Five Questions: Should women routinely be screened for thyroid disease? Should women with subclinical hypothyroidism receive any treatment? What is a normal TSH level? How should hypothyroidism in pregnancy be managed? What is appropriate thyroid hormone replacement rx in hypothyroid women?
Case 1:A 46 year old woman comes to your office forher yearly check-up. She has no complaintsand physical examination is normal. You areabout to send her to the lab, when she asks ifyou are going to do any thyroid tests. Sherecently read that all women should be“screened” for possible thyroid disease. Whatdo you do now?
Question 1:Should a serum TSH be a routinecomponent of the periodic healthexamination in women?
Is a serum TSH the best screeningtest?Yes!! With the exception of the rarepatient with secondary hypothyroidism,a serum TSH is the best screening testfor both hyperthyroidism andhypothyroidism.
Consensus Statements: US Preventive Services Task Force: Recommends screening only in newborns Expert Panel (JAMA, Jan 04): There is insufficient evidence to support population-based screening. American College of Ob-Gyn: No guidelines regarding testing in woman pre-conception or during pregnancy American College of Physicians: Screening of women >50 “may be indicated” ATA (JAMA, 2000): Adults should be screened for thyroid dysfunction with a serum TSH beginning at age 35 and every 5 years thereafter
Institute of Medicine evaluation of theadvisability of covering TSHmeasurements in Medicare patients:After analyzing available evidence anddoing a cost-benefit analysis, the IOMfound the evidence for a benefit ofscreening to be lacking, and thereforedetermined that coverage for screeningshould not be provided as a Medicarebenefit . (2003)
Joint Statement of AACE, ATA andEndocrine Society:Potential benefits of early detection and treatmentof thyroid dysfunction outweigh the potential sideeffects that could result from early detection andtherapy…. Therefore, we favor screening forsubclinical thyroid dysfunction in adults, includingpregnant women and those contemplatingpregnancy.Thyroid, January, 2005
Are there subsets of asymptomaticwomen who should be screened?: Women over the age of 60 Women with other autoimmune disorders, including Type 1 diabetes Women with a strong family history of thyroid disease Women with hypercholesterolemia Women with psychiatric disorders Women taking lithium, amiodarone, or interferon-alpha
Are there subsets of women who shouldbe screened?: Women with prior history of thyroid disease Women planning pregnancy or soon after conception Women who have had previous head and neck irradiation Women with MS or primary pulmonary hypertension Women with Down or Turner syndromes
Case 2:A 56 year old woman presents with a question regardingrecent thyroid studies. “Screening” labwork by her Ob-Gyn showed a TSH of 7.1 uU/ml (0.35-5.5). Asubsequent free T4 was 1.3 ng/dl (normal 0.8-1.8). Shefeels well, but does report some fatigue, and a 3-4 lbweight gain in the last year. Examination is normal andshe appears clinically euthyroid. She understands that ahigh TSH indicates hypothyroidism and wants to know ifshe should be started on a thyroid supplement.What’s the diagnosis and should she be treated?
The diagnosis is subclinicalhypothyroidism: Elevated serum TSH concentration and normal serum thyroid hormone levels in an apparently asymptomatic patient Prevalence is 5-10% in general population, with women over 60 having a prevalence as high as 15-20% Most commonly due to autoimmune thyroid disease
Question 2:Should women with subclinicalhypothyroidism be treated withl-thyroxine?
What are the clinical consequencessubclinical hypothyroidism?: Progression to overt hypothyroidism Abnormal lipids Increased risk of cardiovascular disease Neuropsychiatric symptoms
What is the likelihood of progressionto overt hypothyroidism?:There is significant risk, particularly in 1. Older patients (>60) 2. Patients with positive thyroid antibodies 3. Women—in one study annual rate of progression to overt hypothyroidism was 4.3% in women with +TPO antibodies, 3.0% if no ab’s 4. Patients with TSH>10 5. Patients with prior history of radioactive iodine treatment or thyroid surgery
On the other hand, in somepatients with SCHypo, theTSH will spontaneously returninto the normal range (4-30% indifferent series)—i.e. no rush tostart thyroxine therapy.
Lipids in Subclinical Hypothyroidism: Relationship is controversial Several cross-sectional studies show increased TC and LDL-C Likelihood of abnormality is greater in patients with TSH>10
Walsh et al. Busselton Health Study.Clin Endocrinol, 2005.Cross-Sectional Data: N LDL-Chol (mmol/L)Euthyroid Controls 1906 3.5+1.0SCHypo 119 4.1+1.2*SCHypo (TSH>10.0) 23 4.3+1.3** *p<0.01 vs. controls**p<0.001 vs. controls
Does treatment of SCHypo havebeneficial effect on lipids: Villar et al. (Cochrane Data Base Rev, 2007) - meta-analysis of 12 clinical trials: no effect of T4 rx on total, LDL, HDL cholesterol, triglycerides In six other randomized trials, comparing T4 with placebo, there was significant lowering of LDL and total cholesterol
Summary of SCHypo and Lipids: There is a consistent but modest association of SCHypo with increased total and LDL cholesterol Correction of SCHypo has modest expected effect of decreasing LDL and total cholesterol
Is there increased risk ofcardiovascular disease insubclinical hypothyroidism?
Biondi & Cooper, Endo Rev, 2008:In some epidemiological studies therisk of CHD was increased in youngand middle-aged patients but not inelderly patients with SCHypo. Indeed,SCHypo appeared to exert aprotective cardiovascular effect inpatients older than 85.
Biondi & Cooper, Endo Rev, 2008:There is no evidence that treatment ofsubclinical hypothyroidism has anyimpact on the risk of developing CHDor on all-cause and cardiovascularmortality! Perhaps, treatment shouldbe avoided in the very elderly(Gussekloo et al.).
Neuropsychiatric SymptomsCritical questions are:1. Do patients with SCHypo truly have more symptoms than age-matched euthyroid controls?2. Does treatment with thyroxine ameliorate symptoms?
Canaris et al.: Colorado Thyroid DiseasePrevalence Study, Arch Int Med, 2000: Cross-sectional study of 25,862 participants in statewide health fair Responses to a hypothyroid symptoms questionnaire were recorded in 2336 patients with SCHypo
Many other studies do notsupport an association ofSCHypo with any symptoms!
Bell et al., 2007: Community-based x-sectional study of 1423 “non-healthcare-seeking women”—mean age 54 Utilized Short-Form 36 (SF-36) and Psychological General Well-Being Index (PGWI) to evaluate health-related QOL SCHypo defined as TSH > 4.0 Clin Endocrinol, 66:548, 2007
Bell et al., 2007: There were no differences between women with SCHypo (n=80) and age- matched euthyroid controls (n=240) in terms of: – Anti-depressant use – PGWI score – SF-36 mental composite score – SF-36 physical composite score
The presence of symptoms inpatients with SCHypo remainscontroversial, and symptoms,when present are non-specific. Biondi & Cooper, Endo Rev, 2008
Does treatment improve signsand symptoms of hypothyroidism,quality of life, and psychometrictests in patients with SCHypo?At least 12 placebo-controlledstudies have addressed theseissues and the results areconflicting!
Summary: Treatment ofSubclinical Hypothyroidism: No studies have demonstrated an adverse effect from correction of subclinical hypothyroidism Patients with serum TSH > 10 uU/mL appear to derive the greatest benefits from treatment Adverse effects of therapy are only related to cost and overtreatment--in one study of 339 elderly patients on T4 rx, 41% had low TSH levels (Somwaru, JCEM, 2009)
It seems reasonable to recommendtherapy for the following patients: TSH>10 uU/ml Positive thyroid autoantibodies Lipid abnormalities Psychiatric patients, especially those with depression/bipolar disorders History of radioactive iodine treatment or previous thyroid surgery
It seems reasonable to recommendtherapy for the following patients: Pregnant women Women with infertility “Younger” patients (<60-70 y/o), especially those with cardiovascular risk factors (DM, dyslipidemia, hypertension, smoking, etc.) Avoid therapy in the “oldest” old
All patients with subclinicalhypothyroidism not receivingtreatment must be closelymonitored for the developmentof overt hypothyroidism.
Case 3:A 46 year old woman presents to your office for follow-up of her longstanding hypothyroidism. She is taking l-thyroxine 125 ug/d, and reports that she is feeling“pretty well”, except for some fatigue and a 5 lb weightgain over the last year. Physical examination is normal.Thyroid studies are as follows: Free T4 1.2 ng/ml (0.8-1.8) TSH 4.8 uU/ml (0.35-5.5)Should you make any changes in her dose of thyroidhormone replacement?
Question 3:What is the normal TSH referencerange and what level of TSH should betargeted in the treatment of hypothyroidpatients?
What level of TSH should be targeted?: Simple answer: TSH within the normal range for the assay utilized—usually 0.35 – 5.5 mIU/L BUT….there is now accumulating body of evidence that the upper limit of normal for most assays is too high and appropriate upper limit could be as low as 2.5 – 3.0 mIU/L. This is based on studies that rigorously exclude subjects with even the mildest degrees of thyroid failure in determining the normal range
Studies addressing normal TSH range: Bjoro et al. (Eur J Endocrinol, 2000): Norway, Upper limits of normal: men 3.4; women 3.6 Kratzsch et al. (Clin Chem, 2005): Germany, Normal range: 0.30 – 3.63 NHANES III (JCEM, 2002): United States, Normal range: 0.45 – 4.12 Jensen et al. (Clin Chem Lab Med, 2004): Denmark, Normal range: 0.58 - 4.07 Hamilton et al. (JCEM, 2008): United States, Normal range: 0.55 - 4.10
Conclusions:The prevalence of subclinicalhypothyroidism may be significantlyoverestimated unless an age-specificrange for TSH is used.
My opinion: The upper limit of normal for the serum TSH concentration is probably between 3.0 and 4.0 mIU/mL A reasonable target TSH for most patients with primary hypothyroidism is in the 1.0 – 3.0 mIU/L range
Important Caveats: Lowering the upper limit of normal for serum TSH to 2.5-3.0 will result in ~25 million more Americans being diagnosed with hypothyroidism There is no evidence that treating patients with TSH in 3-5 mIU/L range is beneficial —in fact, benefits of treating patients with TSH levels in 5-10 range are controversial.
Case 4:A 28 year old woman with longstandinghypothyroidism on l-thyroxine therapy comesto you to discuss her plans for starting afamily some time in the next 6 months. Sheasks if there will be any problems related toher current treatment with l-thyroxine.
Question 4:What is the potential impact ofpregnancy on thyroxine treatment inhypothyroid women?
Thyroxine replacement during pregnancy: The daily dose of thyroxine to maintain the euthyroid state in pregnancy will increase in 50-70% of women Average dose increase ranges from 20-50% Increased T4 requirements may be apparent as early as 5-6 weeks of gestation
Mean Serum FT4 and TSH beforeand during pregnancy (n=25): Before During T4 dose (ug/day) 112 112 Serum FT4 (ng/dL) 1.60 0.84 Serum TSH (uU/mL) 1.44 14.1 Kaplan, 1992
Recommendations: Adjust T4 rx to serum TSH<2.0 prior to pregnancy Check TSH early in pregnancy—by week 5-6 Monitor TSH every 5-6 weeks during 1st half of pregnancy; less often in 2nd half of pregnancy T4 dose adjustments should be based on trimester-specific TSH normal ranges—e.g. normal range in 1st trimester is 0.10 – 2.5 Separate T4 ingestion by at least 3-4 hours from iron supplements, calcium supplements, multivitamins, and soy milk
Thyroid Hormone Early Adjustment in Pregnancy(The THERAPY) Trial. Yassa et al., JCEM, 2010 Prospective trial of empiric ~29% increase in T4 dose (2 extra tablets per week) when pregnancy confirmed Intervention significantly reduced risk of maternal hypothyroidism in 1st trimester Only 2 of 25 women required a dose reduction due to over-replacement Only 2 of 25 women required a further dose increase
Thyroid Hormone Early Adjustment in Pregnancy(The THERAPY) Trial. Yassa et al., JCEM, 2010 Conclusions – 29% increase in maternal T4 at confirmation of pregnancy reduces risk of maternal hypothyroidism in first trimester – Monitoring thyroid function once monthly is required through “mid-pregancy”, ~week 20 – The protocol appears safe and mimics normal thyroid gestational physiology
B. What are the adverse effectsof maternal hypothyroidism?
Morbidity Associated with HypothyroidismDuring Pregnancy: Spontaneous miscarriages Gestational hypertension and preeclampsia Premature delivery Increased frequency of neonatal ICU admissions Increased fetal mortality Impaired neuropsychological development
Children of Children of Treated Untreated Women with Women with Control Hypothyroidism Hypothyroidism Children (N=14) (N=48) (N=124)Full Scale IQ Score 111 100* 107% with IQ <85 0 19* 5Freedom fromdistractibility score 103 97* 102Verbal IQ score 111 101* 107Performance IQ score 109 99* 105*P-value <0.01 for comparison of untreated vs. control children
Conclusion:Undiagnosed hypothyroidism in pregnantwomen may adversely affect theirfetuses; therefore, screening for thyroiddeficiency during pregnancy may bewarranted.
Unresolved Issue:Should all women be screened forhypothyroidism prior to or shortly afterconception? ■RECOMMENDATION 74There is insufficient evidence to recommendfor or against TSH testing preconception inwomen at high risk for hypothyroidism. LevelI-USPSTF
■RECOMMENDATION 76Serum TSH values should be obtainedearly in pregnancy in women at highrisk for overt hypothyroidismLevel B-USPSTF
Case 5:A 52 year old woman returns for follow-up oflongstanding hypothyroidism. She is doing wellon brand-name of l-thyroxine, but she has readthat a combination of T4/T3 is superior to T4alone and wonders whether that would be agood idea for her. In addition, at the time of herlast refill, she was told by her pharmacist thatshe could save some money by switching to ageneric T4 preparation. What should you tellher? Thyroid studies done one week prior toher visit showed a TSH of 1.2 uU/mL.
Are all levothyroxine preparationstherapeutically equivalent?Appropriate studies comparing allavailable brand-name and genericpreparations have not been performed,so a definitive answer is not available!
Cost Differences:Brand Cost of 90 0.1 mg tabsSynthroid $63.97Levoxyl 44.97Generic 25.97So difference in cost for one year supplyof Synthroid vs. generic = $152 Source: www.drugstore.com
Endocrine Society, ATA, AACE“Best Physician Practices” Guidelines: Patients should be maintained on the same brand name l-thyroxine product Change from one brand to another, change from a brand to a generic product, or change from one generic to another generic requires repeat TSH testing in 6-8 weeks Small differences in l-thyroxine doses may have significant adverse clinical outcomes
My Opinion:Use a brand name preparation andconsistently prescribe that brand for agiven patient. Any change in brand orto a generic requires a follow-up TSHin 6-8 weeks.
T4-T3 Therapy vs. T4 Monotherapy forHypothyroidism: Meta-Analysis ofRandomized Controlled Trials: Included 11 studies with total of 1216 patients No difference was found between treatments for any of the following: depression, anxiety, bodily pain, fatigue, quality of life, body weight, total and LDL cholesterol, and triglycerides Adverse events did not differ between regimens Conclusion: T4 monotherapy should remain the treatment of choice for hypothyroidism J Clin Endocrinol Metab, 2006
Conclusions from availablestudies:There is insufficient evidence atthis time to support the routineaddition of T3 to T4 replacementin hypothyroid patients. Resultsof the Bunevicius study have notbeen confirmed in subsequentRCT’s.