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

2. Definitions Hypothyroidism Thyrotoxicosis Subclinical 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.

3. Subclinical thyroid disease - management decisions
Do we treat?
Should we treat?
What are our expectations of treatment?
What should patients expect?
What are the benefits of treatment?
What are the risks of treatment?

4. Hypothalamic-pituitary-thyroid axis
HYPOTHALAMUS
TRH T3
PITUITARY GLAND
TSH ve
feedback
loop T3
THYROID
GLAND
THYROID HORMONES
T4 + T3
Systemic effects

5. Thyroid hormone action in target cells
rT3
MCT-8 D2 D2 D3 T3 T3 T2
NUCLEUS T3
T3 effects R X T R T3
Legend
D2 – type II iodothyronine
deiodinase
D3 – type III iodothyronine
MCT-8 – monocarboxylase
transporter-8
RXR – retinoid X receptor
TRE – thyroid response
element
transcription
mRNA
Protein
TRE
T3 responsive gene
CYTOPLASM 5

6. 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):
2Hollowell et al. JCEM 2002; 87(2):

7. 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

8. Aims of therapy Prevention of progression to overt hypothyroidism
To reverse symptoms
Improve lipid profile and reduce cardiovascular risk

9. 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

10. 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
33 patients – double blind trial for 1 yr - 8/14 with T4 Rx vs 3/12 with placebo1
Double blind crossover trial 1yr - 17 women 4/17 benefited2
→ 2 no benefit to therapy
37 patients – randomised double blind3
40 women (TSH 5-10) – 6 month randomised trial4
1Cooper et al. Ann Int Med 1984; 101: Nystrom et al. Clin Endo (Oxf) 1988; 29: 63-75
3Jaeschke et al. J Gen Int Med 1996; 11: Kong et al. Am J Med 2002; 112(5):

11. 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

12. 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:
2Danese et al. JCEM 2000; 85:
3Vanderpump et al. Clin Endo (Oxf) 1995; 43: 55-68

13. Treatment Low dose T4 Risks of T4 therapy 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

14. 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:

15. Subclinical hypothyroidism - management decisions
Do we treat?
Should we treat?
What are our expectations of treatment?
What should patients expect?
What are the benefits of treatment?
What are the risks of treatment?

16. Other controversial areas
Screening
Pregnancy – beware!

17. 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

18. Aetiology Exogenous Endogenous Other causes Aetiology to exclude
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

19. Endogenous subclinical hyperthyroidism - aetiology
Multinodular goitre
Underlying Graves’ disease
→ needs investigation and diagnosis
Ix: clinical examination
+/- uss
uptake scan
autoantibodies

20. Risks of subclinical hyperthyroidism
Progression to overt hyperthyroidism
2ary to MNG = 5%/yr1
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:
2Sawin et al. NEJM 1994; 331:
3Forfar et al. Int J Cardiol 1981; 1: 43-8

21. Risks of subclinical hyperthyroidism
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)
Other CV abnormalities4
Increased LV mass
Increased systolic BP
Impaired diastolic function
1Mudde et al. Clin Endo (Oxf) 1992; 37: Foldes et al. Clin Endo (Oxf) 1993; 39: 521-7
3Bauer et al. Ann Intern Med 2001; 134(7): Biondi et al. JCEM 2000; 85:

22. Treatment Exogenous subclinical hyperthyroidism N.B. thyroid cancer
Reduce T4 and repeat TFTs
N.B. thyroid cancer
Endogenous subclinical hyperthyroidism
Monitor every 6 months; Ix complications
Antithyroid drugs
131I
Surgery
Warfarinise if AF

23. 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:

24. Subclinical hyperthyroidism - management decisions
Do we treat?
Should we treat?
What are our expectations of treatment?
What should patients expect?
What are the benefits of treatment?
What are the risks of treatment?

25. 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!

26. 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