Medical thyroid disease. Issues for the GP. Dr Simon Page

Transcription

1 Medical thyroid disease Issues for the GP Dr Simon Page

2 Advice and Guidance 90 A+G requests July-Dec related to thyroid disease management Sub clinical hyperthyroidism 12 Hyperthyroidism 3 Thyroid and pregnancy 2 Hypothyroidism 7 Sub clinical hypothyroidism 6 Positive TPO antibodies 2 T4/T3 combination therapy 3 Amiodarone 1

3 Case 1 - Hyperthyroid I would be grateful for your advice on this 46 year old lady who has been seen by my colleague for weight loss and tremors. She has also been finding that her periods have stopped but she has no change in bowel habits. Patients initial concern was around if she was suffering from cancer and on blood testing she has been found to be hyperthyroid. Her eyes have also become more prominent but I have asked her to check if this has always been the case by checking some previous photographs. She is fairly certain this a definitely a change. She also has a family history with her mum and siblings who have had thyroid problems. Her thyroid antibody results are positive. I have given her the treatment options and currently she would prefer Carbimazole and I have started her on 15mgs daily with a repeat TFT to be done in one months time. She has been advised about implications for her blood counts and she will be having her FBC done at the same time as her TFT but is aware of the risk of sore throat. Based on the investigations I believe that this is hyperthyroidism of autoimmune origin and I can not feel any goitre in the neck but I would like to ascertain whether there are any further investigations which need to be done. Do we need to give her any different treatment? She is not keen on radioiodine initially as she works as a carer and this would have implications I would value your advice on her management

4 Case 2 - Hyperthyroid Thank you for your advice on this 32 year old lady who is previously known to Dr (Renee) Page with thyrotoxicosis. She was initially diagnosed in 2007, however she has defaulted several appointments. Eventually she was discharged from your clinic after she did not attend an appointment in She has been fairly stable on a dose of Propylthiouracil 50mg a day which she has been on from at least 2011, prior to that she had taken 100mg a day for a short period as well. Her most recent TSH in July 2012 was 3.6 and she is asymptomatic in herself. I was wondering what the long term plan would be in terms of her monitoring and whether she is to stay on PTU? If you feel you need to see her in clinic to discuss more therapeutic options or whether we need to monitor her more carefully in primary care. Please let me know.

5 Diagnosis diseases to consider Causes The top three Autoimmune Thyroid Disease Toxic multi-nodular goitre Toxic adenoma Also rans De-Quervain s thyroiditis Thyrotoxicosis factitia Hamburger toxicosis Drug-induced Amiodarone Type 1 Iodine driven Type 2 Thyroiditis related to metabolite Lithium Painless thyroiditis Iodinated contrast Post imaging procedure underlying thyroid autoimmunity Interferon alfa Painless thyroiditis Trigger for AITD

6 Hyperthyroidism management ATA/AACE guidelines Thyroid 2011, 21, NICE CKS 2013 Three Options ATD Carbimazole Propylthiouracil Radioactive iodine Near total thyroidectomy

7 Different approaches American (ATA), European (ETA), Japanese Thyroid (JTA) Associations Index case middle aged female with new diagnosis of GD RAI ATD Surgery ATA 69% 31% No ETA 22% 77% No JTA 11% 88% No Wartofsky et al., Thyroid 1991, 1,

8 Hyperthyroid management - NICE Thionamide therapy (CBZ and PTU) with a confirmed biochemical diagnosis of hyperthyroidism. Not essential for mild disease if prompt definitive treatment with radioiodine is planned. PTU not recommended first line, (bd or tds dosing, risk of severe liver injury, ANCA positive vasculitis), except in: First trimester of pregnancy. Thyroid storm. People with minor reactions to CBZ who refuse radioactive iodine or surgery. NICE CKS recommends seeking specialist advice before initiating thionamide therapy. Beta-blockers (such as propranolol and atenolol) are recommended. They are usually the only treatment required in thyrotoxicosis secondary to thyroiditis

9 New patient New patient If confirmed hyperthyroidism clinically and biochemically: Refer to Endocrine service START therapy with CBZ +/- betablocker Usual advice about sore throats Evaluate clinical and laboratory response in 4-6 weeks Suggested starting dose ft4 (nmol/l) > 50 40mg CBZ od mg CBZ od mg CBZ od

10 Long term management Diagnostic clarity aids long term management

11 ATD: Duration 23 RCTs, 3115 participants Overall trial quality poor Allocation Concealment Assessor blinding Loss to follow-up 4 trials 1 trial 6 vs 18mths titrated dose 58% vs 37% relapse 1 trial quasi-randomised B+R 6 mths vs 12 mths No difference 41% vs 35% Treatment over 18mths No benefit Abraham et al., Cochrane Library of Systematic Reviews.

12 ATD: Titration vs R 12 trials Relapse rates similar T 54% vs B@R 51% Side effects T B@R Rashes 5% vs 10% Withdrawal 9% vs 19% No clear benefit from block and replace regimen Not endorsed (other than in selected cases) by ATA guidelines 2011 Abraham et al., Cochrane Library of Systematic Reviews.

13 Radioactive iodine therapy (RAI) Used for over 60 years Safe Cheap - ~ per dose Devoid of major side effects (other than hypothyroidism!) Benign thyroid disease Toxic goitre Non-toxic goitre Malignant thyroid disease

14 % hypothyroid RAI standard practice Since ~ 1980 Standard dose of 400 mbq Omit CBZ 7 days before dose Re-start 7 days after dose if severe hyperthyroidism 80-90% 1 dose ~ 10% 2 doses < 1% 3 doses Repeat dose at 6 mths if not off ATD/hypothyroid Hypothyroidism post RAI Graves' disease Toxic adenoma yr 10yrs 25 yrs Time since radioactive iodine

15 Radiation safety Description of Radiation Precaution 400 MBq Time for Precautions Use separate crockery and cutlery to other people in the home, and wash it up separately Keep at least 1 metre distance from other adults Avoid long journeys on public transport, and trips to theatre, cinema, family parties, church and pub Avoid prolonged close contact at home. Sleep separately from partner, keep at least 1 metre away from others in home To stay off work, if work involves adults only Do not give blood or urine samples Avoid close contact with children of the following ages (stay off work for this length of time if working with children of this age) Children under 3 yrs Children between 3and 5 yrs Children between 5 and 16 yrs Avoid close contact with pregnant women (stay off work for this length of time if working with pregnant women) Avoid pregnancy 2 days 4 days 4 days 4 days 4 days 7 days 21 days 16 days 11 days 21 days 6 months

16 The eyes

17 The eyes Number of pts RAI Improvement No change Progression RAI plus prednisolone No eye disease clinically evidence No steroid cover Non-severe (but active) TAO Prednisolone 0.5mg/kg for 4 weeks, tailor over 3 mths Severe TAO Defer RAI till eye disease treated Consider ATD or surgery if urgent Bartelena et al. N Engl J Med. 1998;338:73 78

18 Thanks for your A+G request. Case 1 - Hyperthyroid I agree that Ms Bowen has autoimmune thyroid disease likely Hashitoxicosis given the TPO titre of >1300. Starting carbimazole as you have done is the right thing to do since she needs to have her thyroid hormone levels lowered to the normal range as soon as possible to help with symptoms. You may consider treatment with propranolol 10-20mg tds if her symptoms are marked and she has no contraindication this could be withdrawn once her TFT have improved. I assume this is her 1 st episode? If so then a 12 month course of carbimazole is reasonable, with TFT monitoring every 6-8 weeks and dose titration to deliver normal range T4 and T3 levels. After this the CBZ can be withdrawn to see if she has gone into remission post treatment TFT bloods at 4 and 12 weeks after stopping CBZ are advised. Assuming she remains euthyroid, then further TFT would be required only if she developed further symptoms. Having said that an annual TFT to spot early hypothyroidism would be appropriate given the high TPO antibody level. A scan of the thyroid is not required. 10 th Oct 2014 ft4 40 ft TSH < th Jan 2015 TSH 4.2

19 Case 2 - Hyperthyroid Thanks for this A+G request. She was seen by Dr Renee Page in She has a diagnosis of autoimmune thyroid disease with raised TPO antibodies. Therefore it is reasonable to consider that she might have gone into remission and her TSH is now detectable. I would suggest stopping the PTU and repeating her TFT in 4 weeks and 12 weeks time to look for any early signs of recurrent hyperthyroidism. If she remains euthyroid then no further monitoring is needed unless she develops recurrent symptoms. If her hyperthyroidism recurs then re-start PTU and arrange a referral to the endocrine service at the Treatment Centre. TSH July Jan

20 Sub-clinical hyperthyroidism What is it? Normal ft4 and ft3 Suppressed TSH Does it matter? 3-5 fold increased risk of AF Increased risk of osteoporosis

21 Case subclinical hyperthyroidism A&G Endocrinology Reason for referral - Subclinical hyperthyroidism I would value your opinion as to whether any further investigation is warranted for this 75 year old lady. She has had a suppressed TSH but normal T4 (current level 14.2) and T3 current level 6.2 since She has osteoporosis and review of her thyroid status has been requested by the Metabolic bone team prior to commencement of treatment. She is asymptomatic. I would value your advice as to whether anything further is required. She is not keen to have an out-patient appointment unless this is absolutely necessary. She is generally fit and healthy, aside from the osteoporosis. She takes Calcium and Vitamin D but no other regular medication. She has regular follow-ups for mild aortic regurgitation, which is not progressive and asymptomatic. Yours sincerely

22 Case subclinical hyperthyroidism Thanks for this A+G request This patient has had sub-clinical hyperthyroidism since at least May 2000 her T4 levels are mid range but her T3 is at the upper end of the range. Likely cause is nodular thyroid disease. This is acknowledged as a contributory factor in osteoporosis. Reasonable to treat, although there are no clinical trials to support this recommendation it is endorsed by 2011 American Thyroid Association Guidelines I suggest starting Carbimazole 5mg daily and review TFT in 6 and 12 weeks ideally you would want the TSH to return to the normal range but it may not do so for a while as it has been suppressed for so long. If tolerated then low dose CBZ may be appropriate in the long term, but a dose of RAI is also an option which could be considered perhaps try medical therapy 1 st

23 Case - SCH 76 year old male Cognitive impairment PAF Feb 2010 Admitted with PAF ft4 17.8; ft3 5.7; TSH < 0.01 TPOAb 25.9 (normal) CXR right sided retrosternal goitre CBZ 5mg CBZ

24 Subclinical hyperthyroidism ATA Change of advice 2011 Recommendation 65 When TSH is consistently (> 3 mths) < 0.1 mu/l then treatment should be strongly considered in patients Over 65 yrs of age Post-menopausal women not on HRT or bisphosphonates Patients with cardiovascular risk factors Patients with cardiac disease Patients with osteoporosis Patients with symptoms of hyperthyroidism Recommendation 66 When TSH is consistently (> 3 mths) below the lower limit of normal but > 0.1 mu/l then treatment should be considered in patients Over 65 yrs of age Patients with cardiac disease Patients with symptoms of hyperthyroidism ATA Guidelines 2011

25 Thyroid disease and pregnancy

26 Thyroid disease and pregnancy Key points Positive TPO antibodies in 1 st trimester predict: Post partum thyroiditis Increased risk of miscarriage Mild hyperthyroidism in 1 st trimester (HCG) Does not usually require treatment May be associated with hyperemesis Increased TBG (and other binding proteins) lead to increased total T4 levels during pregnancy If on thyroxine dose adjustment 25-50% usually needed Pregnancy specific reference ranges

27 A+G request pre pregnancy M is trying for a second pregnancy TSH was normal at 2.8 mu/l. Saw a Dr whilst visiting Poland in April 14. Repeat bloods TSH 7, TPO antibodies positive. She was started on thyroxine 50mcg od. UK review May 2014; stop thyroxine for 3 weeks to repeat TFT to see if she was hypothyroid or not. 16th June TSH of 4.0, TPO antibody at iu/ml. Clearly she is not currently hypothyroid, but it would appear that she was borderline in Poland. She is aware that she is likely to develop hypothyroidism in the future. Keen to conceive, anxious that the thyroid may be contributing to her oligomenorrhoea. She would be keen to take low dose thyroxine if this returned her to a regular cycle.

28 A+G request - pre pregnancy My advice would be to re-commence low dose thyroxine therapy initially 25 mcg daily with repeat TFT 4-6 weeks later the objective would be to keep the TSH level in the range mu/l which is considered optimal for women planning pregnancy. The T4 dose may need to be titrated to achieve this. TSH July Oct Dec ft ft3 5.2

29 BMJ 2011, May 9;342 Association between thyroid autoantibodies and miscarriage and preterm birth: metaanalysis of evidence. The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.

30 T4 in Euthyroid Women with Positive TPO Antibodies Protocol 984 pregnancies (11.7% positive TPO Ab) Women with AITD randomised to T4 (n=57) or no T4 (n=58) T4 dose 0.5 mcg/kg/d TSH < mcg/kg/d TSH mc/kg/d TSH > 2 or anti-tpo titre > 1500 Treatment started 3-7 days after booking visit 10.4 weeks Mean T4 dose was ~ 50 mcg/day Results Serum TSH levels in T4 treated group were constant Serum TSH rose in nontreated group Miscarriage rates were lower in T4 treated patients comparable with the 869 TPO ab negative comparison group Negro et al., JCEM 2006, e-publication

31 Pre-term TSH delivery 25% 4 3 Results TPOab + 2 TPOab - 1 TPO+ and T4 TPO+ TPO- Miscarriage Weeks 14 of gestation % TPOab + and T4 TPO+ TPO-

32 ATD and pregnancy Transient hcg mediated hyperthyroidism does not generally require therapy. PTU recommended if ATD started in 1 st trimester. CBZ recommended if ATD started in 2 nd or 3 rd trimester. Refer women with hyperthyroidism on treatment. If on CBZ: Switch to PTU as soon as pregnancy confirmed Switch back to CBZ at beginning of 2 nd trimester (or continue PTU and monitor LFT) Graves disease tends to become less severe as pregnancy progresses Usually possible to reduce dose/stop ATD TRAb monitored placental transfer ATA 2011; NICE CKS 2013

33 Pregnancy and thyroxine Dear colleague, I would be grateful for your advice regarding this 25 yr old lady who is hypothyroid and on 250mcg thyroxine. Her TSH was 3.2 this month and she is estimated to be 4/40 pregnant. She has had 1 prior pregnancy but was not known to be hypothyroid back then. I would appreciate your advice regarding what we should aim for in terms of her TSH target and how much we should increase her dose by given that her thyroxine requirements are already quite high. Many thanks Dear Dr You should aim for the TSH to be in the reference range for pregnancy 1 st trimester is Hence a small increase in thyroxine dose would be appropriate to 275 mcg daily with repeat TFT in 4 weeks please state the stage of pregnancy on the request form as the reference range varies by trimester. An amended TFT report will be issued from the labs taking into account Mrs Smith s pregnancy

34 Reference ranges 1 st trimester 2 nd trimester 3 rd trimester TSH ft ft These will be appended to our reports but please note that these are only added if we are aware that the patient is pregnant.

35 Pregnancy and Thyroxine Check thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels before conception if possible. At diagnosis of pregnancy, immediately increase the levothyroxine dose (25-50 mcg) and check TSH and FT4 levels while waiting for referral to a specialist. Monitor TSH and FT4 levels: Every 4 weeks during titration of levothyroxine. Every 4 weeks during the first trimester, and again at 16 weeks and at 28 weeks of gestation, in a woman who is on a stable dose of levothyroxine. More frequent tests may be appropriate on specialist advice. NICE CKS 2011

36 Post partum thyroiditis 80% 20%

37 Issues in the Management of Hypothyroidism

38 Positive TPO antibodies Dear Colleague, I would be most grateful for your advice regarding the above named gentleman. He has been diagnosed with vitiligo a few months ago and he was seen in the skin clinic. He was given steroids for his vitiligo. The skin clinic arranged some thyroid tests. I have recently reviewed his results and his TSH has come back as 1.9. His thyroid peroxidase antibody level was which is way above the upper normal limit. Clinically this chap is euthyroid and he has got no complaints regarding thyroid dysfunction. I was wondering about the significance of the elevated thyroid peroxidase antibody level or whether we should just monitor things. I would be most grateful for your advice regarding this. Thank you.

39 Positive TPO antibodies Dear Dr X The positive TPO antibodies indicate Hashimoto s thyroiditis, although currently his TSH is normal suggesting normal thyroid function. He has a 2-3% annual risk of developing progressive hypothyroidism. Hence an annual monitoring set of thyroid function tests is recommended. If hypothyroidism develops then he would require treatment with an appropriate dose of thyroxine. Hope that helps

40 ATA Hypothyroidism guidelines Levothyroxine is recommended as the preparation of choice for the treatment of hypothyroidism due to its: efficacy in resolving the symptoms of hypothyroidism long-term experience of its benefits favorable side effect profile ease of administration good intestinal absorption long serum half-life low cost Levothyroxine replacement therapy has three main goals: (i) to provide resolution of the patients' symptoms and hypothyroid signs, including biological and physiologic markers of hypothyroidism (ii) to achieve normalization of serum thyrotropin with improvement in thyroid hormone concentrations (iii) to avoid overtreatment (iatrogenic thyrotoxicosis), especially in the elderly mcg/kg

41 Dear Colleague Case raised TSH despite Thyroxine This lady was noted to have hypothyroidism in 2010 but was not taking her thyroxine in 2011 and was persuaded to start doing so in July You will be able to see her results on NoTIS. Essentially her TSH has gradually fallen as the dose of thyroxin has been increased. The latest dose was up to 225 and her TSH in November 2014 was 9.8. She tells me she is still taking the same amount of drug but her TSH has risen to 65, T4 of 4.2 on a dose of 225. I cannot believe that her requirements are so great to cause this change and it does look at though the poor adherence to agreed therapy. Can you advise if you do ever see cases where patients do require significantly high doses, and if so how one plays it so to minimise risk. Kind Regards

42 Absorption Co-administration of food is likely to impair levothyroxine absorption. If possible, levothyroxine should be consistently taken either 60 minutes before breakfast or at bedtime (3 or more hours after the evening meal) for optimal, consistent absorption. Drugs which potentially interfere with absorption include: Ferrous sulphate Calcium carbonate PPI Aluminium containing antacids Sucralfate Selevamer (phosphate binder) 4 hour gap ATA guidelines 2014 Thyroid 2014, 12,

43 Drug interference recent data Population based electronic linkage study Population increases in TSH % > 5mu/l rise Iron 0 22 mu/l P < % Calcium 0 27 mu/l P < % PPI 0 12 mu/l P < % Oestrogen 0 08 mu/l P < % Population decrease in TSH % < 5mU/l fall Statins 0 17 mu/l P-value % There was no effect with H 2 receptor antagonists or glucocorticoids. Irving et al., Clin Endocrinol. 2015;82(1):

44 Other considerations Variation associated with brand of T4 used Reassess 6-8 weeks post change Atrophic gastritis (Pernicious anaemia) May require dose adjustment H Pylori gastritis Reassess once treated Coeliac disease Reassess once on GFD Short bowel syndrome 1 mg T4 daily personal experience ATA guidelines 2014 Thyroid 2014, 12,

45 Compliance an option Recommendation If prescription of daily levothyroxine is not successful in maintaining a normal serum thyrotropin, weekly oral administration of the full week's dose of levothyroxine should be considered in individuals in whom adherence cannot otherwise be sustained. Supraphysiological T4 levels for 24 hrs, ft3 and TSH remain stable Weak recommendation. Low-quality evidence. ATA guidelines 2014 Thyroid 2014, 12,

46 Try not to Fiddle! Recommendation Although it may be helpful to follow changes in clinical symptoms longitudinally in patients treated for hypothyroidism, symptoms alone lack sensitivity and specificity and therefore are not recommended for judging adequacy of replacement in the absence of biochemical assessment. Therefore, symptoms should be followed but considered in the context of serum thyrotropin values, relevant comorbidities, and other potential causes. Weak recommendation. Low-quality evidence. ATA guidelines 2014 Thyroid 2014, 12,

47 Effect of small changes in T4 dosage effect on symptoms, well being and QoL 56 patients with primary hypothyroidism (at least 100mcg/day T4 dose) Baseline TSH mu/l Randomised to receive 3 thyroxine doses in random order TSH TSH Low placebo Low mcg Middle + 25mcg Middle usual dose High +50 mcg High mcg Outcomes: hypothyroid symptoms questionnaire, treatment preference, SF-36, GHQ-28, cognitive function Walsh JP et al., JCEM 2006

48 Results Low Medium High P TSH < T < T < No effect on Weight Visual analogue scale Pulse SF-36 SBP/DBP GHQ-28 Ankle jerk relaxation times were faster!! Cognitive function tests

49 The Nightmare Fuseli 1781

50 Case I should be grateful for your advice on this patient whom you have seen in the past. She stopped seeing you when she started to see a private Doctor. The reason for this is because she wanted to try T3 alone. I am concerned as the Doctor that she has liaised with doesn't appear to be registered with the GMC anymore. She intermittently has thyroid function tests checked and her T4 is clearly very low as she is not taking any T4 and her T3 is too high. However, she feels well in herself. As she is not seeing this Doctor anymore I asked her if she would consider going back to you to be seen on the NHS, and she would be willing to see you but would like to know, if possible, whether or not it would be possible to treat her mainly with T3, although sh e would be willing to try a small dose of T4. The reason that she worries about taking T4 is that she gets very anxious when she takes T4. I should be most grateful for your advice as I am concerned about her condition and this is the first time she has agreed to stop seeing the other Doctor. I look forward to hearing from you. Yours sincerely

51

52 T4/T3 combination Thanks for this A+G referral. Dr X no longer works at NUH hence I have reviewed the case and lab data. I share your concerns over the patient s unstable thyroid hormone levels which is often seen in cases where T3 is used in addition to T4. This is not an approach that is endorsed by the British Thyroid Association and it is not my practice to use such a combination in treating straightforward hypothyroidism. T3 has too short a half life to allow safe monitoring, and this is one of the main reasons for not recommending its use. In addition blinded clinical trials have not found the claimed advantages in terms of QoL that some patients report. We would be pleased to offer an opinion for this lady but I suspect the advice will be similar from my colleagues also and she may, therefore be disappointed. Hope that helps!!!

53 T4/T3 combination double blinded trial 110 patients Double blind placebo controlled cross over design; 10 week treatment phase, 4 week washout 10mcg T3 substituted for 50mcg T4 Assessments of Thyroid biochemistry Clinical parameters QoL Cognitive function We conclude that in the doses used in this study, combined T(4)/T(3) treatment does not improve well-being, cognitive function, or quality of life compared with T(4) alone. Walsh et al JCEM 2003, 88,

54 Meta-analysis (2006) No difference in the effectiveness of combination versus monotherapy in any of the following items: Bodily pain Depression Anxiety Fatigue Quality of life Body weight Total serum cholesterol, triglycerides, LDL and HDL lipoprotein. Adverse events did not differ between regimens (RR 1.19, 95% CI 0.63, 2.24) Grozinsky-Glasberg S et al. JCEM 2006;91:

55 BTA Statement 2007 The BTA keeps an open mind on whether an appropriate formulation of T4/T3 would, in future provide health and QoL benefits for a subgroup of patients Based on current evidence from rigorous studies of large numbers of patients using currently available formulations of synthetic thyroid hormones, combined T4/T3 cannot be recommended because of a lack of benefit and a small number of undesirable and harmful effects seen on combination treatment.

56 Armour Thyroid Porcine thyroid extract 1 grain ~ 60mg contains ~ 38mcg T4 and 9mcg T3 Ratio of T4:T3 is 4:1 physiological ratio 14:1 Concentrations of T4/T3 not stable FDA enforcement led to withdrawal of bottles of Armour Thyroid in Not available on British Pharmacopeia BTA executive committee statement 2007 No evidence to favour the prescription of Armour Thyroid in the treatment of hypothyroidism over thyroxine sodium.

57 Final case Female 69yrs Hypothyroid ft4 6 pmol/l TSH 4.0 mu/l Started thyroxine Referred as felt worse on throxine despite normal T4 levels LH 0.2 FSH 1.6 Prolactin 2313 SST Baseline cortisol min cortisol 327 Felt better once started on Hydrocortisone WHY??

58 Guidelines no shortage! Hyperthyroidism NICE 2013 Clinical Knowledge Summary BTA 2006 Guidelines RCP 2007 RAI for benign thyroid disease Consensus guidelines British Medical Journal 313(7056), ATA 2011 Endocrine Practice 17(3), Questions? Hypothyroidism NICE 2011 Clinical Knowledge Summary BTA 2006 Guidelines RCP 2009 Consensus statement on the management of primary hypothyroidism. ATA 2014 Thyroid 2014, 24(12),