Ms J is a 14-year-old girl who presents to her pediatrician for increasing episodes of nosebleeds. The nosebleeds are occurring 3 to 4 times per week and have been effectively managed at home. The patient’s mother explains that her daughter has always bruised easily but denies any family history of bleeding disorders. The mother notes other changes in her daughter over the last 6 to 8 months, including increased rate of speech, complaints of leg pain with little exercise, increased episodes of headaches, more irritable mood than usual, and bulging of her eyes. Upon further questioning, the patient’s mother reveals that her daughter is hot all the time and has to go outside in short sleeves even during the winter to cool off. The mother states that the mood changes and complaints of feeling hot started 2 to 3 years prior. There is a history of hypothyroidism in her mother, aunt, and maternal grandmother. The mother denies noticing any weight loss in her daughter, but says that her daughter eats all the time and never gains weight.
Medical History
Ms J has been seen by her pediatrician on 3 prior occasions. In January she was seen for a sports physical to play tennis and had a heart rate of 102 beats per minute and a blood pressure of 130/52 mm Hg recorded. Her pediatrician notes in her record that the patient is upset about receiving immunizations, thus elevating her blood pressure and heart rate. In March, Ms J is seen for a sore throat and cough; her heart rate is 115 beats per minute. In August, she is seen for a wound associated with a jellyfish sting 1 week prior; her heart rate is 123 beats per minute recorded. Her mom reported occasional nosebleeds that had been occurring for 3 to 4 years, according to the medical records.
Additionally, the patient’s medical history includes a diagnosis of absence seizures starting at age 7 years; for which she was enrolled in a blind research study for epilepsy. Ms J was put on several different trial medications until initiating sodium valproate, which effectively controlled her absence seizures for 4 years. She discontinued sodium valproate approximately 18 months prior to her current visit.
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Physical Examination
Upon physical examination, the patient’s skin is warm and moist. The patient is noted to have moderate exophthalmos. Her lungs clear to auscultation bilaterally, with mildly increased respiratory rate (Table 1). Hair is noted to be thin and dry. No other abnormalities are noted on examination.
Table 1. Vital Signs
| Weight, lb | 149 |
| Temperature, °F | 99.2 |
| Pulse, bpm | 91 |
| Respiratory rate per min | 23 |
| Pulse oximetry, % | 98 |
Laboratory Results
The complete blood cell count (CBC), prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT) are all within normal range. Thyroid panel demonstrates elevated thyroxine hormone (free T4) and severely decreased thyrotropin, consistent with diagnosis of hyperthyroidism (Table 2). The patient is referred to a pediatric endocrinologist.
Table 2. Abnormal Laboratory Results
| Measure | Result | Normal Values |
| Free T4 | 6.7 | 0.9 – 1.4 |
| TPO antibodies | >1,000 | <35 |
| Thyrotropin | 0.01 | 0.50-4.30 |
Diagnosis
The pediatric endocrinologist completes the patient’s workup and diagnoses her with Graves disease. The exact length of time the patient was hyperthyroid before receiving the correct diagnosis and treatment remains unknown. Ms J had been having symptoms consistent with hyperthyroidism 2 to 3 years before beginning to actively pursue medical treatment (Table 3). The increased episodes of nosebleeds and concern about her exophthalmos are what finally prompted her parents to seek acute medical attention.
Table 3. Signs and Symptoms of Hyperthyroidism
| Increased appetite, unintentional weight loss |
| Tachycardia, heart palpitations, arrhythmia |
| Irritability, nervousness, shakiness/tremor, anxiety |
| Rapid speech |
| Hair thinning, brittle hair |
| Heat intolerance |
| Increased sweating |
| Increased bowel movements, diarrhea |
| Changes in menstrual cycle |
| Enlarged thyroid gland, neck swelling |
| Muscle weakness, fatigue |
| Trouble sleeping, insomnia |
Graves Disease
Graves disease is an autoimmune disorder in which thyrotropin (formerly known as thyroid-stimulating hormone) receptor antibodies stimulate the thyrotropin receptor, causing increased thyroid hormone synthesis and thyroid gland growth.1,2 Graves disease is the most common cause of hyperthyroidism, followed by toxic multinodular goiter, toxic adenoma, and thyrotropin-secreting pituitary adenoma.1,2 Clinical manifestations specific to Graves disease include ophthalmopathy (lid lag, exophthalmos, proptosis) and pretibial myxedema (nonpitting, edematous pink-brown nodules on shins).1,2 In addition to the eyes and skin, systemic manifestations of Graves disease affect the heart, skeletal muscle, bone, and liver.1,2 Life-threatening thyroid storm can occur in patients with untreated Graves disease or following thyroidectomy or abrupt cessation of antithyroid drugs.1,2
Epidemiology of Graves Disease
The prevalence of hyperthyroidism in the United States is estimated at 1.2%, with an incidence of 20 to 50 per 100,000 person-years.1,2 Graves disease is the most common cause of hyperthyroidism in the US, affecting about 1 in 200 people. 3 Graves disease is more commonly seen among adults, specifically those aged 20 to 50 years, than among children.1 Graves disease is far more common in women than men, with lifetime risk estimated at 3% and 0.5%, respectively.1 One study evaluating pediatric cases of thyrotoxicosis found that approximately 96% were caused by Graves disease.4
There is limited and conflicting research comparing the prevalence of hyperthyroidism between different races and ethnicities. In one study from Brazil, Black race was associated with an increased risk for overt hyperthyroidism.5 In contrast, authors of a review article noted that the frequency of hyperthyroidism appears to slightly higher in White populations than in other races.6
Risk factors for Graves disease include pregnancy (especially postpartum), viral infections, overconsumption or overexposure to iodine, increased emotional stress, tobacco abuse, and treatment with interferon-α.1
Diagnostic Tests
Diagnostic tests for Graves disease include1,2:
- Thyrotropin receptor antibody — high sensitivity and specificity
- Thyroid peroxidase and antithyroglobulin antibodies
- Hyperthyroid thyroid function tests:
- Increased free T4 and/or triiodothyronine (T3) levels
- Decreased thyrotropin levels
- Radioactive iodine uptake:
- Increased diffuse uptake
Treatment for Graves Disease
The 3 main treatment options for overt Graves disease in children include1,2: 1) antithyroid drugs; 2) radioactive iodine treatment of the thyroid gland; and 3) thyroidectomy. Radioactive iodine is the most common therapy used and destroys the thyroid gland.1,2 Methimazole and propylthiouracil can be used to block thyroid production of T3 and T4 as short-term treatment before surgery or radioactive iodine, or as long-term treatment in patients who want to avoid definitive therapy.1,2 Total thyroidectomy is definitive treatment and requires lifelong hormone replacement.1,2 Beta-blockers can be used for symptomatic relief of tachycardia, tremors, palpitations, anxiety, and diaphoresis.1,2
Risk for thyroid storm is related to Ms J’s parents, and the patient and her parents agree to starting medical management with a trial of methimazole. A few days after initiation, the patient presents to her pediatrician with a blotchy rash, severe itching to the point of bleeding, and mild swelling of her extremities. Also noted is a small fat pad developing over her lower lumbar/upper sacral spine with dimples on either side. The pediatrician, with input from the endocrinologist, decides to discontinue methimazole. The patient is placed on the beta-blocker propranolol 40 mg three times daily until her appointment with a surgeon to discuss thyroidectomy.
After a thyroid panel is repeated, the patient is told that radioactive iodine is no longer an option because of the risk for thyroid storm given her elevated T4 and T3 levels and the discontinuation of methimazole. While it is unfortunate that the patient had an adverse reaction on methimazole, this reaction is likely the result of prolonged progression of her disease over a drawn-out period, which ruled out the option of radioactive iodine.
Ms J’s total thyroidectomy is performed. During surgery, her blood pressure becomes elevated. She remains in recovery for an additional 4 hours while clinicians stabilize her blood pressure to normal. She is discharged the following day and is started on levothyroxine. After surgery, the patient gains 40 pounds while medication adjustments are being made. One year after surgery, the patient’s medication dosage is appropriately titrated and she has lost the postsurgical weight gain. She is currently well-controlled on levothyroxine and does not have any known adverse effects. Ms J currently has blood draws every 3 months for maintenance.
Hyperthyroidism and Epilepsy
The patient in this case was previously treated for epilepsy using different trial medications for 4 years before receiving a diagnosis of Graves disease. The seizure threshold is lowered in patients with preexisting epilepsy who have increased levels of thyroid hormones (T4 and T3).7 Increased hormone levels decrease the seizure threshold, and patients with Graves disease are often unable to be well-controlled on antiepileptic drugs when there are excess levels of T3 circulating in the blood.8 Findings from one study demonstrated that T4 may lower the seizure threshold in patients with epilepsy, as petit mal status epilepticus was able to be induced by T4 given at high doses.9 Another case study involving a patient who developed generalized convulsions with Graves disease suggests that treatment with antithyroid medication might improve idiopathic generalized epilepsy.10
As the patient in this case did not have thyroid panels checked, it is unclear whether the patient’s overactive thyroid may have been a contributing factor to her epilepsy requiring trials of several medications to control seizure frequency. It is possible that her thyroid levels were elevated long before discovery, as she complained of symptoms consistent with hyperthyroidism for a few years before being diagnosed with Graves disease. If the patient had been evaluated for hormone imbalances during treatment and evaluation of her absence seizures, it may have revealed her hyperthyroidism more quickly and allowed for a different treatment outcome than immediate surgery.
Conclusion
This case demonstrates the importance of recognizing the signs and symptoms of hyperthyroidism in the adolescent population in a timely manner. When a teenager complains in a primary care setting of continued irritability and exercise intolerance, it is important to not simply dismiss this as normal teenage behavior. Completing a thorough review of systems and questioning the patient about other concerning symptoms, which may indicate hormonal imbalances, can result in more efficient progression of diagnosis and treatment. Ordering a thyroid panel involves only a simple blood draw, and is an easy and efficient process that can quickly diagnose whether a patient needs further treatment and evaluation for thyroid disorders.
Kolyse Caver, PA-C, is a graduate of Augusta University’s PA program who is currently working in neurology; Rachel Fink, PA-C, is an assistant professor for Augusta University’s PA program.
References
1. Pokhrel B, Bhusal K. Graves disease. In: StatPearls. StatPearls Publishing; 2021 Jan-. Updated July 21, 2020. Accessed July 30, 2021. https://www.ncbi.nlm.nih.gov/books/NBK448195/
2. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421. doi:10.1089/thy.2016.0229
3. Srinivasan S, Misra M. Hyperthyroidismhttps://pedsinreview.aappublications.org/content/36/6/239 in children. Pediatr Rev. 2015;36(6):239-248. doi:10.1542/pir.36-6-239
4. Leung AKC, Leung AAC. Evaluation and management of children with thyrotoxicosis. Recent Pat Endocr Metab Immune Drug Discov. 2017;11(1):22-31. doi:10.2174/1872214812666180327112540
5. Olmos RD, Figueiredo RC, Aquino EM, Lotufo PA, Bensenor IM. Gender, race and socioeconomic influence on diagnosis and treatment of thyroid disorders in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Braz J Med Biol Res. 2015;48(8):751-758. doi:10.1590/1414-431X20154445
6. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016;388(10047):906-918. doi:10.1016/S0140-6736(16)00278-6
7. Faigle R, Sutter R, Kaplan PW. Electroencephalography of encephalopathy in patients with endocrine and metabolic disorders. J Clin Neurophysiol. 2013;30(5):505-16. doi:10.1097/WNP.0b013e3182a73db9
8. Su YH, Izumi T, Kitsu M, Fukuyama Y. Seizure threshold in juvenile myoclonic epilepsy with Graves disease. Epilepsia. 1993;34(3):488-92. doi:10.1111/j.1528-1157.1993.tb02589.x
9. Sundaram MB, Hill A, Lowry N. Thyroxine-induced petit mal status epilepticus. Neurology. 1985;35(12):1792-173. doi:10.1212/wnl.35.12.1792
10. Maeda T, Izumi T. Generalized convulsions with diffuse spike and wave bursts emerging with Graves’ disease. Neuropediatrics. 2006;37(5):305-307. doi:10.1055/s-2006-955966
