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

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.

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?

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

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

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 Prevention of progression to overt hypothyroidism To reverse symptoms 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 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: 18-24 2Nystrom et al. Clin Endo (Oxf) 1988; 29: 63-75 3Jaeschke 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: 631-42 2Danese et al. JCEM 2000; 85: 2993-3000 3Vanderpump et al. Clin Endo (Oxf) 1995; 43: 55-68

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

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 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?

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 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

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

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: 197-204 2Sawin et al. NEJM 1994; 331: 1249-52 3Forfar et al. Int J Cardiol 1981; 1: 43-8

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: 35-9 2Foldes et al. Clin Endo (Oxf) 1993; 39: 521-7 3Bauer et al. Ann Intern Med 2001; 134(7):561-8 4Biondi et al. JCEM 2000; 85: 4701-5

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

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 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?

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