recommended by national and international guidelines

? Genetic predisposition to benefiting from combination Rx

T3/T4 combination

Grozinsky-Glasberg JCEM 2006, 91, 2592

Desiccated pig thyroid extract

Contains T4:T3 in 4:1 ratio – physiological ratio 14:1

Higher than physiological doses of T3

No good evidence to support T3 mono therapy

Dangers of too much T3: heart, osteoporosis