Subclinical thyroid disease Thomas Galliford Consultant Physician and Endocrinologist West Herts NHS Trust.

Subclinical thyroid disease

Thomas GallifordConsultant Physician and Endocrinologist

West Herts NHS Trust

Definitions

• Hypothyroidism– impaired production or secretion of thyroid hormones.

• Thyrotoxicosis– biochemical and physiological manifestations of excessive

quantities of the thyroid hormones.

• Subclinical hypothyroidism– Subclinical hypothyroidism refers to mildly increased serum TSH

(or thyrotropin) levels in the setting of normal free thyroid hormone concentrations.

• Subclinical hyperthyroidism

– serum TSH (or thyrotropin) ≤ 0.1mU/l and normal serum free thyroid hormone concentrations.

Subclinical thyroid disease - management decisions

1. Do we treat? 2. Should we treat?

3. What are our expectations of treatment?4. What should patients expect?

5. What are the benefits of treatment?6. What are the risks of treatment?

Hypothalamic-pituitary-thyroid axis

Systemic effects

PITUITARY GLAND

THYROIDGLAND

THYROID HORMONEST4 + T3

TSH

-vefeedback

loop

HYPOTHALAMUS

TRH

T3

T3

D2

CYTOPLASM

transcription

T4

T3

T3

T4

T3

rT3

T2

mRNA

D3

D3MCT-8

Protein

T3 effects

NUCLEUS

D2

RXR

TR

T3

TRE

T3 responsive gene

LegendD2 – type II iodothyronine deiodinaseD3 – type III iodothyronine deiodinaseMCT-8 – monocarboxylase transporter-8RXR – retinoid X receptorTRE – thyroid response element

Thyroid hormone action in target cells

Subclinical hypothyroidism• Biochemistry:

– TSH↑, fT4 and fT3 normal• Prevalence:

– Whickham study1

• 2779 people• Overt hypothyroidism 19/1000• Subclinical hypothyroidism 5.9% < 45yrs

10.4% > 45yrs 17.4% > 75yrs– NHANES2

• 16533 people• Subclinical hypothyroidism 4.3%

• Presentation: – routine screening– evaluation of common non-specific symptoms– (investigation of hypercholesterolaemia)

1Tunbridge et al. Clin Endo (Oxf) 1977; 7(6): 481-93 2Hollowell et al. JCEM 2002; 87(2): 489-499

Causes• Normal

• Predominant cause autoimmune thyroid disease (Hashimoto’s)

• Causes to exclude: – artifactual e.g. heterophilic antibodies → assay error– non-compliance with T4 replacement– severe non-thyroidal illness– chronic renal failure– primary adrenal failure– RTH

• Risks factors: – treated hyperthyroidism– Hx of neck irradiation– co-existent autoimmune disease– medication e.g. lithium, amiodarone

Aims of therapy

1. Prevention of progression to overt hypothyroidism

2. To reverse symptoms

3. Improve lipid profile and reduce cardiovascular risk

Aims of therapy - 1

• Prevention of progression to overt hypothyroidism– Whickham follow-up1

• ♀ elevated TSH and +ve Abs = 4.3%/yr (38x risk of ♀ TSH N, 0Abs)

• ♀ elevated TSH and -ve Abs < 3%/yr

1Vanderpump et al. Clin Endo (Oxf) 1995; 43: 55-68

Aims of therapy - 2• To reverse symptoms

– If symptoms are present, common and non-specific

– symptoms are not necessary to make the diagnosis

– 4 randomized prospective placebo-controlled trials (Health related QoL scores, psychometric testing, symptom scores)

→ 2 statistically significant benefit 1. 33 patients – double blind trial for 1 yr - 8/14 with T4 Rx vs

3/12 with placebo1

2. Double blind crossover trial 1yr - 17 women 4/17 benefited2

→ 2 no benefit to therapy1. 37 patients – randomised double blind3

2. 40 women (TSH 5-10) – 6 month randomised trial4

1Cooper et al. Ann Int Med 1984; 101: 18-24 2Nystrom et al. Clin Endo (Oxf) 1988; 29: 63-753Jaeschke et al. J Gen Int Med 1996; 11: 744-9 4Kong et al. Am J Med 2002; 112(5): 348-54

• Reverse symptoms contd– Data are inconsistent with suggestions of improved memory,

increased peripheral nerve function, improved fertility, improved hypothyroid symptoms

– Body weight does not decrease with thyroxine therapy1,2

1Cooper et al. Ann Int Med 1984; 101: 18-24 2Nystrom et al. Clin Endo (Oxf) 1988; 29: 63-75

Aims of therapy - 3

• Improve lipid profile and reduce cardiovascular risk– cross-sectional studies have shown an increase in serum total

cholesterol and LDL-cholesterol in patients with subclinical hypothyroidism1

• 69 patients

– Meta-analysis showed a mean reduction in total cholesterol 0.2mmol/l, LDL-chol 0.26mmol/l with treatment of subclinical hypothyroidism2

• 250 patients

– Whickham 20yr follow-up3

→ rates of death from all causes or CV risk not significantly higher than euthyroid individuals

1Staub et al. Am J Med 1992; 92: 631-422Danese et al. JCEM 2000; 85: 2993-30003Vanderpump et al. Clin Endo (Oxf) 1995; 43: 55-68

Treatment

• Low dose T4– 25µg - 50µg– Suppress TSH into normal range– Annual TFTs subsequently

• Risks of T4 therapy– Poor compliance1

→ 27% patients overtreated

1Parle et al. Br J Gen Pract 1993; 43(368): 107-9

Recommendations/Guidelines

• Investigate other causes where appropriate and treat• BTA:

– individual clinical evaluation and discussion between patient and doctor

• Consensus statement RCP and SfE1:– antibody +ve Rx; monitor if TSH 5-10mU/l; treat if >10mU/l

• ATA/AACE guidelines 2006: – In patients with microsomal (thyroid peroxidase) antibodies

treatment with thyroxine is recommended, as the conversion rate from subclinical to overt hypothyroidism is around 5% a year

– In patients whose serum thyroid stimulating hormone concentration is only slightly raised (less than 10 mU/l) without thyroid antibodies it is acceptable to defer treatment provided that secure follow up can be achieved as the conversion rate to overt hypothyroidism is less than 3% a year

1Vanderpump et al. BMJ 1996; 313: 539-44

Subclinical hypothyroidism - management decisions

1. Do we treat? 2. Should we treat?

3. What are our expectations of treatment?4. What should patients expect?

5. What are the benefits of treatment?6. What are the risks of treatment?

Other controversial areas

• Screening• Pregnancy – beware!

Subclinical hyperthyroidism

• Biochemistry: – TSH ↓ (≤ 0.1mU/l), fT3 and fT4 normal→ Biochemistry reflects the fact that before clinical features of thyrotoxicosis are present, pituitary thyrotrophs are responding to minor increments in thyroid hormones and switching off TSH production.

• Presentation: – routine screening– subtle symptoms and signs of thyrotoxicosis

• Prevalence: – difficult to estimate– 1210 patients > 60yrs at single GP practice 1.3%1

1Parle et al. Clin Endo(Oxf) 1991; 34: 77-83

Aetiology

• Exogenous – overtreatment with T4 (thyrotoxicosis factitia)

• Endogenous – underlying thyroid disease

• Other causes– medication e.g. dopamine, steroids, amiodarone– Hyperemesis gravidarum

• Aetiology to exclude– central/secondary hypothyroidism

Endogenous subclinical hyperthyroidism - aetiology

1. Multinodular goitre

2. Underlying Graves’ disease

→ needs investigation and diagnosis

Ix: clinical examination +/- uss uptake scan

autoantibodies

Risks of subclinical hyperthyroidism

1. Progression to overt hyperthyroidism– 2ary to MNG = 5%/yr1

2. Atrial Fibrillation– Framingham2

• cohort 2007 persons ≥ 60yrs, 10-yr f/u• 61 subclinical hyperthyroidism RR of AF 3.1 compared to

biochemically euthyroid group

– Limited evidence that in patients with subclinical hyperthyroidism in established AF revert to SR once Rxed or DCCV3

– Increased risk of systemic embolism in thyrotoxic patients with AF (?around 10% increase)

1Wiersinga. Neth J Med 1995; 46: 197-2042Sawin et al. NEJM 1994; 331: 1249-523Forfar et al. Int J Cardiol 1981; 1: 43-8

Risks of subclinical hyperthyroidism

3. Osteoporosis– Thyrotoxicosis is a recognised risk factor for OP– ATA also regards subclinical hyperthyroidism as a risk factor

for OP– Reduction in BMD at neck of femur and radius in patients with

subclinical hyperthyroidism 2ary to MNG compared 1,2

– Increased # risk3 → suppressed TSH from any cause increases fracture risk 3-4 fold in post-menopausal ♀ (n=686)

4. Other CV abnormalities4

– Increased LV mass– Increased systolic BP– Impaired diastolic function

1Mudde et al. Clin Endo (Oxf) 1992; 37: 35-9 2Foldes et al. Clin Endo (Oxf) 1993; 39: 521-73Bauer et al. Ann Intern Med 2001; 134(7):561-8 4Biondi et al. JCEM 2000; 85: 4701-5

Treatment

• Exogenous subclinical hyperthyroidism 1. Reduce T4 and repeat TFTs

N.B. thyroid cancer

• Endogenous subclinical hyperthyroidism1. Monitor every 6 months; Ix complications2. Antithyroid drugs3. 131I4. Surgery 5. Warfarinise if AF

Recommendations/Guidelines

• Consensus statement RCP and SfE1: – no consensus on whether patients with subclinical

hyperthyroidism should receive treatment• American College of Physicians:

– no guidance• BTA:

– individual clinical evaluation and discussion between patient and doctor, although there is a consensus that treatment may be worthwhile in the elderly (AF, #) decision needs to be based upon individual case

• AACE recommendations:– all patients with subclinical hyperthyroidism should undergo

periodic clinical and laboratory assessment to determine individual therapeutic options.

• ATA 2006:– Subclinical hyperthyroidism has been shown to affect the health

of untreated patients adversely,and subclinical hypothyroidism may also have important health consequences.

1Vanderpump et al. BMJ 1996; 313: 539-44

Subclinical hyperthyroidism - management decisions

1. Do we treat? 2. Should we treat?

3. What are our expectations of treatment?4. What should patients expect?

5. What are the benefits of treatment?6. What are the risks of treatment?

Summary• Discussed thyroid hormone action, subclinical hypothyroidism and

subclinical hyperthyroidism

• Aetiology is important as it directs management and therefore further investigation is warranted

• Subclinical hypothyroidism– Benign condition

– Symptoms not to be relied on and may not improve with treatment

– Check thyroid antibodies; watching and waiting is an acceptable Rx option

– Benefits and risks of treatment relatively low

– Beware if patient pregnant!

Summary - 2

• Subclinical hyperthyroidism– Less likely to be a benign condition because of aetiology and

complications more severe

– Much lower tendency to treat than subclinical hypothyroidism

– Benefits and risks of treatment much higher

– Suggest referral to an endocrinologist