Learning Objectives Pediatric Thyroid Conundrums Harvey Chiu, MD Associate Clinical Professor of Pediatrics UCLA Mattel Children s Hospital Division of Pediatric Endocrinology Understand the urgency of congenital hypothyroidism Understand the presentation of acquired hypothyroidism in pediatrics Understand pitfalls in thyroid function tests Understand preferred treatments for hyperthyroidism in pediatrics Overview Thyroid Low High Nodule Case 1 You are called about a neonate, DOL 7, because of an abnormal newborn screen for her thyroid tests TSH 45 miu/l, 2.0 ng/dl. When you discharged this child from the newborn nursery on DOL 2, she was feeding well and otherwise had no problems. What is your level of concern? A. This can wait until my next availability in 2 months. B. If the parents see something worrisome, they can be added onto my schedule prior to that 2 month visit. C. This requires emergent intervention. Congenital Incidence: 1:3000-4000 Technesium-99 Thyroid Scan Agenesis Dyshormogenesis Ectopic Associated Malformations Williams syndrome Characteristic facies (low-set ears) Cardiovascular malformations Mental/growth retardation CHARGE syndrome Colomboma, heart defects, cholanal atresia, retarded growth and development, genital hypoplasia, ear anomalies Pendred Syndrome Sensorineural hearing defect Apical cell iodine transport defect Must be done within a few days of treatment initiation, while TSH still high
Thyroid Agenesis Lack of thyroid gland development Thyrotropin receptor-blocking antibody History of maternal autoimmune disease Hashimoto s thyroiditis Graves disease 1:50,000-100,000 infants overall [1:70 (+)maternal Hx] Can measure TRBAb Resolves in 3 months t 1/2 TRBAb 7.5 days Clinical Presentation of Congenital Unexplained postmaturity Open posterior fontanel Prolonged jaundice Macrosomnia Hypothermia Poor feeding 160 EARLY and AGGRESSIVE INITIATION of Treatment is Essential for Optimal Neurological Development Treatment Intervention Thresholds 140 Mental Developmental Index 120 100 80 60 40 20 0 High dose Low dose High dose Low dose Severe Mild Every day of delay may result in loss of IQ! Early (<13 days) Late ( 13 days) TSH (miu/l) 60 50 40 30 20 10 0 Repeat TFT's, start treatment without results Repeat TFT's, confirm results to start treatment Repeat TFT's, confirm results, discuss options TSH not elevated Bongers-Schokking JJ, et al. J Pediatr 2000; 136_ 292-7. Léger J, et al. JCEM 99: 363-384, 2014. False Negatives of TSH screening Treatment Gestational age <37 wks LBW/VLBW or ill/nicu pts Screening <24 hrs age Same-sex (monozygotic) twins Hypothalamic-pituitary immaturity Drug/Illness-induced TSH suppression Too early (ideally 48-72 hrs of life) Fetal blood mixing Brand Levothyroxine 10-15 mcg/kg/d Term infant ~3.5 kg 50 mcg po qd x 1 week 37.5 mcg po qd thereafter Repeat thyroid function test screening in 2 weeks! Mercado M, et al. Early Hum Dev 16:131-141, 1988. Carswell JM, et al. JCEM 98: 610-617, 2013.
Evaluation Case 1b TSH/ 99m TcO4 Thyroid Scan Don t wait to start treatment! Your newborn presents with jaundice, an open fontanelle, and a weak cry. You are told that the newborn thyroid screen is normal. Ectopic Thyroid Gland Indefinite Treatment No Thyroid Tissue Visualized Serum Thyroglobulin, Neck Ultrasound Does this physical finding change your differential diagnosis? Undetectable Thyroid agenesis Indefinite Treatment Detectable Measure TSH-receptor blocking Antibodies If elevated, suggests Transient Hypothalamic-pituitary hypothyroidism! Newborn Screen for Congenital Hypothalamic-Pituitary Primary TSH With Backup T4 Most programs in USA, Canada, Mexico Europe, and Japan Pros Detection of Primary (1 in 4,000 newborns) Cons Misses Central Misses Delayed TSH rise (commonly seen in LBW infants < 2500 g) Primary T4 with Backup TSH Pros Detection of Central (1 in 50,000 newborns) Cons Misses Primary (cutoff of <10 th percentiles to improve sensitivity) ~5% of cases of congenital hypothyroidism Congenital midline brain defects Cleft lip or palate Septo-optic dysplasia Pituitary aplasia Pit-1 or Prop-1 gene mutations Birth trauma/asphyxia pituitary stalk transection Case 2 2 yo presents: HR 220 bpm bp 130/80 mm Hg T 103 F Multiple episodes of diarrhea There is a strong family history of autoimmune thyroid disease What is your DDx? What tests do you want? Thyroid Stimulating Immunoglobulin Graves Disease thyroid hormone secretion Acute release of T4/T3 Thyroid Storm effects of thyrotoxicosis binding protein (transthyretin) cellular responses to thyroxine Uncoupling of oxidative phosphorylation substrate utilization oxygen consumption thermogenesis
thyroid hormone secretion -Thyroidectomy -Radioactive iodine Rx -High-dose iodine Rx -Thyrotoxicosis facticia Thyroid Storm effects of thyrotoxicosis -Infection -Acute medical illness -Non-thyroid surgery -Trauma Symptoms High fever (usually T > 102 F) almost invariable Disproportionate to an associated infection Excessive diaphoresis Marked sinus tachycardia GI Nausea, vomiting, diarrhea, jaundice CNS dysfunction Hyperirritability, anxiety Confusion, apathy, coma Life-threatening exaggerated thyrotoxicosis! Studies Treatment Serum thyroid functions tests not necessarily different than uncomplicated thyrotoxicosis TSH T4 T3 Thyroid scan 123 I 2-hr uptake 99 Tc pertechnetate 20-30 min uptake production & secretion of T4/T3 Hydrocortisone 100 mg/m 2 /d qid Methimazole 0.4-0.7 mg/kg tid Potassium Iodide 300-500 mg (6-10 drops) tid Lithium Cholestyramine Plasmapheresis tissue effects of T4/T3 Propranolol 2 mg/kg qid Supportive treatment -fever, bp Acetaminophen External cooling Fluids Underlying illness/injury Anti-Thyroid Drug Options Propylthiouracil (PTU) Hepatocellular necrosis Dose-independent (unpredictable) Methimazole (MMI) Cholestasis Dose-dependent 29 cases Liver 20 cases Failure 9 deaths 2 deaths Pediatric cases: 14 3 deaths 5 transplants Rivkees, SA, et al. Int J of Ped Endocrinol 2009, 1-8. Pediatric cases: None Propylthiouracil (PTU) and Hepatotoxicity Drug-induced liver injury liver transplant 1. Acetaminophen (50%) 2. Isoniazid (17%) 3. PTU (10%) [1:2000-4000 children] Liver failure is rapidly progressive & poorly reversible PTU should never be first-line treatment in children with Graves disease! Russo MW, et al. 2004 Liver Transplantation; 10(8): 1018-1023. Rivkees SA, Mattison DR. 2009 Int J Pediatr Endocrinol.
Case 3 6 yo presents with concerns for no height gain for over 2 years. There has been constipation and dry skin, but no cold intolerance. His mother describes a watery feel to his upper chest for several months. EXAM HEENT: Marked alopecia. No thyromegaly. Diffuse supraclavicular fullness of skin. Fatigue Constipation Dry skin Cold intolerance Abrupt deceleration in height gain Preserved weight gain - seldom obesity Slipped capital femoral epiphyses Effects on Growth Dermal Effects Growth Hormone production Hyaluronan synthetase Thyroxine IGF-1 production Thyroid Hormone H 2 0 H H 2 0 2 0 H 2 0 Hyaluronic acid H 2 0 H H 2 0 2 0 H 2 0 Myxedema IGF-1 signaling Degradation Preparation for mitosis DNA replication S Hair Cell Cycle G 2 15% M Mitosis and cell division G 0 G 1 Commitment to DNA replication Quiescence Case 3 The patient comes to you for f/u 1 year later, at age 7 years of age, on Levothyroxine 75 mcg once daily, and is found to have the following labs: TSH 2.1 miu/l (0.5-4.7) 0.5 ng/dl (0.8-2.0) What would you do? A. Increase his dose of Levothyroxine. B. Repeat his labs but in a different assay!
analog assay analog assay Easily automated for rapid results Binding Protein Bound T4 Solid-phase Capture Antibody Labeled T4 analog Labeled T4 analog Binds with solid phase anti-t4 antibody Should not bind with Thyroxine Binding Protein Most analogs are proprietary? Binding with Albumin and Transthyretin Inaccurate estimation of true analog assay by Equilibrium Dialysis Semi-permeable Membrane Dialysate Fluid Quantitate Solid-phase Capture Antibody Binding Protein Labeled T4 analog Bound T4 Which Assay? FT4 Analog FT4 Equilibrium Dialysis Rapid (1 day) Time Slow (4-7 days) Easy Availability Specialty Lab Less Accuracy Most $140.61 Cost $121.14 FT4 Assay Limitations Inter-assay variances Comparison of 26 Assay Methodologies * Mean Range: 0.79-1.17 ng/dl 38% > 10% difference 8% > 20% difference Intra-assay comparability Similar results for an individual 6 months apart * Steele BW, et al. 2005 Arch Pathol Lab Med. 129 310-317.
Case 3 Levothyroxine Requirements Now the patient comes back at age 8 years, on a very high dose of Levothyroxine 150 mcg once daily. His TFT s are as follows: TSH 21.4 miu/l (0.5-4.5) 0.5 ng/dl (0.8-2.0) Why might his Levothyroxine dosage be so high? A. He needs to take his Levothyroxine with food. B. He is becoming rebellious long before his teenage years. C. He is not taking his Levothyroxine ideally. Should be taken fasting Absorption Soy protein, bran, fiber Ferrous sulfate Calcium carbonate Aluminum hydroxide Cholestyramine Sucralfate Sodium polystyrene sulfonate Celiac disease Small bowel disease TBG Estrogen Pregnancy Tamoxifen Raloxifene Metabolism Phenytoin Carbamazepine Phenobarbital Rifampin Unknown Mechanisms Sertraline Lovastatin Case 3 Now the patient has started taking his Levothyroxine 150 mcg once daily on a fast, and his FT4 has increased to a quite high level, but his TSH remains high: TSH 21.4 miu/l (0.5-4.5) 3.5 ng/dl (0.8-2.0) Clinically, he is tachycardic and tremulous How do you explain his lab results? Could the TSH be a lab error? Interference in the TSH immunoassay! Interfering Heterophile Antibodies High Prevalence/Low Specificity -Limited affinity to multiple human and animal antigens Signal Ab TS H Binding Ab Signal Ab * * Heterophile Ab False positive ( detected TSH) Low Prevalence/High Specificity -High affinity to very specific animal antigens (human anti-mouse Ab) Binding Ab TS H Signal Ab * Heterophile Ab Binding Ab False negative ( detected TSH)? Heterophile Antibodies TSH Assays Most have adequate reagents to absorb interfering heterophile antibodies Interference - antibody and epitope dependent Choose a different assay that utilizes different reagents Precipitate with PEG Dilute TSH Observe for non-linear TSH results as Ab dilute out Pretreat sera with heterophile Ab-blocking tubes (Scantibodies, Santee, CA) Take Home Points Congenital hypothyroidism is an emergency! Newborns screening programs commonly miss secondary (hypothalamic-pituitary) hypothyroidism. in children presents with growth failure, and seldom obesity. PTU should never be first line treatment in children! A by Equilibrium Dialysis is the gold standard. Heterophile antibodies may complicate TSH assessments.