Thyroid Disease: Thyroid Gland: In Situ Overview Kenneth B. Ain, M.D. Professor of Medicine The Carmen L. Buck Chair of Oncology Research Director, Thyroid Oncology Program Div. of Endocrinology & Molecular Medicine Dept. of Internal Medicine University of Kentucky Medical Center &Veterans Affairs Medical Center, Lexington, KY Copyright retained by Dr. Kenneth B. Ain T4 (Pro-Hormone) levothyroxine OH I I I N O O O e s a in I d o i 5 e - d d '- e i 5 o d i n a s e OH OH I I I N O I N O O O O O I I T3 (Active Hormone) reverse T3 (Inactive Metabolite) triiodothyronine Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Free T4 0 . 03% of Total T4 Free T4 Metabolically available to tissues. Feedback regulation. T4 Bound to Serum Proteins l T4 (TBG, TBPA, a Albumin, etc.) Tot 99 . 97% of Total T4 Regulates Gene Transcription Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain 1 Relationship Between TSH Levels and Free T4 1000 100 10 1.0 Normal 0.1 0.01 Undetectable Hypothyroid Euthyroid Hyperthyroid Free T4 Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Spencer CA, et al. J Clin Endocrinol Metab. 1990;70:453-460. Causes of Hypothyroidism Clinical Features of Hypothyroidism • Primary Tiredness – Destructive Puffy Eyes Enlarged Thyroid (Goiter) • Hashimoto’s thyroiditis • Secondary Forgetfulness/Slower Thinking •Post-131I therapy Moodiness/ Irritability Hoarseness/ • Pituitary tumor Deepening of Voice • Post-thyroidectomy Depression •Pituitaryyg granuloma – RiblReversible Persistent Dry or Sore Throat • Pituitary apoplexy Inability to Concentrate • Endemic goiter: Thinning Hair/Hair Loss Difficulty Swallowing – Iodine deficiency Loss of Body Hair Slower Heartbeat – &/or natural goitrogens Dry, Patchy Skin Menstrual Irregularities/ • Iodine Excess • Tertiary Heavy Period • Drugs: thioureas, lithium, etc. • Hypothalamic disease Weight Gain Infertility – Congenital – Tumor Cold Intolerance – Craniopharyngioma • Thyroid agenesis Elevated Cholesterol Constipation • Ectopic thyroid Muscle Weakness/ Family History of Thyroid Cramps • Dyshormonogenesis Disease or Diabetes Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Hypothyroidism and Depression Many Patients With Hypothyroidism Have Many Common Features Report No Symptoms Depression Hypothyroidism 50 Euthyroid Mild Thyroid Failure • Constipation 40 >35% •Appetite decrease • Bradycardia ts, % Hypothyroid n • Cardiac and lipid 30 • Decreased concentration >25% • Sleep decrease • Decreased libido abnormalities • Suicidal ideation • Delusions • Cold intolerance 20 •Weight loss • Depressed mood • Delayed reflexes • Appetite increase/ Participa • Diminished interest •Goiter 10 decrease • Sleep increase • Hair and skin • Weight increase changes 0 • Fatigue 01234 Number of Symptoms Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. Nemeroff CB, J Clin Psychiatry. 1989;50(suppl):13-20. Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575. 2 Special Considerations Levothyroxine: Therapy of Need for Therapy With Other Populations Hypothyroidism • Pregnant women • Pure levothyroxine is best • Pharmacokinetics – Thyroid failure may impede the intellectual development of the child – No role for thyroid extract – Serum half-life: 7 days – Increased LT doses may be necessary 4 • Mixed bag of compounds – GI absorption 81 (± 21)% – TSH levels should be monitored each trimester • Raw animal product – Time of oral absorp.: 2-4 hrs • Postpartum thyroiditis • Differing pharmacokinetics – Volume of distribution 12 liters – Can lead to symptomatic thyrotoxicosis and/or hypothyroidism – NlfhiNo role for chronic use o f (13-14% body weight) – Reported prevalence varies from 2% to 21% (higher in type I DM) T3/T4 mixtures – Time to steady-state: – Has been associated with postpartum depression • Different pharmacokinetics 6-8 weeks – Can lead to chronic hypothyroidism • Endogenous deiodinases • Special considerations • Elderly Patients • No proven advantages – Cardiac disease • Treat underlying disease – Symptoms obscured by co-morbid conditions • Dose: individually titrate • May start with lower doses – May worsen or be confused for dementia or psychiatric problems – Replacement: 1.6 mcg/kg/day – Elderly – Suppression: 2.0 mcg/kg/day • Compliance issues paramount • May start with lower doses Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Thyrotoxicosis (“Too much thyroid hormone”): Cardiac symptoms common in Causes Thyrotoxicosis • Thyroid Stimulation – Immunoglobulins [Graves’ Disease] • Sinus Tachycardia: 40% – HCG [Trophoblastic Tumors] – TSH [TSH-secreting pituitary tumors] • Atrial Fibrillation: 20% • Intrinsic Thyroid Autonomy – Toxic Adenoma • Intra- or infranodal block: 5% – Toxic Multinodular Goiter • Intraventricular conduction defect: 15% • Thyrotoxicosis without Hyperthyroidism – Inflammatory disease [Subacute thyroiditis, painless thyroiditis] • PVC’s, V Tach, PAT: rare – Extrathyroidal Source [Hormone ingestion, Ectopic Tissue] Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Graves’ Disease Graves’ Ophthalmopathy • Risks: • Key Features – Cosmetic problem – Thyrotoxicosis – Restriction of eye movement – Hyperplastic Goiter – Diplopia – Corneal ulceration – Ophthalmopathy – Optic nerve damage and blindness – Other Autoimmune findings: • Evaluate: • Localized dermatological myxedema – Lids: retraction • Thyroid acropachy (similar to clubbing: rare) – Cornea: ulcer, keratitis • Discriminate from: – Proptosis: may need decompression surgery – Muscles: diplopia, may need surgery – Exogenous L-T4 – Nerve: papilledema, field defect, loss of color vision & acuity – Toxic adenoma or multinodular goiter • Treatment: – Transient thyrotoxicosis from thyroiditis – Keratitis or chemosis: lubrication & protection – Rapidly worsening proptosis: systemic steroids, XRT – Abnormalities of thyroid hormone binding or resistance – Severe proptosis &/or diplopia: orbital decompression surgery Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain 3 Treatment of Thyrotoxic Graves’ Disease Other Causes of Thyrotoxicosis • Surgery (bilateral subtotal thyroidectomy) • Toxic autonomous nodule (TSH receptor mutation) • Risk of surgery, anesthesia, recurrent laryngeal nerve damage, – Tx: I-131 vs Surgery permanent hypoparathyroidism, Scar • Requires careful preparation & beta-blockers • Toxic Multinodular Goiter • Anti-thyroid Drugs: propylthiouracil (PTU) & methimazole (Tapazole) – Tx: I-131 vs Surgery – Uses: • acute reduction in thyroid hormone; preparation for surgery or I-131 • Transient thyroiditis • Primary therapy (remission <20%); Use in pregnancy – Tx: Beta-blockade & supportive care – Side Effects: • Exogenous Levothyroxine • Minor: rash, urticaria, transient leukopenia – Psychiatric counseling • Major (rare): agranulocytosis, aplastic anemia, hepatitis, SLE-like • Radioactive Iodine (131I): • Pituitary Tumor (extremely rare) – Safe, administered orally, relatively inexpensive – Inappropriate TSH, Evaluate with MRI, Often aggressive – No evidence for long-term adverse effects (aside from hypothyroidism) – Tx: Surgery (if resectable), Gamma-knife, anti-thyroid Rx, – Frequently 1st line therapy; can be used at any age octreotide Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Post-Partum Thyroiditis : • Prevalence: approx 10% of pregnancies; <25% clinically obvious Thyroid Cancer • Presentation: Overview of Diagnosis & Clinical – Onset of thyrotoxicosis: 1 - 6 months PP Management – Onset of hypothyroidism: 4 - 12 months PP – Some with thyrotoxicosis or hypothyroidism only • Associations: – Type I Diabetes Mellitus: 25% PPT – Possible associations with miscarriage – Post-partum Depression: hypothyroid phase – TPO-Abs: + Abs have 33% PPT • Screening: – All patients with Type I Diabetes Mellitus – Patients with positive antibodies Copyright retained by Dr. Kenneth B. Ain Thyroid Cancer Statistics: 2007 • Incidence around 34,000 U.S. cases – 75% Female/25% Male – 1.6% of cancers of all ages – 3. 8% of cancers in children (0-19 yrs) • Mortality: 1,530 in U.S. – 58% Female/42% Male • Prevalence: > 450,000 cases in U.S. Copyright retained by Dr. Kenneth B. Ain 4 Presentations of Thyroid Cancer Clinical vs. Occult Disease • Thyroid nodule Solitary nodule • 5-60% (depending on method) of thyroid glands Dominant nodule of multinodular gland contain a microscopic (<1.0 cm) focus of papillary • Cervical Node or Mass cancer • Distant metastases • Macroscopic (>1.0 cm) Nodules – Lung – Single: 10% malignant – Bone – Single Dominant in multinodular gland: 10% malignant –Brain – Palpable Nodule in irradiated gland: 30% malignant • Incidental to Resection of Benign Thyroid Mass Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain 5 Evaluation of Thyroid Nodules The Management Team •Exam & History • Surgeon: Thyroid Surgery is a specialty – Size, Location, Nodes There are very few “THYROID SURGEONS” – Is patient thyrotoxic? • Yes: Get thyroid scan • Pathologist: “Thyroid pathologist” is even rarer • NO: Do NOT do scan!!! • Fine Needle Aspiration Biopsy Have a very low threshold for getting 2nd opinions – Requires some expertise • Endocrinologist (Rarely oncologist) – Specially trained Cytologist – Results (If Adequate Sample): Life-long follow-up • Benign (95-98%