Ordering and interpreting thyroid tests in children

Paul Kaplowitz, MD, PhD Children’s National Medical Center,

Washington, DC

Objectives

• To review indications for thyroid testing

• To discuss which tests are most helpful

• To review cases which highlight difficulties in interpreting thyroid tests

• To briefly discuss management of hypothyroidism and hyperthyroidism

• This talk will be short on physiology but hopefully long on practical advice

What is the physiologic role of thyroid hormones (T4 and T3)?

Thyroid physiology in brief

The simplest answer……

To keep us from To keep us from

having symptoms of having symptoms of

hypothyroidismhypothyroidism

Thyroid feedback regulation

• The hypothalamus and pituitary both sense free T4 & free T3; ↑ TSH to normalize T4 and T3– In theory, ↑ TSH =

primary hypothyroidism

– Practice is a lot more complicated, especially in borderline situations

• Overactivity of the thyroid will increase T4 and T3 and will always suppress TSH to very low levels (<0.1)

When should thyroid tests be ordered in children

• Any child with an enlarged thyroid

• Signs or symptom suggestive of hypothyroidism– New onset of fatigue

– Cold intolerance

– Acquired growth failure (may be the only sign)

– Constipation, dry skin

• Follow-up of abnormal newborn screening test result

When to order thyroid tests #2

• More than one sign or symptom suggestive of hyperthyroidism (including goiter)

– Hyperactivity

– Unintentional weight loss

– Unexplained tachycardia

– Heat intolerance

– Declining school performance

Situations where thyroid testing is low yield…..

• Obesity (unless there is an accompanying slowing of linear growth)

– Even severe hypothyroidism causes only modest (5-10 lb) weight gain which is mainly water, not fat

• Mild short stature (3-10th %ile) with normal growth rate

• Infants w/ failure to thrive (i.e. poor weight gain)

• History of thyroid disease in a relative but no signs or symptoms in the child

• Menstrual abnormalities

• Hyperactivity alone

What thyroid tests should you order for screening purposes?

• TSH: most useful single test (normal range is ≈0.5-5.0 IU/ml; can be slightly higher in infants)

• Free T4 is more accurate than total T4

– Little affected by high or low levels of thyroid binding protein

• Normal in teens on OCPs which ↑ TBG levels

– Each lab has a somewhat different normal range, usually between about 0.9 and 1.6 ng/dl

– More accurate method: free T4 by equilibrium dialysis = more expensive; not needed for screening

What thyroid tests should you order for screening purposes?

• Total T4: less reliable than free T4 (affected by thyroid binding globulin changes)

• Be aware of age-dependence of normal range

– Under 5 years of age range is 7-15 mcg/dl

– Between 6 and 10 yrs range is 6-13

– Over 10 years and adults: range is 5-12

• Since free T4 assays widely available and not expensive, there is no good reason to use total T4 as a screening test

What thyroid tests should you NOT order for screening purposes?

• T3: occasionally will be mildly elevated when the free T4 and TSH are normal

– Main use is in diagnosis of hyperthyroidism

• Free T3: no more helpful than T3 + costs more

• Thyroid antibodies (thyroid peroxidase Ab more specific than thyroglobulin Ab)

– Present in about 5% of children: non-specific

– May be useful in children who have mildly ↑ TSH

• If elevated, → ↑ risk of hypothyroidism in future

• We never treat based on + antibodies alone

Thyroid case #1

• A 10 year old child seen in your office for a routine exam has a diffusely enlarged thyroid. There are no thyroid-related symptoms. The free T4 is 0.9 (low-normal) and the TSH is 30.

– What is the most likely diagnosis?

– What additional test(s) would confirm it?

– What would be the main short-term benefit of treatment?

Thyroid case #2

• You order thyroid tests on a 5 year old boy who growing along the 5th %ile. His exam is normal and there is no goiter. The free T4 is 1.3 (normal), but the TSH was 0.35 (normal 0.5-4.5).

– Is this child hyperthyroid and does he need to see an endocrinologist ASAP?

– Are additional tests needed?

Thyroid case #3

• A 13 year old girl is experiencing more fatigue but her history and her physical exam is normal. The free T4 is 0.84 (lab normal 0.9-1.6) and the TSH is 1.6.

– Does this child have primary hypothyroidism?

– Are these results likely the cause of her symptoms?

– Does this child have secondary (pituitary) hypothyroidism?

– What additional tests if any are indicated?

Thyroid case #4

• As part of an obesity work-up in a 12 year old girl whose height is increasing along the 90th %ile, you find a free T4 of 1.10 and a TSH of 6.5 (normal 0.5-4.5). There is no goiter and the exam is normal except for the obesity.

– Does this child have hypothyroidism?

– Should we call this “subclinical hypothyroidism”?

– Should you refer right away for evaluation and treatment or follow in your office?

The argument for treating “subclinical” hypothyroidism

• “The pituitary knows best” – any patient with even a slightly elevated TSH is by definition in a mildly hypothyroid state regardless of what the level of free T4 is

• Adult studies show that a small % of such patients progress to overt hypothyrodism over time (? 5% per year), particularly if they have elevated thyroid antibodies

The argument against treating subclinical hypothyroidism

• Mild TSH elevation per se results in no symptoms

• Most patients with mildly elevated TSH show no evidence of progression over many years: TSH often remains ± elevated

– Some patients like this have been found to have mutations in the TSH receptor

• Few have goiters suggesting a sick thyroid

• Treating these patients long term with l-thyroxine may normalize TSH (“treating the number”) but rarely benefit the patient

Copyright ©2009 The Endocrine Society

Distribution of TSH results in the second test according to the category of the first TSH

measurements in untreated patients

Lazar, L. et al. J Clin Endocrinol Metab 2009;94:1678-1682

CNMC study of children with mildly elevated TSH who were taken off T4 & retested

• At CNMC many patients were started on T4 with normal free T4 and mildly ↑ TSH– TSH mostly <20 or <40 in newborn period

• Some of these patients had over time a need for increasing T4 doses and likely had true hypothyroidism

• A subset of patients did not require a dose increase or had a normal TSH on relatively small doses: 25-50 µg/day

• These patients given a ≥ 1 mo trial off T4– 21/34 had been started on T4 in 1st year of life

Patient characteristics

26.5%26.5%20.5%23.5%17.6%

99786

32.7 ± 17.1 µg/day

33.9 ± 13.7 µg/day

Highest initial TSH6-910-2021-40> 40

Down syndrome

Mean T4 dose at start of treatmentMean T4 dose after mean of 3.5 yrs Rx (range 0.5-8.5 yrs)

What happened off treatment?

0/340/34> 15

4/34 (12%) (3 restarted T4)

0/3410 – 15

12/34 (35%)1/345.0-9.9

18/34 (53%)33/34< 5.0

5.17 ± 3.262.43 ± 1.07Mean ± SD

TSH off l-thyroxineTSH while on

l-thyroxine

Conclusion of study

• Many patients are started on thyroid hormone who do not have true hypothyroidism– Often in 1st year of life

– Often because of the presumption that kids with normal free T4 and modest TSH increase will sooner or later develop overt hypothyroidism

• It is reasonable for patients started on T4 when TSH mildly elevated (<20) or who maintain a normal TSH on a low dose of T4 (25-50 mcg) to be given a 1 month trial off thyroid hormone

So what to do with children with normal T4 and TSH of 5-9?

• There is no rush to have these patients seen by an endocrinologist

• Patients with goiters should be referred

– they have a greater chance of having thyroid disease

• For others, suggest repeating free T4 and TSH in 6-12 months to see if there is a rise in TSH to > 10, in which case the child should be seen

– In nearly all cases the TSH either decreases to normal or remains in the 5-10 range

• Should one use thyroid antibodies to decide if the child should be treated?

Thyroid case 5

• A 14 year old girl who has complained of irregular periods has a free T4 of 1.72 (normal 0.9-1.6) and a TSH of 1.1 (0.5-4.5). There is no goiter. What would you tell the parents?

Thyroid case #6

• The newborn screening lab calls to report that an 8 day old infant tested at 2 days of age had a T4 of 8 but a TSH of 212

• What would you do next? (may be >1 answer)

– Send another blood spot to the state lab for confirmation (T4 normal so maybe a lab error)

– Tell parent to call for a peds endocrine appt

– Discuss the case with a pediatric endocrinologist

– Send child to a commercial lab for a T4 and TSH

Thyroid case # 7

• A 15 year old girl complains of rapid heart rate, difficulty sitting still, and failing grades in school. She has lost 20 lb in the past year and is not dieting. Pulse is 116, and thyroid gland is diffusely enlarged. Free T4 is 4.8, T3 520 (80-200) and TSH <0.01.

– Are any additional tests needed?

– How would you advise the parents regarding type of treatment and getting her in to see a pediatric endocrinologist?

Thyroid case #8

• You see another 10 year old girl for a well child exam with a diffusely enlarged thyroid. There are no nodules palpable. There are no symptoms of hypo- or hyperthyroidism. Her free T4 is 1.24 and TSH is 2.1 (0.5-5.0).

– Is any other blood testing needed?

– Does the child need a thyroid ultrasound?

– What is the most likely diagnosis?

– Is treatment of this child needed?

Thyroid case #9

• A 12 year old girl is screened for thyroid disease because of a + family history of hypothyroidism. Exam is normal. Her free T4 is normal at 1.5, but the TSH is 0.03. Thinking this is a lab error, you repeat tests a week later and get essentially the same results (you add a T3 which is 170 (normal 80-200)).

– Is this (early) hyperthyroidism?

– What would you do next?

Thyroid Testing: Summary

• Try to avoid ordering thyroid tests in situations where diagnostic yield is very low

– Far more likely to see a borderline result than one requiring immediate action

• The fewer thyroid tests you order, the less time you will spend figuring out what to do about results which are outside of the normal range but of dubious clinical significance

• For children who really need treatment for hypo-or hyperthyroidism, the free T4 and TSH levels are not borderline.

How many of you have received a fax that looks like this?

Why does endocrinology at CNMC screen patient labs before giving appointments?

• We get a very large number of requests for consults based largely on an abnormal blood test, most often thyroid tests

• It is possible to tell just by reviewing tests which children are unlikely to need any treatment

• When parents tell our schedulers that the request is based on an abnormal lab test, they are told to ask the referring physician to fax the tests to our office

How many such requests do we get?

• We have been tracking this for the past 3 months

• There have been 64 requests related to normal T4 and TSH between 5 and 9– Now 4.4 - 9 since labs lowered their TSH normal range

• Of those, 5 also had goiters and were given appointnements, but the other 59 were not

• Also 16 requests for other non-significant thyroid test results such as we have discussed earlier

Should we try to see these children to reassure the worried parents?

• Right now, the wait time for new appointments in endocrinology is 1-3 months depending on location

• Many parents and PCPs feel this is too long for them to have to wait

• If we scheduled everyone requesting an appt, wait times for patients whom we might be able to help with growth, puberty, and miscellaneous endocrine problems would be significantly greater

• Result would be more unhappy parents and pediatricians

When is referral of a thyroid problem urgent?

• Moderate to severe symptomatic hypothyroidism

– Typically the free T4 will be low and TSH >20

– Patients usually start to feel better a week or two after starting T4 replacement

• Moderate to severe symptomatic hyperthyroidism

– Typically the total T4 is >15, free T4 >2.0, and TSH is <0.1

– Patients usually start to feel better within 4-6 weeks of starting anti-thyroid medications