The Thyroid Gland A Primer for the Primary Care Physician

The Thyroid Gland A Primer for the Primary Care Physician Brandon Allard, M.D. Sioux Valley Clinic - Endocrinology October 13, 2005 Overview       Introduction Thyroid Physiology Thyroid Tests Hypothyroidism Hyperthyroidism Structural Thyroid Disease (Goiter/ Nodules/Thyroid Cancer) Introduction The Thyroid Gland  Named after the thyroid cartilage (Greek: Shield-shaped)  Wharton 1656: “glandulae thyroidaeae” “whose purpose is to….. beautify the neck…. particularly in females to whom for this reason a larger gland has been assigned” The Thyroid Gland  Vercelloni 1711: “a bag of worms” whose eggs pass into the esophagus for digestive purposes  Parry 1825: “a vascular shunt” to cushion the brain from sudden increases in blood flow Beware of “Experts” Thyroid Physiology Thyroid Embryology  Derived from endodermal tissue at base of tongue  Embryonal remnants form Thyroglossal duct; pyramidal lobe; lingual thyroid  Fuse with C-cells (neural crest origin), derived from the the 5th branchial arch  C-cells scattered through posterior/superior lobes Thyroid Anatomy endocrine gland (20 - 25 g)  Fills the tracheoesophageal space  Overlies RLN bilaterally  Largest  Parathyroids lie at each pole (usually!) Thyroid Histology  Follicles contain colloid  Epithelium is cuboidal, and monolayer  Minimal stroma  Colloid contains thyroglobulin and thyroid hormone precursors Thyroid Ultrastructure F: Follicles I: Stroma “Bumps” are follicular cells Cells have “rough surface” of microvilli • • • • TSH  A pituitary glycoprotein  Heterodimeric (alpha and beta subunits)  Alpha is common to several pituitary glycoprotein hormones  Beta is unique  Incomplete specificity, so cross-talk is possible  Circulates at pico-molar concentrations (10-12)  Second messenger systems needed Thyroglobulin  Major protein product of follicular cells  Released into circulation with thyroid hormone  “Catalyst” as well as storage role in the thyroid  Native structure essential for T4 production The Concentration of Iodine  Central role in thyroid homeostasis  30-fold concentration of iodine from serum to thyroid  Gut uptake in upper GI tract (stomach / duodenum)  Potent renal reabsorption The Follicular Cell Colloid Pendrin K I TSH Na NIS Na T4 and T3 I Na I Extracellular fluid Thyroid Peroxidase O HO C C C NH2 OH I HO I C C C O NH2 OH Tyrosine H2O2 + O- H2O + O2 Mono-iodo Tyrosine TPO Tetra-iodo Thyronine H2O2 + OH2O + O2 HO I C C C NH2 OH O I Di-iodo Tyrosine Thyroid Hormones  The thyroid produces T3 and T4  T4 ( Tetraiodothyronine )  T3 ( Triiodothyronine ) , Reverse T3 T4 T3 Thyroid Binding Proteins  Thyroid hormones are highly lipophilic  Majority (>99%) circulate bound to proteins  Thyroid binding globulin (TBG) ~70%  Albumin ~15 - 20%  Transthyretin (TTR) ~10%  Lipoproteins ~2 - 5% Binding Protein Abnormalities Decreased binding capacity Increased binding capacity  TBG deficiency (inherited)  Dysalbuminemic  Decreased hepatic  Increased hepatic synthesis synthesis of TBG of TBG     - Malnutrition - Severe illness - Hepatic failure - Hypothyroidism  - Estrogens  - Pregnancy  - Hyperthyroidism  Protein wasting states  Mutations of TBG / TTR Thyroid Hormone Receptor  High lipid solubility ensures easy passage across cell membrane  A member of the T3 “Thyroid-Steroid-Vitamin D Receptor Superfamily”  Action is principally within the nucleus, altering gene regulation Thyroid Hormone Degradation  Deiodination of the inner ring produces rT3 (from T4) or T2 (from T3)  Further deiodination conserves iodine, which is recycled  Final product is thyronine (T0)  Liver and kidneys are main sites of metabolism T4 T3 rT3 T2 Thyroid Hormone Homeostasis Negative feedback of T4 and T3 on the hypothalamus and pituitary, inhibit TSH production and release Both hypothalamus and pituitary depend on local conversion of T4 to T3 in order to “sense” T4 concentrations Thyroid Tests Thyroid Hormone Production Thyroid Tests  TSH - a pituitary hormone  T4 ( Free or Total ) - a thyroid hormone  T3 ( Free, Total, reverse ) - a thyroid hormone Thyroid Tests  TPO, anti-microsomal, and anti-thyroglobulin antibodies (tests sometimes used to confirm Hashimoto’s Thyroiditis)  Thyrotropin receptor antibodies, TSI (tests sometimes used to confirm Grave’s disease) Thyroid Tests  Thyroglobulin - a byproduct of thyroid hormone production  Thyroid Uptake - percentage of iodine taken up in a given time period  Thyroid Scan - a picture of where iodine is being utilized by the thyroid gland Thyroid Tests  Thyroid Ultrasound – the highest resolution imaging study for the thyroid gland  Other Imaging Studies – PET, MRI, CT are other imaging studies that are occasionally used (especially with thyroid cancer) Clinical Application Thyroid Disease in the Community  Hypothyroidism  4.5/1000/year  0.6/1000/year  Hyperthyroidism  0.8/1000/year  0.2/1000/year  Thyroid carcinoma  Up to 10% of autopsies  1% of all cancers Thyroid Disease in the Community  Women are at greater risk than men (5 : 1)  Pregnancy and the post-partum period present a higher risk  In general incidence increases with age Thyroid Disease in the Community  A family history of thyroid disease increases risk substantially  People with autoimmune disorders are at higher risk  Medication/ exposures can increase risk (amiodarone, lithium, radiation therapy) Hypothyroidism Hypothyroidism Case Study  A 60 year old woman presents new symptoms to her family physician  Symptoms include fatigue, dry skin, and depression (weight is stable) Hypothyroidism Case Study  Slow onset one year ago but progressively getting worse  There is a family history of thyroid problems with her sister and mother being affected Hypothyroidism Case Study  Physical exam is remarkable for a slightly enlarged thyroid, very dry skin, coarse hair, and a “dull” swollen face Hypothyroidism Hypothyroidism Case Study  Thyroid tests performed with results as follows: TSH 30 mIU/L ( 0.35 to 5.5 ) Free T4 0.8 ng/dL ( 0.7 to 1.9 ) Hypothyroidism Hypothyroidism Causes of hypothyroidism:  Autoimmune (AKA Hashimoto’s thyroiditis) Surgical removal of thyroid gland   History of radioablation Hypothyroidism Causes of hypothyroidism:  Drug induced (Lithium)  Iodine deficiency (not often seen in USA, most common cause worldwide) Pituitary Dysfunction  Hypothyroidism  Signs and symptoms can be subtle Fatigue, weight gain, and dry skin are common and therefore of limited utility in selecting patients for thyroid screening   Laboratory testing with TSH offers a straightforward screening test Hypothyroidism Unrecognized hypothyroidism results in largely subjective (but important) clinical issues: - Mental health issues - Diminished quality of life Hypothyroidism Other problems associated with hypothyroidism: - Hyperlipidemia / Heart Failure - Infertility (female) - Fetal neuro-cognitive impairment Symptoms of Hypothyroidism        Fatigue Depression Cold intolerance Heart failure/ Hyperlipidemia Constipation Menstrual changes Dry skin / hair loss Hypothyroidism Treatment: Thyroid hormone is easily taken in tablet form Various preparations are commercially available  levothyroxine (generic)  Synthroid (trade name levothyroxine)  Armour thyroid (desiccated thyroid) Hypothyroidism Treatment:  Thyroid hormone is very safe (a natural hormone) and has no side effects unless over/under-dosed  Weight based starting dose of 1.7 mcg/ kg  The elderly and those with cardiovascular disease should start at a low dose and slowly taper upwards Hypothyroidism Treatment:  The goal of treatment is to relieve symptoms and restore normal hormone levels  Thyroid labs ( TSH, Free T4 ) should be within normal range when treated Hypothyroidism Treatment:  I target a low-normal TSH  After any dose adjustment TFT’s need to be tested 2-3 months later (no sooner) Hypothyroidism Treatment:  Once yearly monitoring thereafter unless new clinical symptoms develop  Once on a stable dose, switching hormone products (generic to generic, generic to trade, trade to generic) should be avoided if possible Hypothyroidism Treatment:  Calcium and Iron taken concurrently with thyroid hormone reduce absorption  Thyroid hormone has a very long half life (a missed dose is better taken late than skipped) Hypothyroidism Treatment:  Dose should be increased empirically with discovery of pregnancy (25%)  Thyroid cancer patients are given a modestly supra-physiologic dose to suppress TSH Hyperthyroidism Hyperthyroidism Case Study A 24 year old woman presents for assessment of new symptoms Symptoms include racing heart, anxiety, feeling of warmth, weight loss, disturbed sleep, and light, irregular periods Hyperthyroidism Case Study Symptoms began abruptly and are getting worse There is no family history of thyroid problems The patient also has Type 1 diabetes Hyperthyroidism Case Study Exam is remarkable for a modest goiter, tremor, perspiration and tachycardia Hyperthyroidism Hyperthyroidism Case Study  Thyroid tests performed with results as follows: TSH <0.02 mIU/L ( normal range 0.35 to 5.5 ) Free T4 2.4 ng/dL ( normal range 0.7 to 1.9 ) Hyperthyroidism Symptoms of Hyperthyroidism  Anxiety  Sleep Disturbance  Heat intolerance  Tremor  Racing Heart  Frequent BM’s  Irregular periods  Muscle weakness  Osteoporosis Hyperthyroidism Hyperthyroidism is less common than hypothyroidism but not rare Hyperthyroidism is often unrecognized until serious problems appear (A-Fib, osteoporosis) Poses less risk to pregnancy than hypothyroidism Hyperthyroidism Causes of Hyperthyroidism:  Graves’ disease  Thyroiditis  Exogenous Hyperthyroidism Causes of Hyperthyroidism:  Solitary toxic nodule  Toxic multi-nodular goiter  Drug induced (Lithium, Amiodarone) Hyperthyroidism Treatment:  Dependent on etiology  Radioiodine, anti-thyroid medications and surgery are amongst treatment options  Subclinical hyperthyroidism is generally treated Hyperthyroidism and Atrial Fibrillation  2007 Framingham Study participants over 60 yo.  “Low TSH”: <0.1mU/L  New onset AF at 10 year follow-up exam (n=13).  Only 2/13 (15%) had clinical hyperthyroidism Sawin et al NEJM (1994) Hip Fracture Rate in 9516 Women (per 1000 person years) 30 25 20 15 10 5 0 5+ 3 to 4 0 to 2 # of risk factors Lowest Middle Highest Relative Risk Age 1.5 Disability 2.1 Inactivity 1.7 Caffeine 1.3 Hyperthyroidism1.8 Family history 2.0 Anticonvulsants 2.8 Cummings et al NEJM (1995) To Screen or Not to Screen? That is a good question… Screening There are no clear consensus guidelines ATA (American Thyroid Association) - Recommend all adults be screened (TSH) at age 35 and every 5 years thereafter AACE (American Association of Clinical Endocrinologists) - Recommend screening of women of childbearing age before pregnancy or during first trimester Screening USPSTF (US Preventative Services Task Force) - Conclude there is insufficient evidence to recommend for or against routine screening of adults ACP (American College of Physicians) - Recommend screening all women older than 50 with one or more general symptoms that could be caused by thyroid disease Screening AAFP (American Academy of Family Physicians) -Recommends against routine screening in asymptomatic patients younger than age 60 Screening Any screening statement based on symptomology is clinically useless What percentage of your adult patients are gaining weight, have fatigue, are constipated or have problems with dry skin?... ask them if you dare Screening How do we put this all together? 1) Thyroid dysfunction is common, especially in women 2) An inexpensive screening test with excellent sensitivity and specificity is available (TSH) While it may be appropriate not to mandate screening, there should be a low threshold for testing 3) Screening 4) Patients with hyperlipidemia, osteoporosis, depression, anxiety, infertility (female), irregular menses and new onset atrial fibrillation should be screened once for thyroid disease The fetal risk associated with subclinical hypothyroidism justifies screening of pregnant women on medical-legal grounds alone 5) Screening 6) In the absence of evidence-based screening guidelines of clinical utility, the individual clinician is left to use their judgment when deciding when to obtain thyroid function studies This lack of guidance is not a hindrance to providing good medical care 7) Structural Thyroid Disease ( Goiters, Nodules, & Thyroid Cancer ) Goiter  An enlargement of the thyroid gland Multiple causes ( can be associated with euthyroid, hypothyroid, or hyperthyroid conditions )   When very large, goiter can cause dysphagia difficulty and airway compromise Goiter  Multi-nodular goiter is an enlargement of the gland with associated nodularity Hashimoto’s Thyroiditis (most common cause of hypothyroidism) is often associated with a small goiter   Grave’s disease often presents with goiter Goiter  Treatment of the underlying disorder can often shrink a goiter ( Grave’s, Hashimoto’s ) Multi-nodular goiter generally does not respond to treatment and occasionally requires surgical removal  Goiter Thyroid Nodule  A “lump” in the thyroid gland Often felt by the patient first though generally non-tender Progressively more common with aging   Thyroid Nodule  85% benign, 15% malignant Requires assessment of thyroid hormone levels and biopsy if large enough to palpate FNA (fine needle aspiration) is a simple office biopsy procedure that is the gold standard for assessing larger nodules   Thyroid Nodule  Thyroid incidentalomas are often found with carotid US and neck CT studies Management as per palpable nodules with FNA of lesions greater than 1cm (some authors suggest 1.5cm)  Thyroid Nodule  Surveillance of nodules post-biopsy is without a standard of care Nodule suppression with exogenous hormone is largely ineffective Benign nodules occasionally excised due to cosmesis or mass effect   Thyroid Cancer  Presents as a thyroid nodule FNA will identify about 15% of thyroid nodules as being malignant Treatment begins with total thyroidectomy   Thyroid Cancer  After surgery I 131 is often used to ablate remnant tissue Hormone replacement dose is usually maintained in supraphysiologic range to suppress TSH  Thyroid Cancer  Thyroid cancer generally carries an excellent prognosis Many factors influence the risk for recurrence (age, gender, size of tumor, invasiveness, lymph node involvement) Monitoring for recurrence is obligate   Questions? The Thyroid Gland A Primer for the Primary Care Physician Brandon Allard, M.D. Sioux Valley Endocrinology May 25, 2005