Normal TSH levels: Still an elusive goal?
Belgian Thyroid Club 36th meetingMay 29th 2010
Bernard Corvilain Hôpital Erasme ULB
● Serum TSH is the most sensitive index of thyroid function ► It’s important to determine a reference range or better a “normal” or “optimal” range for TSH
Reference intervals are not equivalent to optimal ranges
● Reference intervals: Limits for a biological parameter between which 95% of the « normal » population is included. It only denotes what are usual values in the population, and does not directly correlate with the ranges for optimal health
Reference intervals
95 %
Reference range
Exclusion of 2.5% ofIndividuals with the
lowest results
Exclusion of 2.5% ofIndividuals with the
highest results
Normal distribution of a biological value:bell shaped curve
Lower limit Upper limit
Reference intervals ≠ optimal ranges
● Optimal range: Range for a biological parameter considered as optimal in terms of health or related complications and diseases– The example of cholesterol
Optimal t-cholesterol< 190 mg/dl
Reference rangeoptimal range
● The difficulty in establishing TSH reference intervals is the choice of the « normal » euthyroidpopulation: age, ethnicity, iodine intake, underlying medical condition and the choice of a reproducible TSH assay
● The difficulty in establishing TSH optimal rangeis to determine which level of TSH is associated with optimal health
TSH reference intervals
● TSH reference intervals should be established from the 95% confidence limits of the log transformed values of at least 120 screened normal volunteers who have:– No detectable thyroid autoantibodies– No personal or family history of thyroid disease– No visible or palpable goiter– No medications except estrogens
~0.3 C Spencer
TSH reference intervals
● General agreement on TSH lower limit ~ 0.4 µU/ml
● A lot of discussion on TSH upper limit: 2.5 µU/ml ? 4 µU/ml?
● General agreement that specific ranges are needed according to age, ethnicity, iodine intake or underlying medical condition
TSH reference intervals
Influence of age
Copyright ©2007 The Endocrine Society
Surks, M. I. et al. J Clin Endocrinol Metab 2007;92:4575-4582
TSH distribution by age groups in the United States: NHANES III study
TSH < 0.4:
2.7 % (20-29)0.9% (50-59)2.6% (80+)
TSH > 4.5:
2.0 % (20-29)3.1 % (50-59)12% (80+)
TSH reference intervals
Influence of ethnicity
Boucai L, Surks MI. Reference limits of serum TSH and free T4 are significantly influenced by race and age in an urban outpatient medical practice. Clin Endocrinol (Oxf) 2009;70:788-93
7.46
5.25
0.24 0.20
TSH reference intervals
Influence of iodine nutrition status
Copyright ©1998 The Endocrine Society
Laurberg, P. et al. J Clin Endocrinol Metab 1998;83:765-769
Influence of iodine status on TSH distribution > 65 yr
Iceland population(relatively high iodine intake)
Jutland population(relatively low iodine intake)
TSH reference intervals
Influence of underlying medical condition (Pregnancy)
0.01
1
2
3
4
5
1.031.23 1.35
First Trimester
(n=7)
0.02
0.530.120.03 0.09
0.310.20
3.67
2.152.51
2.93
4.16
4.80
Second Trimester
(n=5)
Third Trimester
(n=2)
Serum TSH(mIU/L)
6
0.4
4.1
TSH reference intervals during pregnancy
Median
Upper referencelimit
Lower referencelimit
By courtesy ofDaniel Glinoër
0.4
TSH reference intervals
● TSH lower reference limit: ~ 0.4 µU/ml
● It is not possible to establish a universal TSH upper limit. It will depend upon the population being studied, the underlying pathology and iodine intake of that population. ~ 4 µU/ml ?
TSH normal (optimal) values
Is there a morbi-mortality associated with TSH value outside the reference
range?
● Is it harmful to be below the lower limit of TSH?
● Is it harmful to be above the upper limit of TSH ?
Cumulative Incidence of Atrial Fibrillation according to basal thyroid status
JAMA: Vol. 295 No. 9 2006
Subclinical hyperthyroidism and mortality
Subclinical Hypothyroidism and mortality
Is there a morbi-mortality associated with TSH value outside the reference
range?
● Is it harmful to be below the lower limit of TSH? YES
● Is it harmful to be above the upper limit of TSH ? No definitive data. Importance of age
Is there a morbidity associated with TSH values within the
normal range?
● Thyroid cancer (TSH growth factor)
● Cholesterol● BMI Thyroid function● Osteoporosis● Atrial fibrillation
Copyright ©2006 The Endocrine Society
Boelaert, K. et al. J Clin Endocrinol Metab 2006;91:4295-4301
TSH within the normal range and prevalence of malignancy in a thyroid nodule
TSH within the normal range and risk of malignancy in a thyroid nodule
TSH values within the normal range and Cholesterol (Hunt Study)
Asvold et al EJE 2007 156: 181-186
♂: 2.4% (1.7-3.2)change in non HDL cholesterol
per 1 µU/ml TSH change♀: 1.7% (1.2-2.3)
TSH values within the normal range and BMI
Knudsen, N. et al. J Clin Endocrinol Metab 2005;90:4019-4024
TSH values within the normal range and bone mineral density
Bone 2007 40: 1128-1134
TSH within the normal range and atrial fibrillation
High-Normal Thyroid Function and Risk of Atrial Fibrillation: The Rotterdam Study
● Prospectively investigate the role of parameters of thyroid function in the development of Atria Fibrillation in euthyroid patients– part of the population-based Rotterdam Study– 1426 participants– Age > 55 yrs– TSH interval 0.4-4 µU/ml– median follow-up of 8 years
Arch Intern Med. 2008;168(20):2219-2224
Serum TSH level and risk of atrial fibrillation (The Rotterdam study)
00,20,40,60,8
11,21,41,61,8
2
0,4-1,04
1,05-1,51
1,52-2,16
2,17-3,98
Risque de FA(HR)
TSH value (µU/ml)
P value for trend 0,02
105 new cases of atrial fibrillation were identified
Serum FT4 level and risk of atrial fibrillation (The Rotterdam study)
00,20,40,60,8
11,21,41,61,8
11-14,4 14,5-15,9
16-17,9 18-25
Risque de FA(HR)
FT4 value (pmol/L)
P value for trend 0,06
● The range of variation of thyroid hormone within an individual are within narrow limits by comparison with variation between individuals ► even values within the population reference range can be abnormal for an individual patient. Each individual has his own set point
Popu
latio
n re
fere
nce
rang
e
Subclinical hypo ?
Subclinical hyper ? Popu
latio
n re
fere
nce
rang
e
Conclusions (1) ● If we accept the data, there is no optimal value for TSH● The increase in thyroid cancer risk could be due to trophic
effect of TSH● The influence of TSH on other parameters could be due to
small differences in thyroid function i.e small differences in T3 nuclear receptor activation
● A normal low TSH level could have a favorable impact on cholesterol, weight and thyroid cancer, a negative impact on osteoporosis and atrial fibrillation and no impact on other factors
N Sarkosy B Obama
Conclusions (2)● Several weaknesses in these studies
– Only one measurement of TSH at baseline– TSH value may be modified by intercurrent disease– Cross-sectional >> prospective studies– Relation of TSH with non independent variables (BMI,
Cholesterol, Osteoporosis, age …) – A lot of correlations…. And correlation between two
variables does not imply a causal connection
Theory of the stork
Storks bring babies….
Relation between the number of brooding storks in Germany and the number of new born babies between
1965 and 1980
Nature 332, 495 (7 April 1988) | A new parameter for sex educationHELMUT SIES
Conclusions (3)● The upper TSH reference limit is not necessary the
therapeutic threshold for initiating T4 replacement therapy particularly in old patients
● Interventional studies are needed if we want to establish a causal relationship between TSH within the normal ranges and other parameters
● If these results are explained by slight differences in T3 receptor activation, it underline the importance of clinical trials with selective T3 analogs to test in obesity or hypercholesterolemia or in the prevention of atrial fibrillation
Thank youfor your
attention !