You’ve sent some bloods on a child with lethargy. Their free T4 is normal but their TSH is raised.
What does this mean? Do they have subclinical hypothyroidism?
Subclinical hypothyroidism is a hormonal condition. Thyroid-stimulating hormone (TSH) serum levels are raised, while free T4 (FT4) values are normal. We’ll use some cases to think about the different causes of subacute hypothyroidism, but first, let’s explore what it is.
Hypothyroidism can be classified by lab values.
Subclinical hypothyroidism can be defined as either mild or severe, depending on the degree of TSH elevation. A TSH between 4.5 and 10 mlU/l is classified as mild subclinical hypothyroidism, while TSH >10 mIU/l is severe.
Subclinical hypothyroidism is rare in children and adolescents, affecting <2%. It’s more common in adults, especially females, Caucasians and populations with high iodine intake. Around 12% of women over the age of 60 have subclinical hypothyroidism.
What causes subclinical hypothyroidism?
Subclinical hypothyroidism is caused by:
- Autoimmune thyroiditis – aka Hashimoto thyroiditis, in up to 60-80% of cases
- Thyroid dysgenesis – hypoplasia, hemi-agenesis, ectopia
- TSH receptor mutations
- Adrenal insufficiency
- Down syndrome
- Turner syndrome
- Renal failure
- Cystic fibrosis
- Coeliac disease
- Antiepileptics
- Obesity
- Idiopathic
Which drugs can affect thyroid function?
- Decreased TSH secretion: Dopamine and dopamine agonists, somatostatin, glucocorticoids, carbamazepine, oxcarbazepine
- Decreased thyroid hormone synthesis: Methimazole, propylthiouracil, lithium, iodine, amiodarone, interferons, interleukins
- Altered thyroid hormone metabolism: Phenobarbital, phenytoin, valproic acid, rifampin, propranolol
- Altered thyroid hormone binding: Non-steroidal anti-inflammatory drugs, salicylates
- Drugs that interfere with thyroid functions: Fatty acids, androgens, oestrogens, heroin, methadone, mitotane
- Decreased absorption of levothyroxine: Bile acid sequestrants, proton pump inhibitors, calcium carbonate, ferrous sulfate, phosphate binders
Clinical manifestations vary.
Some children and adolescents are more at risk of developing overt hypothyroidism.
Case 1: Ali
8-year, Ali has an elevated TSH and normal free T4.
His weight and height are both normal. He is asymptomatic and does not have a goitre.
His thyroid ultrasound is normal, and thyroid antibodies are negative.
Six months later, his weight and height remain normal, he still does not have a goitre and his thyroid ultrasound is unchanged.
His mother asks, “Should Ali take thyroid hormones?”
Elevated TSH levels in the absence of thyroid antibodies and goitre suggest subclinical hypothyroidism. The most common cause is autoimmune thyroiditis.
Treatment of subclinical hypothyroidism in children is controversial. There is no consensus on whether treatment is even required. Some studies suggest that early treatment can prevent the progression of hypothyroidism and improve cognitive function, while others suggest that it may not be necessary to treat mild cases. Some use a TSH >10 as a threshold to start levothyroxine.
Case 2: Brittany
7-year-old Brittany has a normal free T4 but high TSH.
She is overweight for her height according to her BMI.
She has no family history of thyroid disease, and she does not have a goitre. She has a normal thyroid ultrasound and negative anti-microsomal and anti-thyroglobulin antibodies.
She is referred to an obesity clinic, and after six months, her BMI improves, and her TSH, although still high, has dropped.
Brittany’s subclinical hypothyroidism is likely due to obesity rather than an underlying thyroid disorder. As her TSH has improved and she is asymptomatic, thyroid hormone replacement therapy is not recommended. Instead, the focus should be on maintaining a healthy lifestyle and regularly monitoring thyroid function. She should be encouraged to continue her weight loss journey. This can help improve thyroid function and prevent complications associated with obesity.
Case 3: Chase
10-year-old Chase presents with a midline neck swelling – a goitre.
His TSH is high and free T4 is normal.
He has positive anti-microsomal and anti-thyroglobulin antibodies.
His maternal aunt has Graves’ disease.
An ultrasound shows a goitre with a heterogeneous echotexture.
The high TSH and positive ultrasound suggest hypothyroidism. The presence of anti-microsomal and anti-thyroglobulin antibodies adds another level of risk. He should start thyroxine replacement therapy.
Case 4: Desiree
10-year-old Desiree presents with midline neck swelling.
Her parents first noticed it when she was two years old, and since then, it has gradually been increasing in size. It is soft, cystic, and not tender. It moves on swallowing, and when she sticks out her tongue. There is no pain or discharge, no lymphadenopathy, and she is otherwise well.
Thyroid function tests show a high TSH and normal free T4, with negative thyroid antibodies.
An ultrasound shows a thin-walled, septated anechoic cystic lesion.
The thyroid gland is not visualized in the thyroid fossa.
A thyroid scan shows functional ectopic thyroid tissue within the thyroglossal cyst. There is no tracer uptake in the normal thyroid bed or elsewhere in the body.
Her father asks, “Is this cancer?”
Desiree’s midline neck swelling is consistent with a thyroglossal cyst, a congenital anomaly that arises from the embryonic thyroglossal duct.
The elevated TSH levels indicate that the thyroid gland is not functioning properly, and the absence of tracer uptake in the normal thyroid bed confirms this.
The risk of cancer developing in a thyroglossal cyst containing ectopic thyroid tissue is approximately 1%. Therefore, it is important to confirm the diagnosis and exclude malignancy. Fine-needle aspiration cytology (FNAC) can confirm the diagnosis and exclude malignancy.
Desiree’s FNAC does not show any cancer cells. She undergoes surgical excision of the thyroglossal cyst and tract and is started on L-thyroxine.
Case 5: Ellie
14-year-old Ellie has had chronic kidney disease since the age of four.
She is on regular haemodialysis, and her serum creatinine level is 10.4 mg/dI.
She also has a goitre.
Her TSH is high, and her free T4 is normal. Her thyroid antibodies are negative.
A thyroid ultrasound shows a large, homogenous gland consistent with a goitre.
There is no consensus as to whether patients with chronic kidney disease and subclinical hypothyroidism require hormone replacement. Treatment in these patients is challenging, as several factors can affect the effectiveness and safety of treatment.
The use of thyroid hormone replacement therapy should be carefully monitored. Unnecessary hormone replacement in asymptomatic cases may increase muscle catabolism. This leads to problems maintaining nitrogen homeostasis. Children with a TSH >10 ulU/L should not be started on levothyroxine unless they’re symptomatic.
If TSH reaches 10, then thyroxine may relieve symptoms of hypothyroidism and reduce its effects on the kidney and heart.
The clinical bottom line
The decision to treat subclinical hypothyroidism in children remains a matter of debate. Management should take into account TSH level and the cause of thyroid dysfunction.
Children with TSH >10 ulU/L should be treated whatever the cause, while children with TSH between 5-10 ulUL are treated on an individual basis.
Treatment should be recommended in children with a goitre, anti-thyroid autoantibodies and hypothyroid signs or symptoms.
Children with metabolic abnormalities and progressively deteriorating markers over time should also be treated, as should children with Turner syndrome, Down syndrome or other autoimmune diseases.
Children with a persistent mildly elevated TSH, who are not treated with levothyroxine, should be reassessed every 6 months. After 2 years, if thyroid function tests remain stable, follow-up can be once a year.
References
Cerbone M, Capalbo D, Wasniewska M, Mattace Raso G, Alfano S, Meli R, et al. (2014) Cardiovascular risk factors in children with long-standing untreated idiopathic subclinical hypothyroidism. J Clin Endocrinol Metab. 99:2697–703. doi: 10.1210/jc.2014-1761
Dong Ho Shin, Mi Jung Lee, Seung Jun Kim, Hyung Jung Oh, Hyoung Rae Kim, Jae Hyun Han, Hyang Mo Koo, Fa Mee Doh, Jung Tak Park, Seung Hyeok Han, Tae-Hyun Yoo, Shin-Wook Kang, Preservation of Renal Function by Thyroid Hormone Replacement Therapy in Chronic Kidney Disease Patients with Subclinical Hypothyroidism, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 8, 1 August 2012, Pages 2732–2740, https://doi.org/10.1210/jc.2012-1663
Gallizzi, R., Crisafulli, C., Aversa, T. et al. Subclinical hypothyroidism in children: is it always subclinical?. Ital J Pediatr 44, 25 (2018). https://doi.org/10.1186/s13052-018-0462-4
Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. (2005) Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J Clin Endocrinol Metab. 90:581–5. doi: 10.1210/jc.2004-1231
Karmisholt J, Andersen S, Laurberg P. (2011). Variation in thyroid function in subclinical hypothyroidism: importance of clinical follow-up and therapy. Eur J Endocrinol. 164:317–23. doi: 10.1530/EJE-10-1021
Lee, MK., Kim, Y.M., Sohn, SY. et al. Evaluation of the relationship of subclinical hypothyroidism with metabolic syndrome and its components in adolescents: a population-based study. Endocrine 65, 608–615 (2019). https://doi.org/10.1007/s12020-019-01942-9
Mussa A, Salerno MC, Bona G, Wasniewska M, Segni M, Cassio A, et al. (2013) Serum thyrotropin concentration in children with isolated thyroid nodules. J Pediatr. 163:1465–70. doi: 10.1016/j.jpeds.2013.07.003
Paoli-Valeri M, Mamán-Alvarado D, Jiménez-López V, Arias-Ferreira A, Bianchi G, Arata-Bellabarba G. (2003) Frequency of subclinical hypothyroidism among healthy children and those with neurological conditions in the state of Mérida, Venezuela. Invest Clin. 44:209–18.
Shin DH, Lee MJ, Kim SJ, T. et al. . Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 2012 Aug;97(8):2732-40. doi: 10.1210/jc.2012-1663. Epub 2012 Jun 20. PMID: 2272333
Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. (1995) the incidence of thyroid disorders in the community: a twentyyear follow-up of the Whickham Survey. Clin Endocrinol. 43:55–68. doi: 10.1111/j.1365-2265.1995.tb01894.x
Wu T, Flowers JW, Tudiver F, Wilson JL, Punyasavatsut N. (2006) Subclinical thyroid disorders and cognitive performance among adolescents in the United States.BMC Pediatr. 6:12. doi: 10.1186/1471-2431-6-12
