Joshua Klopper, MD Assistant Professor of Medicine and Radiology Division of Endocrinology, Metabolism and Diabetes joshua.klopper@ucdenver.edu None Topliss and Eastman. MJA Vol 180 16 February 2004
A 33 y.o. white female presents for her annual exam and notes mild fatigue, some difficulty concentrating and dry skin Her vitals and exam are normal Her CBC and BMP are WNL and her TSH is 7mU/ L (ref range 0.5-5) You ask her to repeat her labs in 3 months and her TSH is now 6.8mU/L She asks: What does this TSH mean? How common is this? Do I need any treatment? Biondi et al. Nature ClinPractice Endo & Metab Nov 2005 Vol 1 No 1 BMJ Evidence Centre Oct 2011 The process includes Dietary iodine (I) ingestion Seafood, bread, dairy products Recommended minimum intake is 150 µg/day Active transport and uptake of iodide (I - ) by thyroid gland Stimulated by TSH Occurs via the sodium/iodide symporter Oxidation of I - and iodination of thyroglobulin (Tg) tyrosine residues Coupling of iodotyrosine residues (MIT and DIT) to form T 4 and T 3 Proteolysis of Tg with release of T 4 and T 3 into the circulation
Major role in growth and development Forms proteins Essential for brain development Neural development and function Concentration Memory Cardiovascular function Reproduction Mitochondrial activity and energy expenditure Stimulation of metabolic activity in most tissues TSH TT4 FT4 FT4I TT3 FT3 T3RU The single best test to screen for thyroid dysfunction Indicates an individual s thyroid hormone set point Elevated in primary hypothyroidism Lack of negative feedback by thyroid hormone Suppressed in primary hyperthyroidism Excess negative feedback by thyroid hormone When can one not rely on a TSH? Abnormal pituitary gland Ex.// panhypopituitarism, TSHoma, idiopathic central hypothyroidism
Cooper and Biondi. The Lancet Jan 2012 S0140-6736(11)60276-6 Arch Intern Med. 2000;160:526-534 Arch Intern Med. 2000;160:526-534
Fatigue 3 Cold intolerance 5 Depression Weight gain Weakness 1 Arthralgias Constipation Dry skin 2 Brittle nails Hair loss Menstrual irregularities Carpal tunnel syndrome Poor memory/difficulty concentrating Slow speech 4 Decreased libido PE may be normal with mild hypothyroidism if your clinical suspicion is high, pursue a laboratory evaluation General Hypothermia +/- Goiter Nervous System Somnolence Slow speech Poor concentration Neuromuscular system Delayed relaxation of DTRs GI Large tongue Ascites Cardiorespiratory Hoarse voice Bradycardia Mild hypertension Effusions (pericardial/ pleural) Skin Nonpitting edema Periorbital swelling Coarse hair (secondary/tertiary hypothyroidism) 60-80% Endocrinol Metab Clin N Am 36 (2007) 595 615
In general patients with elevated TSH and positive thyroid antibodies develop hypothyroidism at a rate of ~ 5%/year TPO abs alone ~ 2%/year Odds ratios of developing hypothyroidism Raised TSH alone: 8 for women; 44 for men + TPO abs alone: 8 for women; 25 for men Both increased TSH and abs: 38 for women; 173 for men Clin Endocrinol (Oxf) 1995 Jul;43(1):55-68 Almost all thyroidologists would treat with a TSH > 10mU/L Whether to treat with a TSH between 5-10 mu/l is very controversial Much of the objective data to suggest therapeutic benefit is based on cardiovascular risk Diastolic dysfunction Increased peripheral vascular resistance Diastolic hypertension Increased carotid intimal media thickness Endocrine Reviews 29(1):76 131
Meta- analysis of 11 world- wide prospective cohort studies Subclinical hypothyroidism was defined as TSH 4.5-19.9 miu/l Risk of CHD events, CHD mortality and total mortality was analyzed 55,287 participants with 542,494 patient years of follow- up Median age ranges from studies 46-85 Rodoni et al., JAMA, September 22/29, 2010 Vol 304, No. 12 Rodoni et al., JAMA, September 22/29, 2010 Vol 304, No. 12 High background CV risk Symptoms Goiter + Anti- thyroid abs US evidence of thyroiditis by US Infertility Pregnancy Consider LT4 supplementation Low background CV risk No symptoms No goiter No evidence of autoimmune thyroid disease No fertility issues Elderly No evidence of benefit with LT4 Cooper Endocrine Reviews 29(1):76 131
A 42 y.o. white female presents to discuss her thyroid hormone replacement after being on levothyroxine 88mcg for 6 years with a TSH that has ranged from 1.4-2.1 mu/l. She has generally felt well but recently decided to undergo a body cleanse with a coffee enema followed by a 3 day liquid diet and initiation of a series of antioxidant supplements (she is not exactly sure what is in them). She feels a bit better. One of her friends who encouraged her to undergo the cleanse has told her she is on a natural thyroid hormone replacement called armour thyroid and suggests your patient ask about it. She asks, should I switch to armour thyroid? Armour thyroid Desiccated thyroid hormone LT4 + Liothyronine (T3 - cytomel) combination Levothyroxine (LT 4 ) It feels natural!
T 4 is the primary secretory product of the thyroid gland T 3 is derived from 2 processes The total daily production rate of T 3 is about 15-30 µg About 80% of circulating T 3 comes from deiodination of T 4 in peripheral tissues About 20% comes from direct thyroid secretion 10-12:1 secreted T4:T3 Schimmel and Utiger. Ann Intern Med. 1977 Dec;87(6):760-8 Variable content of thyroxine (T4) and T3 Difficulty in titrating the correct dose of the medication Cardiac risks, especially in elderly patients, of transient supranormal elevations in serum T3 levels Rees- Jones and Larsen. Metabolism Vol. 26, No. 11, 1977 Cooper DS. JAMA. 1989;261:2694-2695 Prospective study 50 euthyroid patients aged 18-65 scheduled for thyroidectomy Prescribed LT4 to achieve normal TSH level 33 included in the non- thyroid cancer group analysis JAMA. 2008;299(7):769-777
JAMA. 2008;299(7):769-777 Escobar- Morreale et al., J Clin Endocrinol Metab 90: 4946 4954, 2005 Levothyroxine For a young, healthy person full replacement is 1.6 mcg/kg In general, you can start ~ 50-100 mcg FDA considers generics to be bioequevalent There could be up > 10% difference in absorbed (effective) dose by FDA standards 125mcg - > 137mcg = ~10% dose change This increase in dose is clinically relevant
Recheck TSH 5-6 weeks after starting therapy or changing the LT4 dose LT4 has a ½- life of 5-7 days It takes ~five ½- lives to reach steady state Treatment goal 0.5-2.5 mu/l Hollowell et al. JCEM 87(2):489 499 65 patients completed the study Each went randomly through three 8- week dosing schedules with cross- over after each period Before breakfast (1 hour) With breakfast QHS (after 2 hour fast) Normal TSH on at least 75mcg of LT4 Bach-Huynh et al. JCEM 94: 3905 3912, 2009
TSH: 1.06 2.93 2.19 Bach-Huynh et al. JCEM 94: 3905 3912, 2009 90 patients Blinded to starting AM LT4 and PM placebo or vice versa No differences in serum Cr, lipids, BP, BMI or HR No differences in mood based on SF- 36 Preference of time to take 34 AM 31 PM 25 no preference Arch Intern Med. 2010;170(22):1996-2003 Malabsorption Syndromes Postjejunoileal bypass surgery Short bowel syndrome Celiac disease Reduced Absorption Colestipol hydrochloride Sucralfate Ferrous sulfate Food (eg, soybean formula) Aluminum hydroxide Cholestyramine Sodium polystyrene sulfonate Calcium Drugs That Increase Clearance Rifampin Carbamazepine Phenytoin Factors That Reduced T 4 to T 3 Clearance Amiodarone Selenium deficiency Other Mechanisms Lovastatin Sertraline Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8 th ed. 2000. Synthroid [package insert]. Abbott Laboratories; 2003.
TSH Level, µiu/ml 6 5 4 3 2 1 Ferrous Sulfate Effect on TSH Levels in Patients With Hypothyroidism P<.001 0 Before Ingestion After Ingestion Campbell NR, et al. Ann Intern Med. 1992;117:1010-1013. Participants, % 100 80 60 40 20 0 Colorado Thyroid Disease Prevalence Study 0.9 Hyperthyroid Overtreated >20% 20.7 Subclinical Hyperthyroid 60.1 Euthyroid 17.6 Subclinical Hypothyroid Undertreated >18% 0.7 Hypothyroid Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. A 42 y.o. woman presents 1 year after initiating LT4 for hashimoto s thyroiditis induced hypothyroidism It took about 3 months to titrate her LT4 to achieve an optimal TSH For the last 9 months her TSH has ranged between 0.8-1.4 on a total of 3 checks (including today) She feels better than when she was diagnosed but not right Difficult to fully describe but just not the same energy, concentration, mood, etc She has no other medical problems, a normal BMI, does not smoke, describes no significant stressors in her life, drinks no more than 3 drinks/week, sleeps generally well 7-9 hours/night and gets moderate exercise (walking/ swimming/biking) at least 4 days/week She asks, should I switch to armour thyroid?
Prospective cohort study of 426 euthyroid females undergoing surgery for benign goiter Patient numbers No hashi 398 Hashi 28 Outcomes Preoperative anti- TPO levels Symptom questionnaire SF- 36 questionnaire Histological evaluation of the thyroid gland for lymphocytic infiltration Ott et al., Thyroid Volume 21, Number 2, 2011 TSH similar in all patients (1.5-1.7) 6.6% of subjects had histological evidence of Hashi Cut- off of anti- TPO levels >121.0IU/mL Best correlation with histopath c/w Hashi Overall symptoms worse in those with +anti- TPO abs Chronic fatigue Dry Hair Easily fatigued Chronic weakness Dysphagia Chronic irritability Chronic lack of concentration Chronic nervousness Pre- operative anti- TPO abs were highest in those with > 6 symptom complaints BMI was statistically higher in this group compared to the others Ott et al., Thyroid Volume 21, Number 2, 2011 Type 1 (D1) and Type 2 (D2) deiodinase enzymes are primarily responsible for converting T4- >T3 in the periphery D1 Primarily liver and kidney D2 Primarily heart and brain Polymorphisms Natural variations in a gene, DNA sequence, or chromosome occurring with fairly high frequency in the general population The most common type of polymorphism involves variation at a single base pair Often occurring in more than 1% of a population Can deiodinase polymorphisms alter conversion of T4 to T3? Gereben et al., Endocrine Reviews 29(7):898 938
Retrospective analysis of 522 patients from the Weston Area T4T3 Study (WATTS) Overall negative study of T4- > T4+T3 Primary outcome was improvement of the GHQ- 12 General Health Questionnaire J Clin Endocrinol Metab 94: 1623 1629, 2009 552 patients had DNA available for genotyping D2 polymorphisms showed an association with psychological well- being Base combinations of thymine (T) and cytosine (C) TT TC CC J Clin Endocrinol Metab 94: 1623 1629, 2009 CC genotype was present in 16% of the population Worse baseline GHQ scores CC genotype demonstrated greater improvement of T4+T3 relative to other genotypes at 3 and 12 months follow- up No impact on circulating thyroid hormone levels J Clin Endocrinol Metab 94: 1623 1629, 2009
Should all hypothyroid patients be treated with combination LT4/LT3 therapy? No Should any hypothyroid patients be treated with combination LT4/LT3 therapy? Reasonable if symptoms persistent on optimal LT4 therapy When using combination LT4/LT3 therapy, the optimal T4:T3 ratio is ~ 10:1. Hypothyroidism is common Especially mild (subclinical) hypothyroidism A TSH is the only diagnostic testing you need in the majority of patients Thyroid abs can be helpful in predicting who will go on to full thyroid failure in mild hypothyroidism The vast majority of patients do well on LT4 therapy alone The optimal TSH level for the majority of patients is 0.5-3 Cooper and Biondi. The Lancet Jan 2012 S0140-6736(11)60276-6