Download Thyroid Disease

Subclinical thyroid disease
Thomas Galliford
Consultant 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.
2.
Do we treat?
Should we treat?
3.
4.
What are our expectations of treatment?
What should patients expect?
5.
6.
What are the benefits of treatment?
What are the risks of treatment?
Hypothalamic-pituitary-thyroid axis
HYPOTHALAMUS
TRH
T3
PITUITARY GLAND
TSH
THYROID
GLAND
THYROID HORMONES
T4 + T3
Systemic effects
-ve
feedback
loop
T3
Thyroid hormone action in target cells
D3
T4
rT3
T4
D2
MCT-8
D3
T3
T2
T3
NUCLEUS
T3 effects
T3
Legend
D2 – type II iodothyronine
deiodinase
D3 – type III iodothyronine
deiodinase
MCT-8 – monocarboxylase
transporter-8
RXR – retinoid X receptor
TRE – thyroid response
element
R
X
R
T3
transcription
T
R
mRNA
Protein
TRE
T3 responsive gene
CYTOPLASM
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
2Hollowell
et al. Clin Endo (Oxf) 1977; 7(6): 481-93
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 therapy
1. 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: 63-75
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
et al. Clin Endo (Oxf) 1988; 29: 63-75
2Nystrom
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
et al. JCEM 2000; 85: 2993-3000
3Vanderpump et al. Clin Endo (Oxf) 1995; 43: 55-68
2Danese
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.
2.
Do we treat?
Should we treat?
3.
4.
What are our expectations of treatment?
What should patients expect?
5.
6.
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
– 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
–
2.
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
et al. NEJM 1994; 331: 1249-52
3Forfar et al. Int J Cardiol 1981; 1: 43-8
2Sawin
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)
–
–
Other CV abnormalities4
4.
–
–
–
1Mudde
Increased LV mass
Increased systolic BP
Impaired diastolic function
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
1.
Reduce T4 and repeat TFTs
N.B. thyroid cancer
•
Endogenous subclinical hyperthyroidism
1.
2.
3.
4.
5.
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
1.
2.
Do we treat?
Should we treat?
3.
4.
What are our expectations of treatment?
What should patients expect?
5.
6.
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