The Number Games and Thyroid Function Arshia Panahloo Consultant Endocrinologist St George s Hospital
Presentation Today: Common thyroid problems and treatments Pregnancy related thyroid problems The suppressed TSH Thyroid Cancer Review of common pitfalls- QUIZ
HYPOTHALAMUS HYPOTHALAMIC FACTOR Portal Circulation PITUITARY PITUITARY HORMONE END ORGAN
HYPOTHALAMUS HYPOTHALAMIC FACTOR Portal Circulation PITUITARY PITUITARY HORMONE END ORGAN END ORGAN HORMONE
Portal Circulation PITUITARY NEGATIVE FEEDBACK
HYPOTHALAMUS TRH PITUITARY TSH TRI IODOTHYRONINE THYROXINE THYROID
Typical Thyroid Hormone Levels in Thyroid Disease TSH T 4 T 3 Hypothyroidism High Low Low Hyperthyroidism Low High High
Thyroid Hormone The plasma thyroid hormones are 3,5,3`,5`-tetraiodo L-thyronine (thyroxine T4) 3,5,3`-triiodo L-thyronine (triiodothyronine T3) Receptor is nuclear (type2) Circulate bound to protein Thyroid Binding Globulin Albumin Prealbumin Plasma half life T 3 (1-3 days) T 4 (4-7 days) Dietary Iodine requirement 50μg/day
Thyroid Hormone Production 100 mcg of thyroid hormone are produced daily Most as T4 and 10% as T3 80% of T4 converts to the more active T3 in the kidney and liver or reverse T3 T3 is ten times more active than T4 reverse T3 has little activity
Over production Thyrotoxicosis Graves disease (80%) Multinodular Goitre (15%) Toxic Solitary Nodule (2%) Thyroiditis (1%) Rare TSH secreting pituitary tumour Excess Thyroxine ingestion trophoblast tumours Robert James Graves (1796-1853)
Thyrotoxicosis Tachycardia Palpitation Lid Lag Agitation Increased Sympathetic locomotor activity Overactivity Weight loss Heat intolerance Fever Poor appetite Myopathy Increased Growth Diarrhoea Grave s thyroid eye disease: Pretibial Myxodema Exopthalmos Chemosis lid lag Diplopia on upgaze
Treatment Carbimazole Propythiouracil Beta Blockers Surgery
Carbimazole vs. Propylthiouracil Carbimazole PTU Serum half-life 4-6 hr 75 min Duration of action 24 hr 12-24 hr Dosing 1-2 x daily 2-3 x day Compliance Higher Lower Cost 4.46 (20mg) 74.79 (300mg) Side-effects Lower Higher
Side-effects of Antithyroid Drugs Skin rash, itching Upper GI side-effects Arthralgia Vasculitis, SLE-like syndrome Blood dyscrasia Hepatotoxicity Congenital malformations
PTU and Liver Injury JCI 2009, 94:1881 Cooper et al.. US FDA database: severe liver injury in 22 adults in 20 years 9 died, 5 needed transplant Severe liver injury in 12 children 3 died, 6 needed transplant Estimated risk of severe liver failure: 1/1000
Raised Liver enzymes: 15/54 (28%)
Hyperthyroidism in pregnancy Grave s Disease affects 2 per 1000 pregnancies It is important to ensure patient euthyroid as soon as possible, preferably prior to conception, to avoid complications: Maternal Thyroid storm Congestive cardiac failure Pre-eclampsia Fetal Fetal growth restriction Prematurity stillbirth
The Foetal pituitary thyroid axis Controlled in similar way to adult Iodine supplied transplacentally < 12/40 maternal T4 but not T3 crosses placenta T4 binds to foetal brain cells, and is converted intracellularly to T3. This is important for brain development. >12/40 fetal thyroid function is independent of mother, provided mothers iodine intake is adequate.
Pregnancy specific thyroid changes T4 synthesis increases 20-40% Half life of thyroid binding globulin increases from 15 min to 3 days. Must measure only Free T4 and T3 hcg and TSH have similar alpha sub-units and receptors. In first trimester hcg can stimulate TSH receptor, and can give a picture of hyperthyroidism. Worse in hyperemesis and multiple pregnancies and trophoblastic disease Thyroid function must be interpreted with caution
Propylthiouracil or Carbimazole in pregnancy? Both have similar placental transfer Earlier reports suggested carbimazole causes aplasia cutis congenita of the scalp Rare congenital defect affecting 0.03% of the population Recent reports show that this is rare and should not influence choice of drug in pregnancy No other teratogenicity Both drugs can cause agranulocytosis patients must report sore throats
Treatment of Hyperthyroidism in pregnancy PTU first line in first trimester If intolerant to PTU, use carbimazole Switch to carbimazole second trimester due to liver toxicity with PTU Lowest dose possible, as both drugs cross the placenta Propanolol can be used if tachycardia, tremor or anxiety Difficult to distinguish between signs of thyrotoxicosis and pregnancy Serial TFT important every 6-8 weeks Failure to gain weight despite good appetite, pulse rate >100 are signs of thyrotoxicosis
Treatment of Hyperthyroidism in pregnancy TSH receptor antibody falls in the second and third trimester, and rises in the puerperium TFT should be measured 6 weekly Anti-thyroid medication titrated Most women can reduce their dose and a third stop treatment in pregnancy This prevents fetal hypothyroidism Anti-thyroid medication will need to be started post partum to avoid relapse
Lactation There are differences between PTU and carbimazole during lactation 0.077% PTU and 0.47% carbimazole reaches breast milk. High dose Carbimazole could cause neonatal hypothyroidism Switch to PTU, may need monitoring of neonatal TFT if patient on carbimazole
Fetal consequences of thyrotoxicosis TSH receptor antibodies can cross placenta and cause Graves disease after 20 weeks (risk is low) Effect proportional to antibody titres Must be measured in all women who may have had Graves disease treated in past with radioactive iodine or surgery at 22/40 If titres high, should monitor for signs of fetal thyrotoxicosis: Fetal tachycardia Growth restriction Oligohydramnios Fetal goitre can obstruct delivery IUD Hydrops fetalis
Hypothyroidism: Types Primary hypothyroidism From thyroid destruction Hashimotos Disease Post radioactive iodine Post surgery Thyroiditis Antithyroid drugs Central or secondary hypothyroidism From deficient TSH secretion, Generally due to sellar lesions such as pituitary tumor or craniopharyngioma Infrequently is congenital Central or tertiary hypothyroidism From deficient TSH stimulation above level of pituitary Lesions of pituitary stalk or hypothalamus Is much less common than secondary hypothyroidism
Hypothyroidism Bradycardia Mental Slowness Poor Memory Decreased locomotor Sympathetic activity Weight gain Underactivity Cold intolerance Hypothermia Poor appetite Myopathy Decreased growth Constipation Dry skin and hair Hoarse voice Puffy face Menstrual Irregularity
Hypothyroidism and Pregnancy Hypothyroid women have increase prevalence of: Infertility Abortion Anaemia Gestational hypertension Placental abruption Post partum haemorrhage Adverse neonatal outcome: Premature birth Low birth weight Neonatal respiratory distress In one study women with sub-clinical hypothyroidism also had preterm delivery and neonatal resp distress
Hypothyroidism 0.3-0.5% of pregnancies Sub-clinical hypothyroidism in 2-3% Antibodies found in 5-15% Most common cause autoimmune thyroiditis, and iodine deficiency
Thyroid Function Tests Pregnancy JCEM 2012 If hypothyroid in pregnancy, adjust dose of T4, so TSH 2.5 Aim for normal TSH in preconception period Normal in thyroxine dose of 30% Universal screening for TPO antibodies in either before or during pregnancy not recommended. But positive TPO are associated with increase miscarriage, preterm delivery, hypothyroidism and post-partum thyroiditis.
Thyroid Function Tests Pregnancy Only first trimester hypothyroidism influences fetal wellbeing It is important to be euthyroid in the preconception period In hypothyroid women TFT should be checked in each trimester Antenatal care is usually midwife led unless other risk factors
Targetted TFT testing seeking pregnancy or newly pregnant Women over 30 With FH of autoimmune thyroid disease or hypothyroidism Women with Goiter Positive antibodies Symptoms of thyroid disease Type-1 diabetes Infertility History of miscarriage and preterm delivery Head and neck irradiation and thyroid surgery On T4 replacement
Hashimotos s Riedels De Quervain s Silent Post Partum Drugs DXT Lithium Amiodarone Interferon Superative Causes of Thyroiditis
Post partum Thyroiditis Common 6 to 12 months postpartum Patients present with transient thyrotoxicosis Resolves by 12 months Occurs in patient who are TPO Ab +,Grave s disease in remission, and chronic viral hepatitis Screen for TSH 3 and 6 months post-partum Annual TSH Increase risk of permanent hypothyroidism in 5 to 10 years
Carcinoma of the Thyroid Patients are initially treated with total thyroidectomy Followed by radio-iodine ablation therapy Followed by life-long suppressive thyroxine therapy to prevent recurrence Please do not lower dose of Thyroxine in these patients.
Tumours of the anterior pituitary can cause syndromes of hormone excess GH ACTH TSH LH/FSH PRL Acromegaly Cushing s disease Secondary thyrotoxicosis (Non-functioning pituitary tumour) Prolactinoma
Suppressed TSH PRIOR TO ADJUSTING MEDICATION Is the suppressed TSH secondary to thyroid over-activity? Excess thyroxine replacement? Hypopituitarism and TSH deficiency? Has the patient had treatment for thyroid Cancer?
Pitfalls in Interpreting Thyroid Function Pregnancy Hypopituitarism Thyroid Cancer Short QUIZ