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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?
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!