1. New Perspectives on Subclinical Hypothyroidism: A Case-Based Review
Paul W. Ladenson, M.D.
Lebanese Society of Endocrinology, Diabetes & Lipids
Beirut
June 30, 2017
High and high-normal thyroid function is linked to greater risk of developing dementia, but not vascular brain disease, according to research published in Neurology.1
Previous research has outlined a definitive role for thyroid hormone in both brain and cardiovascular (CV) function, and dysfunction has been linked to cardiovascular disease.2,3 Given that CV risk factors are being investigated as possible modifiable risk factors for dementia, researchers led by Layal Chaker, MD, MSc, of Erasmus University Rotterdam, Netherlands, investigated the role of thyroid function in dementia, cognitive decline, and vascular brain disease.
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The study examined a subgroup of 9446 participants (mean age: 65 years) prospectively enrolled into the Rotterdam Study. Researchers used Cox models adjusted for age, sex, CV risk factors, and education to investigate the association between thyroid-stimulating hormone (TSH) and free thyroxine with incident dementia. Linear and logistic regression was used to evaluate the associations between thyroid function, cognitive scores, and subclinical vascular brain disease as seen on MRI.
Over the course of follow-up (mean: 8 years), 601 patients developed dementia (Alzheimer's dementia, n=487). Higher levels of TSH were found to be associated with lower dementia risk for both the full and normal ranges of thyroid function, independent of CV risk factors (hazard ratio [HR]: 0.90, 95% CI, 0.83–0.98; and HR: 0.76, 95% CI, 0.64–0.91, respectively). Participants with higher levels of free thyroxine were found to have greater dementia risk (HR: 1.04, 95% CI, 1.01–1.07).
Higher levels of TSH were associated with better cognitive scores (P =.021), and in older women, a 5% decrease in absolute 10-year dementia risk. Notably, thyroid function was not found to be associated with subclinical vascular brain disease.
The results, the authors concluded, suggest that thyroid hormone impacts dementia risk through nonvascular pathways. Alternate hypotheses proposed by researchers include the possibility that excess free thyroxine may alter gene expression in critical neural pathways or that neurotoxicity secondary to oxidative stress may lead to premature neuronal death.
Additionally, participants with preclinical dementia may exhibit behavioral changes, including diet, which may alter thyroid function. “In other words, we may not be observing a true effect of thyroid hormone on dementia risk but rather the opposite,” the authors concluded.
Ultimately, further research is needed to better understand the pathways in which thyroid function affects dementia risk.

2. Subclinical Hypothyroidism Potential Indications for Therapy
Quality of life, neurocognitive deficits, and mood disorders
Prevent progression to overt hypothyroidism, esp. in antithyroid antibody-positive patients
Maternal and fetal consequences in pregnancy
Cardiovascular risks, including ischemic heart disease and heart failure

3. Case 1: 56 y.o. woman
HPI: Seen by her PCP to evaluate fatigue, difficulty losing weight, and decreased short-term memory. Lab testing showed TSH 5.8 mU/L & FT4 1.0 ng/dL, prompting referral to you.
PE: Tired appearing. Wt 174 lbs, Ht 66”, BMI 29.7 BP 126/82 mm Hg, P 76/min. Thyroid: normal.
Other laboratory data:
TPO antibody 34 IU/mL (normal <100)
TC 180 mg/dL, LDL-C 95 mg/dL HDL-C 70 mg/dL, TG 75 mg/dL

4. Canaris GJ, et al. Arch Int Med 2000;160:526-534.
Hypothyroidism Diagnostic Accuracy of Symptoms & Signs
More symptoms were reported by hypothyroid than euthyroid subjects in this study. Reporting more symptoms, particularly symptoms that had changed in the previous year, increased the likelihood of disease.
Furthermore, there was a positive association between the proportion of symptoms reported and progressive thyroid failure, although the relationship was weak.
Sensitivities were low, so that not reporting a specific symptom did not rule out disease, and poor positive predictive values suggested a high number of false-positive individual symptoms.
Positive predictive values were also low (8%-12%), representing the proportion of all subjects reporting the symptom who also had disease. Likelihood ratios (LRs) were calculated to express the odds that a symptom would be reported by someone with hypothyroidism as opposed to someone who is euthyroid. The LRs for individual symptoms were modest (<2.0). However, when calculated for the overt hypothyroid group, LRs exceeded 2.0 for current constipation and the changed symptom, feeling colder. Multiple logistic regression analysis with disease state (overt hypothyroid or euthyroid) as the dependent variable and the 14 symptoms (age and sex as independent variables) identified 2 significant symptoms (P<.05). These were current constipation and feeling colder than the previous year.
Canaris GJ, et al. Arch Int Med 2000;160:

5. Parle J. et al. J Clin Endocrinol Metab 2010;95:3623-3632
Subclinical Hypothyroidism Mood & Cognition
Double-blind placebo-controlled RCT for 12 mos.
In elderly community-living subjects , they gave placebo or L-T4 in a dose adjusted to achieve a normal TSH
Outcomes: Mini Mental State Exam, Middlesex Elderly Assessment of Mental State (orientation, learning, memory, numeracy, perception, attention, and language skills), and Trail-Making memory tests
Among L-T4-treated subjects, euthyroidism was achieved at 6- and 12-mos. in 82% and 84%.
Parle J. et al. J Clin Endocrinol Metab 2010;95:

6. Parle J. et al. J Clin Endocrinol Metab 2010;95:3623-3632
Subclinical Hypothyroidism Mood & Cognition at 12 mos.
Parle J. et al. J Clin Endocrinol Metab 2010;95:

7. Recent Randomized Clinical Trial
Subclinical Hypothyroidism in the Elderly
Recent Randomized Clinical Trial
NEJM – 3 days ago!

8. Subclinical Hypothyroidism PRCT Assessing Efficacy of L-Thyroxine
Double-blind RCT in 737 adults >65 with TSH mIU/L and normal FT4
10 Outcomes: Hypothyroid Symptoms score & Tiredness QOL score at 1 year
L-T4 (median 50 μg) reduced TSH 6.4 mU/L to 3.6 mU/L
No differences in Hypothyroid Symptoms score or Tiredness score
No beneficial effects seen on 2o outcomes, inc. other QOL; cognition; BP, Wt, BMI, & Waist circ., daily living activities, and fatal & non-fatal CV events.
BACKGROUND The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. METHODS We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxinw.
The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points).
RESULTS: The mean age of the at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], −2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, −2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest.
CONCLUSIONS Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism.
________________
health-related quality of life (as assessed by the EuroQoL [EQ] Group 5-Dimension Self-Report Questionnaire [EQ-5D]; scores on the EQ-5D descriptive index range from −0.59 to 1.00, and scores on the EQ visualanalogue scale range from 0 to 100, with higher scores indicating better quality of life),16 comprehensive thyroid-related quality of life (as assessed by the ThyPRO-39 score, a shorter version of the ThyPRO measure,17 at final follow-up only), handgrip strength (as assessed by means of the Jamar isometric dynamometer, with the recorded score as the best of three measures in the dominant hand),18 executive cognitive function (as assessed with the letter–digit coding test, which indicates the speed of processing according to the number of correct responses in matching nine letters with nine digits in 90 seconds; minimum score, 0, with higher scores indicating better executive cognitive function; there is no maximum score),19 blood pressure (systolic and diastolic), weight, body-mass index, waist circumference, activities of daily living (as assessed by the Barthel Index of functional levels in activities of daily living, on a scale ranging from 0 to 20, with higher

9. Subclinical Hypothyroidism Potential Indications for Therapy
Quality of life, neurocognitive deficits, and mood disorders ?
Prevent progression to overt hypothyroidism, esp. in antithyroid antibody-positive patients
Maternal and fetal consequences in pregnancy
Cardiovascular risks, including ischemic heart disease and heart failure

10. Parle et al. Clin Endocrinol 1991;34:77-83
Subclinical Hypothyroidism Progression to Overt Hypothyroidism
Among 1210 patients >60 years old, elevated TSH and normal FT4 found in 12% of women and 3% of men.
73 were untreated and followed for 12 mos.
18% progressed to overt hypothyroidism.
Those with initial TSH >10 mU/L or TPO Ab+ were more likely to progress.
6% reverted to normal TSH, all with TSH 5-10 mU/L
CONTEXT: Patients with subclinical hypothyroidism may revert to normal TSH values. OBJECTIVE: The objective of this study was to examine the time course of the normalization of TSH levels in subclinical hypothyroidism. DESIGN: The patients here reported belong to a cohort of 107 patients with subclinical hypothyroidism whose details have been described previously
(8). In summary, all of them were over age 55 yr and had no
previous thyroid disease. The group of 40 patients who normalized their
TSH values were eight men and 32 women, with mean age of
yr. Three of them had palpable goiter, 15 had symptoms generally
associated with hypothyroidism, and 24 of them were positive for thyroid
peroxidase autoantibodies (TPOAbs). There were five patients
This was a prospective, observational study with no intervention, with a duration of follow-up of months.
SETTING: Outpatients visited an endocrinology clinic of a general hospital.
PATIENTS: Forty patients (32 women, mean age /- 8.2 yr) with spontaneous subclinical hypothyroidism (TSH > 5 mU/liter and normal free T(4)) participated in the study. Each patient normalized their TSH values without T(4) therapy throughout the follow-up. MEASUREMENTS: TSH and free T(4) levels were evaluated every 6 months.
RESULTS: Normalization occurred at a median time of 18 months (range, 6-60 months). Fifteen patients normalized their TSH levels during the first year of follow-up and 27 during the first 2 yr. Ten patients normalized their TSH values at the fourth or fifth year. Only four patients reverted to TSH values less than 2 mU/liter. Final TSH levels achieved by the patients were significantly correlated with the time elapsed until normalizing these levels (r = 0.367; P = 0.020). CONCLUSIONS: There is no clear pattern of TSH normalization, although most patients normalize their TSH values early in the follow-up. The final TSH reached seems to be related to the time of normalization.
PMID: [PubMed - indexed for MEDLINE]
Parle et al. Clin Endocrinol 1991;34:77-83

11. Diez, J et al. J Clin Endocrinol Metab 2005;90:4124
Subclinical Hypothyroidism Spontaneous Resolution is Common
Prospective observational study of 107 outpatients >55 years old with no previous thyroid history newly diagnosed with subclinical hypothyroidism
40 (37%) had spontaneous TSH normalization over months follow-up.
Age 63 years; 32F♂/8M♁
24/40 (60%) TPO Ab+
15/40 (38%) w/symptoms
3/40 (8%) had goiter
CONTEXT: Patients with subclinical hypothyroidism may revert to normal TSH values. OBJECTIVE: The objective of this study was to examine the time course of the normalization of TSH levels in subclinical hypothyroidism. DESIGN: The patients here reported belong to a cohort of 107 patients with subclinical hypothyroidism whose details have been described previously
(8). In summary, all of them were over age 55 yr and had no
previous thyroid disease. The group of 40 patients who normalized their
TSH values were eight men and 32 women, with mean age of
yr. Three of them had palpable goiter, 15 had symptoms generally
associated with hypothyroidism, and 24 of them were positive for thyroid
peroxidase autoantibodies (TPOAbs). There were five patients
This was a prospective, observational study with no intervention, with a duration of follow-up of months.
SETTING: Outpatients visited an endocrinology clinic of a general hospital.
PATIENTS: Forty patients (32 women, mean age /- 8.2 yr) with spontaneous subclinical hypothyroidism (TSH > 5 mU/liter and normal free T(4)) participated in the study. Each patient normalized their TSH values without T(4) therapy throughout the follow-up. MEASUREMENTS: TSH and free T(4) levels were evaluated every 6 months.
RESULTS: Normalization occurred at a median time of 18 months (range, 6-60 months). Fifteen patients normalized their TSH levels during the first year of follow-up and 27 during the first 2 yr. Ten patients normalized their TSH values at the fourth or fifth year. Only four patients reverted to TSH values less than 2 mU/liter. Final TSH levels achieved by the patients were significantly correlated with the time elapsed until normalizing these levels (r = 0.367; P = 0.020). CONCLUSIONS: There is no clear pattern of TSH normalization, although most patients normalize their TSH values early in the follow-up. The final TSH reached seems to be related to the time of normalization.
PMID: [PubMed - indexed for MEDLINE]
Diez, J et al. J Clin Endocrinol Metab 2005;90:4124

12. Case 1: 56 y.o. woman
HPI: Seen by her PCP to evaluate fatigue, difficulty losing weight, and decreased short-term memory. Lab testing showed TSH 5.8 mU/L & FT4 1.0 ng/dL, prompting referral
Offered observation vs. L-T4 trial
Patient chose observation and TSH was 3.8 mU/L in three months. Her symptoms were unchanged.
Plan continued TSH monitoring every 6-12 months

13. Subclinical Hypothyroidism Presumed Indications for Therapy
Quality of life, neurocognitive deficits, and mood disorders ?
Prevent progression to overt hypothyroidism, esp. in antithyroid antibody-positive patients ?
Maternal and fetal consequences in pregnancy
Cardiovascular risks, including ischemic heart disease and heart failure

14. Case 2: 35 y.o. woman
HPI: When evaluated for multiple previous miscarriages, gynecologist found:
TSH 3.9 mU/L (normal )
TPO antibody 146 IU/mL (normal <100)
PE: Euthyroid appearing. Wt 134 lbs, Ht 67” Thyroid: normal.
Other laboratory data:
TC 185 mg/dL, LDL-Ccalc 95 mg/dL
Patient very likely to develop TSH above normal during pregnancy

15. Miscarriages in unselected pregnancies in TAb+ & TAb− women
Thyroid Disease in Pregnancy
Thyroid Autoimmunity and Miscarriage
Miscarriages in unselected pregnancies in TAb+ & TAb− women
Stagnaro-Green, Glinoer. Best Prac Res Clin Endocrinol Metab 2004;18: 3

16. Maraka, et al. Thyroid 2016:4: 580-590
Subclinical Hypothyroidism in Pregnancy Systematic Review and Meta Analysis
Assessed impact of SCH during pregnancy on maternal and neonatal outcomes in 18 cohort studies at low-to- moderate risk of bias
Compared with pregnant euthyroid women, women with SCH had higher risks of:
Pregnancy loss (RR 2.0 [CI 1.7–2.4)
Placental abruption (RR 2.1 [CI 1.2–3.7])
Premature membranes rupture (RR 1.4 [CI 1.0–2.0])
Neonatal death (RR 2.6 [CI 1.4–4.7])
Maraka, et al. Thyroid 2016:4:

17. 10,924 screened with TSH & FT4 at ~12 weeks 10,922 controls had
Subclinical Hypothyroidism in Pregnancy Impact of TSH Screening & L-T4 Therapy
21,846 women randomized
10,924 screened with TSH & FT4 at ~12 weeks
10,922 controls had
tests run postpartum
404 Abnormal TFTS
499 abnormal
242 low FT4
232 high TSH
25 low T4 & high TSH
10,425 normal TFTS
Randomized trial in pregnant women who gave blood samples and were then assigned to screening (i.e., immediate TSH and FT4) or control groups
Screened women with TSH>97.5th %-tile or FT4<2.5 %-tile were Rx L-T4 150 μg/day
390 screened and 404 control women positive
Median gestational age at L-T4 start was 13 weeks and L-T4 adjusted to achieve serum TSH mIU/L
CONTEXT: Patients with subclinical hypothyroidism may revert to normal TSH values. OBJECTIVE: The objective of this study was to examine the time course of the normalization of TSH levels in subclinical hypothyroidism. DESIGN: This was a prospective, observational study with no intervention, with a duration of follow-up of months. SETTING: Outpatients visited an endocrinology clinic of a general hospital. PATIENTS: Forty patients (32 women, mean age /- 8.2 yr) with spontaneous subclinical hypothyroidism (TSH > 5 mU/liter and normal free T(4)) participated in the study. Each patient normalized their TSH values without T(4) therapy throughout the follow-up. MEASUREMENTS: TSH and free T(4) levels were evaluated every 6 months. RESULTS: Normalization occurred at a median time of 18 months (range, 6-60 months). Fifteen patients normalized their TSH levels during the first year of follow-up and 27 during the first 2 yr. Ten patients normalized their TSH values at the fourth or fifth year. Only four patients reverted to TSH values less than 2 mU/liter. Final TSH levels achieved by the patients were significantly correlated with the time elapsed until normalizing these levels (r = 0.367; P = 0.020). CONCLUSIONS: There is no clear pattern of TSH normalization, although most patients normalize their TSH values early in the follow-up. The final TSH reached seems to be related to the time of normalization.
PMID: [PubMed - indexed for MEDLINE]
499 Rx T4 at 13 wks to achieve TSH mIU/L
Lazarus JH et al. New Engl J Med 2012;366:493

18. Subclinical Hypothyroidism in Pregnancy No Impact of Screening & L-T4 Observed
Among children born to hypothyroid mothers, mean IQ scores in the treated and control groups were 99.2 and (∆, 0.8; 95% CI, −1.1 to 2.6; P=0.40)
Proportions of children with an IQ <85 were % and 14.1% in the treated and control groups (∆, 2.1; 95% CI, −2.6 to 6.7; P=0.39).
Intent-to-Treat
Successful Treatment

19. Casey BM et al. New Engl J Med 2017;376
Subclinical Hypothyroidism in Pregnancy
Recent Randomized Clinical Trial
Casey BM et al. New Engl J Med 2017;376

20. Subclinical Hypothyroidism RCT
Screened pregnant women before 20 weeks, and those with TSH >4 mU/L or FT4 <0.86 ng/dL assigned to LT4 or placebo with LT4 adjusted to attain normal TSH or FT4
Their children had annual developmental and behavioral testing for 5 years with IQ primary at 5 years the 10 outcome
677 women with subclinical hypothyroidism underwent randomization at mean 16.7 wks. gestation, and 526 with hypothyroxinemia at 17.8 wks.
Median IQ of children with high-TSH mothers was 97 in LT4-treated group vs. 94 with placebo (P = 0.71).
Mean IQ of children with hypothyroxinemic mothers was 94 in the LT4-treated group vs. 91 with placebo (P = 0.30).
screened women with a singleton pregnancy before 20 weeks of gestation for subclinical
hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal
free thyroxine (T4) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hypothyroxinemia,
defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low
free T4 level (<0.86 ng per deciliter). In separate trials for the two conditions, women were
randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed
monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T4
level (depending on the trial), with sham adjustments for placebo. Children underwent annual
developmental and behavioral testing for 5 years. The primary outcome was the IQ
score at 5 years of age (or at 3 years of age if the 5-year examination was missing) or death
at an age of less than 3 years.
RESULTS
A total of 677 women with subclinical hypothyroidism underwent randomization at a mean
of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of
gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was
97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92
to 96) in the placebo group (P = 0.71). In the hypothyroxinemia trial, the median IQ score
was 94 (95% CI, ) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo
group (P = 0.30). In each trial, IQ scores were missing for 4% of the children. There
were no significant between-group differences in either trial in any other neurocognitive or
pregnancy outcomes or in the incidence of adverse events, which was low in both groups.
CONCLUSIONS
Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and
20 weeks of gestation did not result in significantly better cognitive outcomes in children
through 5 years of age than no treatment for those conditions

21. Subclinical Hypothyroidism RCT
There were no significant between-group differences in either trial in any other neurocognitive or pregnancy outcomes or in the incidence of adverse events, which was low in both groups.
CONCLUSIONS: Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not result in significantly better cognitive outcomes in children through 5 years of age.
screened women with a singleton pregnancy before 20 weeks of gestation for subclinical
hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal
free thyroxine (T4) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hypothyroxinemia,
defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low
free T4 level (<0.86 ng per deciliter). In separate trials for the two conditions, women were
randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed
monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T4
level (depending on the trial), with sham adjustments for placebo. Children underwent annual
developmental and behavioral testing for 5 years. The primary outcome was the IQ
score at 5 years of age (or at 3 years of age if the 5-year examination was missing) or death
at an age of less than 3 years.
RESULTS
A total of 677 women with subclinical hypothyroidism underwent randomization at a mean
of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of
gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was
97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92
to 96) in the placebo group (P = 0.71). In the hypothyroxinemia trial, the median IQ score
was 94 (95% CI, ) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo
group (P = 0.30). In each trial, IQ scores were missing for 4% of the children. There
were no significant between-group differences in either trial in any other neurocognitive or
pregnancy outcomes or in the incidence of adverse events, which was low in both groups.
CONCLUSIONS
Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and
20 weeks of gestation did not result in significantly better cognitive outcomes in children
through 5 years of age than no treatment for those conditions

22. Subclinical Hypothyroidism Potential Indications for Therapy
Quality of life, neurocognitive deficits, and mood disorders ?
Prevent progression to overt hypothyroidism, esp. in antithyroid antibody-positive patients ?
Maternal and fetal consequences in pregnancy ?
Cardiovascular risks, including ischemic heart disease and heart failure

23. Case 3: 74 y.o. man
HPI: 74-year-old man at routine health assessment to have a serum TSH 7.1 mU/L with FT4 0.9 ng/mL.
Taking atorvastatin 10 mg daily
PE: Euthyroid appearing. Wt 176 lbs, Ht 69” Thyroid: normal.
Other laboratory data
Repeat TSH 7.0 mU/L
TPO antibody 12 IU/mL (normal <100)
TC 180 mg/dL, LDL-Ccalc 95 mg/dL HDL-C 70 mg/dL, TG 75 mg/dL

24. Thyroid Disorders in the Elderly
September 16, 1999
Subclinical Hypothyroidism & Cardiovascular Events
Incidence of Cardiovascular Events
Prospective Studies
Effect of Mild Hypothyroidism
Comment
Atomic Bomb Surv. 2004
Yes
All cause mortality; Middle aged men
Busselton study 2005
Mean age 50
Whickham survey 1977 No
20 year F/U
Rotterdam study 2000
5 year F/U
CV Health Study 2006
>age 65
Health Aging Study 2005
Mean age 75; ↑ CHF risk
Leiden Plus 2004
Age >85

25. Mild Hypothyroidism CHD Events: Individual Patient Meta Analysis
Context:
Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk.
Objective:
The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs).
Data Sources and Study Selection:
A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes.
Data Extraction:
Individual data of participants from six cohorts for CHD mortality followed up for person-years and participants from four cohorts for CHD events.
Data Synthesis:
Among adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87–1.53 vs HR 1.26, CI 1.01–1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87–1.56 vs HR 1.26, CI 1.02–1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status.
Conclusions:
CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.
Affiliations
Rodondi N, et al. JAMA. 2010;304:1365–1374. 3

26. Mild Hypothyroidism CHD Mortality: Individual Patient Meta Analysis
Context:
Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk.
Objective:
The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs).
Data Sources and Study Selection:
A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes.
Data Extraction:
Individual data of participants from six cohorts for CHD mortality followed up for person-years and participants from four cohorts for CHD events.
Data Synthesis:
Among adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87–1.53 vs HR 1.26, CI 1.01–1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87–1.56 vs HR 1.26, CI 1.02–1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status.
Conclusions:
CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.
Affiliations
Rodondi N, et al. JAMA. 2010;304:1365–1374. 3

27. Razvi S, et al. Arch Intern Med. 2012;172:811-817.
Ischemic Heart Disease Events in Patients with
Subclinical Hypothyroidism + Levothyroxine
Investigated association of L-T4 treatment of SCH with IHD morbidity and mortality.
UK General Practice Research Database to identify new SCH cases (TSH 5-10 mIU/L w/ nl. FT4) in and capture outcomes through March 2009.
HRs adjusted for IHD risk factors, baseline TSH, and L-T4 initiation of as time-dependent covariate
Results: SCH identified in 3093 individuals yrs and 1642 >70 yrs, with L-T4 therapy in 53% and 50%, respectively, for median f/u 7.6 yrs
Razvi S, et al. Arch Intern Med. 2012;172: 3

28. Ischemic Heart Disease Events in Patients with
Subclinical Hypothyroidism + Levothyroxine
Patients Years Old
Untreated
Cumulative Fatal & Nonfatal IHD Events
L-T4 treated
Multivariate-adjusted cumulative event plots for levothyroxine sodium–treated and untreated individuals with subclinical hypothyroidism for fatal and nonfatal ischemic heart disease. A, Younger patients (P = .02). B, Older patients (P = .56). Multivariate analysis shown is adjusted for age, sex, body mass index, socioeconomic deprivation score, total cholesterol level, index serum thyrotropin level, smoking status, systolic and diastolic blood pressure, history of diabetes mellitus, and levothyroxine use as a time-dependent covariate.
Adjusted HR, 0.61; 95% CI,
P = 0.02
Razvi S, et al. Arch Intern Med. 2012;172: 3

29. Patients >70 Years Old
Ischemic Heart Disease Events in Patients with
Subclinical Hypothyroidism + Levothyroxine
Patients >70 Years Old
L-T4 treated
Untreated
Cumulative Fatal & Nonfatal IHD Events
Multivariate-adjusted cumulative event plots for levothyroxine sodium–treated and untreated individuals with subclinical hypothyroidism for fatal and nonfatal ischemic heart disease. A, Younger patients (P = .02). B, Older patients (P = .56). Multivariate analysis shown is adjusted for age, sex, body mass index, socioeconomic deprivation score, total cholesterol level, index serum thyrotropin level, smoking status, systolic and diastolic blood pressure, history of diabetes mellitus, and levothyroxine use as a time-dependent covariate.
Adjusted HR, 0.99; 95% CI,
P = 0.56
Adjusted HR, 0.61; 95% CI,
Razvi S, et al. Arch Intern Med. April 23, 2012 3

30. Conclusions Subclinical Hypothyroidism
Minimal TSH elevation with normal free T4 may reflect mild thyroid failure or the normal elderly state.
Nonspecific symptoms and decreased qualities of life are not reliably relieved by thyroid hormone therapy in patients with subclinical hypothyroidism.
Not all patients with subclinical hypothyroidism progress, and even thyroid autoantibodies do not reliably predict who will. 3

31. Conclusions Subclinical Hypothyroidism
Although maternal and fetal benefits of treating subclinical hypothyroidism at weeks of pregnancy have not been established, a case can still be made for promptly treating individual patients who have been identified.
There may be increased risk of cardiovascular events and mortality in middle-aged adults (40-70 years) with subclinical hypothyroidism, but this does not appear to be present in individuals > 70 years old. 3