Clinical Applications: Thyroid Dysfunction and Diagnosis Online Training

Welcome to the Thyroid: Dysfunction and Diagnosis Online Training course. This course will review the physiology of the thyroid and common causes and diagnosis of thyroid function.  It will also focus on the essential role that thyroid tests play in the diagnosis and monitoring or patients with thyroid dysfunction. Select Next to continue. This course was developed by Dr. Steven Brimmer.   Upon successful completion of this course you will be able to: Outline the causes and management of hyperthyroidism and hypothyroidism State the key aspects in effective use of thyroid tests Describe the role of thyroid tests in the management of thyroid cancer Two primary thyroid hormones: Thyroxine – T4 – “pro-hormone” Thyroid gland produces primarily T4   Triiodothyronine – T3 – most active 85% of T3 produced by peripheral deiodination Functions Alter gene expression, protein production Regulate metabolism of proteins, fats, carbohydrates Essential for normal development of fetal / newborn brain function Kaplan. Clinical Chemistry, 4th Ed. Thyroid. Chapter by Fernandez-Ulloa, 2003. p.827-48. American Thyroid Association. Thyroid Disorders and Pregnancy.   www.thyroid.com Regulation primarily through hypothalamic / pituitary axis Controlled by negative feedback Thyroid disease classified by: Concentration of thyroid hormones Too little — Hypothyroidism Too much — Hyperthyroidism   Location of pathology Primary (1°) disease involves thyroid gland Secondary (2°) disease involves pituitary Tertiary (3°) disease involves hypothalamus Hypothalamus TRH TSH TSH Thyroid Gland Target Tissue T4 T3 T4 → T4 → T3 in brain in pituitary Pituitary 1° Disease 2° Disease 3° Disease Kaplan. Clinical Chemistry, 4th Ed. Thyroid. Chapter by Fernandez-Ulloa, 2003. p.827-48. Country Population Hypothyroid Hyperthyroid Great Britain 1 Wickham Study (n=2779)  randomly selected 9.3% females 1.3% males 3.9% females 0.2% males United States 2 NHANES III data 0.3% overt 4.3% subclinical 0.5% overt   0.7% subclinical Colorado 3 Statewide health fair  (n= 25,862) 0.4% overt 9.0% subclinical 0.1% overt 2.1% subclinical Netherlands 4 Nijmegen Biomedical Study (n=5167) 0.4% overt 4.0% subclinical 0.4% overt 0.8% subclinical China 5 Chemical Company Employees in Ningbo (n=10,405) 0.3% overt 3.4% subclinical 0.4% overt   0.8% subclinical China 6 Young women Mean age 27.6 0.3% overt 7.2% subclinical 1.0% overt  0.8% subclinical Spain 7 Subset  >60 yrs. 6.9% 3.3% 1  Vanderpump et al. Clin. Endocrine (1995) 43:55-68 2  Hollowell et al. J Clin Endocrinol Metab (2002) 87:489-99. 3  Canaris et al. Arch Intern Med. 2000;160:526-534 4  Hoogendoorn  et al. Clin Chem. 2006 (52):104-11. 5  Mao Chin Med J (Engl). 2010 ;123(13):1673-8. 6  Wang et al. European Journal of Endocrinology (2011) 164 263–268 7  Lucas. Endocrine. 2010 :38(3):391-6.   Hazard rate (per 1000 women/year) Age (years) Hypothyroidism Hyperthyroidism Risk of hypothyroid disorders increases with age  Vanderpump et al. Clin. Endocrin (1995) 43:55-68 Total T4 / Total T3 Free T4 / Free T3 T3 uptake Thyroxine-binding globulin TSH Third generation TSH Anti-thyroperoxidase antibody (Anti-TPO) TSH Receptor Antibody (TRAb) Thyroid Stimulating Immunoglobulin (TSI or TSAb) Thyroglobulin Anti-thyroglobulin antibody   99%+ of thyroid hormones are bound to proteins Total T4 and Total T3 tests measure bound and free together Free hormone concentration correlates with clinical status Total hormone concentration depends on binding proteins Due to much lower concentrations, T3 and, especially Free T3, are difficult measurements T4 T4 T3 T3 99.97% 99.7% Active hormone Estimating Free thyroid hormone concentration: T uptake: first method used to estimate binding protein status Result is ratio of patient binding to reference sample (THBR) Adjusts Total T4 result for binding proteins: Free T4  (estimate) = Total T4 x THBR Measure actual free T4 Reference methods:  equilibrium dialysis or ultra-filtration Routine immunoassays << Recommended approach ~1990 noted that small changes in FT4 caused large changes in TSH – noted log / linear relationship Sensitivity of TSH to change in FT4 makes TSH most sensitive test to indicate thyroid disease TSH, µIU/mL EUTHYROID EUTHYROID FREE T4 ESTIMATE Interassay %CV TSH, µIU/mL 3rd Generation Assays 2nd Generation Assays 1st Generation Assays Functional Sensitivity Profoundly Low Mildly Low Euthyroid Range Nicoloff, Spencer, J Clin Endo Met, 71, 1990, 553-558 For optimal diagnostic use, TSH assay needs to be able to measure very low concentrations 3rd generation TSH tests were first to have necessary sensitivity with adequate precision American Association of Clinical Endocrinologists: TSH assay should always be used as the primary test to establish the diagnosis of primary hypothyroidism. The most valuable test is a sensitive measurement of TSH level. The sensitive TSH assay is the single best screening test for hyperthyroidism and in most outpatient clinical situations, the serum TSH is the most sensitive test for detecting mild (subclinical) thyroid hormone excess or deficiency.   Anti-TPO: Thyroperoxidase (TPO) converts iodide to organic iodine for synthesis of thyroid hormones. Antibodies in certain autoimmune diseases (e.g. Hashimoto’s thyroiditis) block the enzyme’s function Presence of these antibodies assists in differentiating autoimmune disease from other hypothyroid conditions. TSI or TRAb: Antibodies to TSH receptor can block receptor binding or stimulate the receptor. Present in 95% of patients with Graves’ disease. TRAb: Antibodies to TSH receptor can block receptor binding or stimulate the receptor. Presence of these antibodies helps confirm Graves’ disease. Dysfunction, Disease & Diagnosis     Overt Disease: patient has symptoms of thyroid disease as well as abnormal results for thyroid tests Subclinical Disease: no thyroid disease symptoms  are present, but thyroid test results are abnormal British Thyroid Association. http://www.british-thyroid-association.org/info-for-patients/Docs/TFT_guideline_final_version_July_2006.pdf Abnormal thyroid hormone levels due to non-thyroidal illness: Known as Euthyroid Sick Syndrome   Greater changes seen with more severe acute illness   T3 most affected / TSH least affected   Thyroid status returns to normal on recovery from acute illness Interpret thyroid test results with care in acutely ill patients: Total and free thyroid hormone results may be impacted by changes in binding proteins   TSH may be depressed, then rebound high briefly during recovery   Drugs used can also impact thyroid tests   Glucocorticoids and dopamine cause decreased TSH   Amiodarone increases TSH Hypothyroidism….Insufficient hormone FT4 TSH Hypothyroid Symptoms: feel colder frequently tired dry skin forgetfulness depression constipation irregular menstruation No symptom is unique to Hypothyroidism American Thyroid Association. Hypothyroidism brochure. www.thyroid.org American Thyroid Association. Hypothyroidism  booklet. www.thyroid.org   Myxedema coma  (rare): Life threatening, mortality rates 25% to 75% Extreme hypothermia (24°C to 32.2°C) Complication of long term hypothyroidism Cardiovascular disease/dysfunction Hypercholesterolemia Impaired cardiac function (diastolic and systolic) Increased systemic vascular resistance Decreased cardiac output Thyroid. The Merck Manual. 18th ed. 2006. p.1192-1206. Landenson PW.  Thyroid. ACP Medicine. 2010. p.1-25. Rodriguez I. J Endocrinol. 2004 Feb;180(2):347-50.   Iodine deficiency (Globally) Autoimmune disease (Hashimoto’s thyroiditis) Surgical removal of part or all of the thyroid gland Radiation treatment with I131 American Thyroid Association. Hypothyroidism brochure. www.thyroid.org Risk Factors for Autoimmune Hypothyroidism: Family history:  autoimmune thyroid disease Age:  Risk increases > 50 years Gender: More common in women Ethnicity: more common in Caucasians and Asians History of other autoimmune disease American Thyroid Association. Hypothyroidism brochure. www.thyroid.org American Thyroid Association. Hypothyroidism  booklet. www.thyroid.org Overt Disease Test Result TSH High Free T4 Low Free T3 Low to Normal Anti-TPO May be present TRH TSH TSH Thyroid Gland hypothalamus pituitary T4 >> T3 T4 T3 T4 >> T3 Target Tissue T4 T3 To evaluate structural abnormalities: Thyroid scan Ultrasound Clarke & Dufour, ed. Contemporary Practices in Clinical Chemistry. (2006) Chapter 32 by Cook. Thyroid Disorders. P.365-375. American Thyroid Association. Hypothyroidism booklet.  www.thyroid.org Subclinical Disease Test Result TSH High Free T4 Normal Free T3 Normal Anti-TPO May be present Progresses to overt disease in 3% to 20% of cases   Clarke & Dufour, ed. Contemporary Practices in Clinical Chemistry. (2006) Chapter 32 by Cook. Thyroid Disorders. P.365-375. American Thyroid Association. Hypothyroidism booklet.  www.thyroid.org Thyroxine (T4) replacement Outpatient lifetime therapy w/ daily dose except myxedema patients – hospitalized Initial dose may have to be adjusted after 6 to 10 weeks, take TSH levels and adjust accordingly Once dose is adjusted to patient monitor TSH & Free T4 annually American Thyroid Association recommends against changing thyroxine brand. If dose or brand is changed, need to monitor TSH 6 to 12 weeks later. American Thyroid Association. Hypothyroidism brochure. www.thyroid.com   Symptoms are subtle: Decreased activity Increased sleep Feeding difficulty Constipation Prolonged jaundice Rastogi M. Orph J of Rare Disea. 2010 5:17 Deficiency present at birth Permanent Transient Causes ~85% Thyroid Gland development disorder 10% to 15% hormone synthesis disorder Risk of mental retardation Cretinism in severe cases Preventable with T4 therapy Therapy needs to start quickly Rastogi MV. Orphanet J Rare Dis. 2010 Jun 10;5:17. Prevalence varies Country Years Prevalence Country Years Prevalence China (Tianjin) 1982–2001 1:6467 Philippines 1996–2003 1:3284 Norway 1985–1988 1:4868 Spain 1985–1988 1:3234 France 1985–1988 1:4289 USA 1991–2000 1:3044 Germany 1985–1988 1:4116 Singapore 1981–1999 1:3000 New Zealand Up to 1983 1:3475 Saudi Arabia 1985–1991 1:2097 Indonesia (Bandung) 2000–2002 1:3469 Pakistan 2000–2002 1:1000 Screening of newborns for congenital hypothyroidism : guidance for developing programs.  Vienna : International Atomic Energy Agency, 2005. American Thyroid Association. Thyroid Disease and Pregnancy.  www.thyroid.com Congenital Hypothyroidism: Diagnosis Initial tests Total T4 screen TSH Free T4 Other tests Ultrasound Thyroglobulin Thyroid uptake/scan Rastogi M. Orph J of Rare Disea. 2010 5:17 Test Value TSH High Free T4 Low Total T4 Low to Normal Hyperthyroidism…Excess hormone FT4 TSH Hyperthyroid Symptoms: nervousness / anxiety irritability increased perspiration heart racing hand tremors difficulty sleeping thinning of skin fine brittle hair muscle weakness No symptom is unique to Hyperthyroidism American Thyroid Association. Hyperthyroidism brochure. www.thyroid.com Thyroid storm Life threatening, requires immediate therapy Confusion, psychosis, coma Fever, nausea, vomiting, diarrhea Cardiovascular collapse Cardiovascular disease/dysfunction Decreased systemic vascular resistance Increased cardiac output Systolic hypertension Thyroid. The Merck Manual. 18th ed. 2006. p.1192-1206. Graves’ disease (~70%) Multi-nodular goiter Thyroiditis American Thyroid Association. Hyperthyroid Brochure. www.thyroid.org Graves’ Disease Family history: relatives w/ Graves’ Disease Gender: 5 - 10x higher risk in females Age: typically < 40 years Other autoimmune disorders Emotional or physical stress: Stressful life events or illness increases risk Pregnancy: increases the risk www.mayoclinic.com/health/graves-disease/DS00181/DSECTION=risk-factors Overt Disease Test Result TSH Low Free T4 High Free T3 High to Normal Anti-TPO May be present TRAb May be present TSI May be present Clarke & Dufour, ed. Contemporary Practices in Clinical Chemistry. (2006) Chapter 32 by Cook. Thyroid Disorders. P.365-375. American Thyroid Association. Hypothyroidism booklet.  www.thyroid.com TRH TSH TSH Thyroid Gland Target Tissue T4 T3 T4 T3 T4 >> T3 T4 >> T3 hypothalamus pituitary Subclinical Disease Test Result TSH Low Free T4 Normal Free T3 Normal Rarely progresses to overt hyperthyroidism 0.5% to 0.7% of cases Repeat tests in 2 to 4 months   Anti-thyroid Medication methimazole (Tapazole®) propylthiouracil  (PTU) Radioactive iodine (Thyroid ablation) Surgery (Partial & Complete removal) Following radioactive Iodine or surgery, patients may become hypothyroid, requiring treatment with thyroid hormone. American Thyroid Association. Hyperthyroidism brochure. www.thyroid.org American Thyroid Association. Thyroid Disease & Pregnancy brochure. www.thyroid.org   Excess hormone present at birth Usually secondary to maternal Graves’ disease Rare: 0.01% of pregnancies Presence of TSI is risk factor Higher levels, higher risk Fetal risks Preterm delivery Death Growth restriction Usually resolves within 4 months Endocrine Society’s Clinical Guidelines. J Clin Endocr Metab. 2007;92(8):S1-S47 Polak M, et al. Horm Res 2006;65:235–242 Test Result TSH Low Free T4 High Free T3 High to Normal Initial tests include: TSH Free T4 Free T3 Polak M, et al. Horm Res 2006;65:235–242 Hypothyroidism, untreated Maternal hypertension, preeclampsia, anemia, Spontaneous abortion, fetal death, abnormal brain development Hyperthyroidism, untreated Miscarriage, placenta abruption, preterm delivery Preeclampsia Both should be treated Endocrine Society’s Clinical Guidelines. J Clin Endocr Metab. 2007;92(8):S1-S47. Lazarus JH. British Medical Bulletin. 2010 Dec 23;1-12. Physiologic State TSH Free T4 Free T3 Primary Hyperthyroidism Low High High Secondary Hyperthyroidism Normal to High High High T3 Hyperthyroidism (T3 toxicosis) Low Normal High Subclinical Hyperthyroidism Low Normal Normal Primary Hypothyroidism High Low Low to Normal Secondary Hypothyroidism Normal to Low Low Low to Normal Subclinical Hypothyroidism High Normal Normal Thyroid. The Merck Manual. 18th ed. 2006. p.1192-1206. Mueller AF, et al.  Neth J Med. 2008 Mar;66(3):134-42. TSH Low Low Low Normal Normal Normal Normal High High High High Free T4 Free T4 T3 No primary dysfunction Hyperthyroidism Thyrotoxicosis Subclinical hypothyroidism T3  toxicosis Subclinical hypothyroidism Overt hypothyroidism Central hypothyroidism or Thyroid hormone resistance Supersellar pathology or Non-thyroid illness   Symptoms: Lump in the front of the neck Hoarseness or voice changes Swollen lymph nodes in the neck Trouble swallowing or breathing Pain in the throat or neck Most often it is not thyroid cancer, but need to rule cancer out. > 90% of thyroid nodules are non-cancerous Source: National Cancer Institute, U.S. National Institute of Health. www.cancer.org Follicular Cancer Papillary Cancer Solid Adenocarcinoma Four types of cancer  Papillary     70 to 80% Follicular    10 to 15% Medullary    5 to 10% Anaplastic    5% Biomarkers: Thyroglobulin: Normally secreted by thyroid follicular cells Excess released in differentiated thyroid cancer Calcitonin: Synthesized/secreted by C-cells in medullary thyroid cancer Spencer CA, et al. Nat Clin Pract Endocrinol Metab. 2008 Apr;4(4):223-33. Krahn J, et al. Clin Biochem. 2009 Mar;42(4-5):416-9 Thyroid. The Merck Manual. 18th ed. 2006. p.1192-1206 Differentiated thyroid cancer Follicular Papillary Thyroglobulin made only in thyroid tissue Using thyroglobulin to monitor: Immediately after treatment should not be present Presence indicates cancer may still be present Long term routine monitoring detects recurrence Need to include anti-thyroglobulin test TG measurements are not standardized; will vary between methods Thyroid. The Merck Manual. 18th ed. 2006. p.1192-1206. British Thyroid Association. http://www.british-thyroid-association.org/info-for-patients/Docs/TFT_guideline_final_version_July_2006.pdf. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Thyroid. 2009 Nov;19(11):1167-214. American Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19(6):565-612   Calcitonin – best marker for Medullary thyroid cancer Diagnosis Baseline measurement correlates w/ tumor mass Monitoring therapy Measure post-operatively Rising levels suggest possible recurrence British Thyroid Association. http://www.british-thyroid-association.org/info-for-patients/Docs/TFT_guideline_final_version_July_2006.pdf American Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19(6):565-612 Reviewed the causes and management of hyperthyroidism and hypothyroidism   Discussed effective use of thyroid tests   Established use of TSH as the best initial test for thyroid diysfunction   Discussed role of thyroglobulin and Calcitonin in the management of thyroid cancer