Selected Thyroid Tales for the Busy Pediatrician

Transcription

1 Selected Thyroid Tales for the Busy Pediatrician Brandon Nathan, M.D. Associate Professor University of Minnesota April 26, 2014 Brandon Nathan, MD Disclosures: I have no financial relationships to disclose. I will not discuss off label use and/or investigational use in my presentation.

2 Table of Contents 1. Prologue Getting on the Same Page 2. The Boy with Brittle Hair 3. The Girl with Tapping Toes 4. There and back again (not a Hobbit tale) 5. The Prenatal Visit with a Twist 6. The Obesity Trap Prologue Getting on the Same Page: Making Sense of Thyroid Tests

3 Objectives 1. Explain the rationale for ordering (or not) the most common thyroid function tests (TSH, T4, T3). 2. Identify the autoantibodies typically present in Hashimoto s thyroiditis, Graves disease, and subacute thyroiditis. 3. Discuss the forms of thyroid disease that can occur in Down syndrome and how to screen for them 4. Plan a discussion of the possible thyroid function test results in an obese pediatric patient and their significance The Hypothalamic Pituitary Thyroid Axis Images.MD

4 Phenolic ring (outer) I I Tyrosyl ring (inner) COOH OH O CH 2 Type I, II MDI I I T4 I I OH CH 2 NH 2 Type III MDI R O R R O R I I I I T3 rt3 Adapted from Sperling, 2nd ed. Thyroid Binding Globulin Can Alter Total T4 TBG primary protein TBG deficiency results T4 carrier of thyroid (T4 in normal free T4 and and T3) hormone in the low total T4 T3 T4 blood. T4 OCPs, pregnancy, result Other carriers include in TBG excess and T3 TBG T4 transthyretin and elevated total T4, normal T4 albumin (equally (q free T4 important for T3). T4 T4 T3

5 Common Thyroid Function Tests TSH: Thyroid Stimulating Hormone Circadian rhythm to TSH secretion fluctuations of up to 50% can be observed (highest TSH levels overnight, ih and dlowest in afternoon) T4: Thyroxine (DIT + DIT) Total: Screening of Hypothyroidism Free: Screening for Hypothyroidism (represents 0.03% of total hormone in blood) T3: Triiodothyronine (MIT + DIT) Useful marker of Graves disease severity Total and Free (0.3% of total amount in blood) levels can be obtained but total is more reliable assay. rt3: Reverse T3 Higher levels observed in critically ill patients, suggests sick euthyroid syndrome Useful Thyroid Autoimmunity Screens Thyroid Peroxidase Antibody (TPO) May be elevated in both Hashimoto s and Graves Thyroglobulin Antibody (ATG) May be elevated in both Hashimoto'ss andgraves Thyrotropin Receptor Antibody (TRaB) Detects TSH stimulatory or blocking antibody Thyroid Stimulating Immunoglobulin (TSI) Pathonogmonic of Graves Disease (~90%) though occasional cases of Hashimoto's may have mildly elevated TSI TSH Bi di I hibit I l bli (TBII) TSH Binding Inhibitory Immungloblin (TBII) Found in patients with Graves Disease. Most useful in determining as etiology for hypothyroidism in infant born to mom with Graves.

6 2. The Boy with Brittle Hair The Boy with Brittle Hair 13 year old boy presented to primary care provider after being referred by none other than his hairdresser She had pointed out that he should go see his doctor and his hair seemed to be more brittle than before When asked, the child had denied fatigue, admitted to cold intolerance, and had some dry skin but these were all subtle and he never complained about them Remained a straight A student

7 Boy with Brittle Hair MPH Physical exam show mildly edematous facies Tanner stage 1, testes 3 cc in volume. Dry skin in lower extremities Bone Age consistent with 10 year old male (3 yr delayed) TSH 596 IU/L( ) Free T mg/dl ( ) TPO Ab 642 (<40) Tg Ab 128 (<20) Hashimoto s (Lymphocytic) Thyroiditis Most common etiology of acquired hypothyroidism in pediatric population Goitrous vs. Atrophic Results from lymphocytic infiltration i (T & B cell) of gland 90-95% of cases associated with elevated antibody titers to thyroid peroxidase or thyroglobulin Strong genetic component Positive family history in 30-40% Rates in monozygotic twins 50% vs. 5% in dizygotic May be preceded by transient hyperthyroid period caused by release of preformed hormone from gland ( Hashitoxicosis ) Up to 12% in one series (Nabhan ZM, et.al. J Peds, 2005)

8 Most Common Presenting Signs and Symptoms in Acquired Hypothyroidism SYMPTOMS None except growth failure Fatigue Coarse, brittle hair Dry, patchy areas of skin Cold Intolerance Constipation Modest weight gain SIGNS Delayed Relaxation phase of DTR Delayed bone age Pubertal Delay Precocious Puberty (van Wyk- Grumbach Syndrome) Associated with enlarged testes/phallus in boys from cross reactivity of TSH at FSH and LH receptors Before and After Thyroid Hormone Pancini and DeGroot, thyroidmanager.com

9 Therapy for Hypothyroidism Caused by Hashimoto s Levothyroxine: typical dose mg/m 2 /day Thyroid hormone replacement results in resolution of symptoms and restoration of growth Severe cases may result in incomplete catch-up growth, especially in pubertal children In severe cases, screening for concomitant Addison s disease should be performed as well. Change from low to normal metabolic rate can precipitate adrenal crisis in a patient who also is Addisonian. 3. The Girl with Tapping Toes

10 The Girl with Tapping Toes A 10 year old girl was referred to her pediatrician for evaluation of ADHD She had become more disruptive in class, constantly shifting in her seat and tapping her feet Her grades had deteriorated over the course of the last year, going from A s/b s to C s Mom noted similar off the wall behavior at times and that she figured she was going g through a growth spurt given the amount she was eating On swim team, but times have worsened compared to last year The Girl with Tapping Toes On exam, HR 122, BP 136/60 Very fidgety in her chair (leg swinging) Notable exam findings: Resting tremor Soft, non-tender goiter Subtle proximal muscle weakness Labs: TSH <0.003 IU/L Free T mg/dl T3 622 (60-180) TSI

11 Features of Graves Disease Most common cause of hyperthyroidism in children Female (6:1) Incidence of 1 per 100,000 person years Form of Autoimmune thyroiditis Stimulating antibodies against TSH receptor, resulting in thyroid hormone synthesis and release Lymphocytic infiltrate within gland Strong genetic predisposition (Fam Hx + in 60%) MHC and CTLA-4 account for 50% of inherited susceptibility (Birrel G, et.al. Arch Dis Child, 2003) Monozygotic twins concordance rate 30-60% vs 3-9% in dizygotic The HPT Axis in Graves Disease Images.MD

12 Diagnosing Graves Disease Common Presenting Signs/Symptoms Goiter (98%) Tachycardia (82%) Nervousness/School Difficulties (82%) Hypertension / Increased Pulse Pressure (80%) Proptosis (65%) Voracious appetite (60%) Tremor (52%) Weight loss (50%) Subtle Common Signs/Symptoms Heat intolerance (30%) Proximal muscle weakness Growth Acceleration Loose Stools Insomnia Fatigue/Lethargy Advanced Bone Age Goiter in Graves Disease Images.MD

13 Ophthomalogical Findings are Less Common in Pediatric Graves Exophthalmos Images.MD Images.MD Medical Therapy in Graves Disease Beta-blockers: Atenolol Iodine Thionamides: PTU or Methimazole Block: 1) incorporation of oxidized iodide; 2) coupling of MIT and DIT Possible immunomodulatory effect (Franklyn JA, NEJM, 1994) Remission Rates ~20-40% Remission Rates 20 40% Highest likelihood in smaller glands, higher BMI, lower T3 levels (Glaser N, e.al. JCEM, 1997) Can result in agranulocytosis, fulminant hepatitis, rash

14 I131 Ablation is Accepted Therapy in Pediatric Graves I-131 Ablation Safe and efficacious form of therapy (except pregnancy) Gaining acceptance as 1 st line therapy for kids > 10 years I-131 concentrated within thyroid gland, organified, and β emissions result in tissue damage Should result in permanent hypothyroidism but may take 1-6 months to occur. Risks for future cancer linked to inadequate doses. I-131 patients have overall lower risk for thyroid tumors compared to untreated Graves patients (Rivkees S, JCEM, 2007) Therapeutic Options in Graves Thyroidectomy Indications: Very large glands (> 100 grams), failed medical management, younger pts Requires experienced pediatric head and neck surgeon Complication Risk: Bleeding, infection, hypoparathyroidism, vocal cord paralysis

15 4. High, Low and Back Again High, Low, and Back to Normal 16 year old boy complaining of chronic fatigue and had thyroid function tests obtained as part of evaluation Initial Labs: TSH < 0.03 (0.5-4), free T4 1.7 ( ) Reports tremors, no palpitations, no increase in appetite, no symptoms related to gland itself (pain, swelling) Straight A student no drop off in grades. Non-focal exam without goiter Eval: TSH < 0.03, free T4 2.54, TPO neg, ATG neg, TSI normal I-123 uptake scan: 2% (normal 15-30%)

16 High, Low, and Back to Normal At 4 weeks after presentation: Asymptomatic, TSH 0.03, free T4 1.0, T3 151 What s going on? Subacute Thyroiditis AKA DeQuervian or Granulomatous Thyroiditis May be painful or painless Often preceded by upper respiratory virus Typical pattern: transient hyperthyroid period (2-4 weeks) recovery with elevated TSH or even transient hypothyroid period. Return to euthyroid state within 2-6 months Antibody tests negative, ESR elevated Tm/Iodine uptake scan shows low uptake Tx: Anti-inflammatory agents if gland painful, beta-blockers to during hyperthyroid period, thyroid hormone rarely required Emedicine.com

17 Increased HYPERTHYROI HYPOTHYROID D PHASE EUTHYROID PHASE PHASE EUTHYROID* Increased TS H Norma l Free T4 Normal Suppressed *Up to 5% may remain hypothyroid Decreased Time ( h ) Follow-up to Patient 12 weeks after presentation Asymptomatic, TSH 6.13, free T4 0.79, T weeks after presentation Asymptomatic, TSH 2.80, free T4 0.88, T3 152

18 The Prenatal Visit with a Twist The Loaded Prenatal Visit A couple who recently moved to Kansas City is expecting their first child in 10 weeks. Previous prenatal work-up has established that the infant has Trisomy 21. What thyroid risks should you discuss with this family and how will you plan to monitor this child s thyroid status?

19 Down Syndrome and Thyroid Disease Congenital Hypothyroidism Approximately 1% risk compared to % in general population Etiology debated, but appears to be more related to persistent TSH elevation with normally formed gland rather than athyrosis Autoimmune Thyroiditis Graves Disease Prevalence of 6.5/1000 (Goday-Arno A, et.al. Clin Endocrinol, 2008) Hashimoto s Disease 30% of population have + ATG or TPO, 10-20% with abnormal TSH and/or T4 Subclinical Hypothyroidism (Elevated TSH/Normal T4) Total T4 in Infants with Down Syndrome vs. General Population van Trotsenburg, ASP. et al. J Clin Endocrinol Metab, 2003

20 T4 Supplementation: A Benefit for All Children with Down Syndrome? Van Trotesenberg ASP, et.al. J Clin Endocrinol Metab, 2005 Current AAP Guidelines for Screening in Down Syndrome Screening at birth (newborn screen) TSH at 6 months TSH at 12 months and yearly thereafter AAP Committee on Genetics, Pediatrics, 2001

21 6. The Obesity Trap The Obesity Trap 14 year old female patient presents to your office with concerns about a persistent weight gain for the past several years She complains of symptoms of fatigue but does not endorse cold intolerance, dry skin, neck symptoms, or constipation. Mom was diagnosed with a thyroid problem 3 years ago and wants her daughter checked as well.

22 BP 132/82, HR 84 BMI >99% Obese adolescent female No acanthosis nigricans No goiter on exam Normal skin and neurologic exam TSH: 5.14 ( ) Free T4: 1.1 Obesity and Thyroid Function Increased TSH levels (4-10IU/L) are frequently identified in obese children and adults- subclinical hypothyroidism 10-23% of obese children will have an elevated TSH when tested. Autoimmune markers rare (3-7% of obese patients with elevated TSH) Normal to slight elevations in free T4 and increased T3 levels are typical. Mechanisms for increase in TSH remain unclear but may well be mediated by an increase in hypothalamic h TRH secretion secondary to elevated leptin levels. Elevated T3 levels may be an adaptive response to increase energy expenditure achieved through differential deiodinase expression.

23 Elevated TSH is likely a consequence rather than a cause of obesity Wolters B, et.al.eur J Pediatr Endocrinol, 2013 TSH and T3 levels fall in response to weight loss Lifestyle intervention or surgery Treatment of elevated TSH in obese patients has demonstrated no improvement in clinical course Treatment not indicated unless evidence for autoimmune thyroiditis Summary Graves and Hashimoto's are the most common forms of acquired hyper and hypothyroidism in children TrAB, TPO, and ATG should be ordered in suspected cases of autoimmune thyroiditis Subacute thyroiditis follows a hyper-hypo-euthyroid pattern over months, may have a tender or non-tender gland, and is not associated with thyroid antibodies Monitor for persistent hypothyroidism Children with Down syndrome are at increased risk for congenital hypothyroidism y and acquired thyroiditis compared to general population Screening should include yearly TSH, free T4 with low tx threshold Modest elevation in TSH is common in pediatric (and adult) obese patients, typically normalizes with weight loss, and does not require treatment unless associated with autoimmune markers.