A 17-year-old fully vaccinated boy with obesity, who is without access to routine pediatric care, presents with 1 month of bilateral lower extremity fatigue with minimal activity and 1 week of episodic nighttime chest discomfort, palpitations, and muscle cramping. Starting 1 month ago, he has experienced intermittent bilateral leg fatigue with ambulation described as feelings of weakness and tiredness in his thighs and calves. Beginning a week ago, he reported occasional muscle cramping in his arms and legs. Each night during that week, he has had an episode of palpitations and chest “cramping,” which both improve in 1 minute after ambulation. These symptoms worsened the night before presentation, with multiple episodes of chest cramping happening back-to-back with increasing severity. He reported generalized fatigue as well as a 10-kg weight gain in the last year. He denied fever, constipation, hair loss, dark urine, recent history of exertion, cold intolerance, rash, shortness of breath, changes in sleep, paresthesia, or syncopal episodes. The patient has no family history of arrhythmias, congenital heart disease, or coronary heart disease, but he did report a family history of hypothyroidism of unknown etiology. He does not take any medications or supplements and denied any illicit drug use. He did not seek care with a primary care pediatrician prior to the current presentation.He initially presented to the emergency department of another hospital, where he was found to have an elevated creatine kinase (CK) of 3175 U/L (52.92 μkat/L; reference range: 0.917–2.83 μkat/L), creatinine of 1.4 mg/dL (123.76 μmol/L; reference range for age/sex: 53.05–88.42 μmol/L), normal troponin and electrocardiogram (EKG) results, and normal urine study results, including negative results for hemoglobin and myoglobin. His vital signs were typical, and his physical examination was notable for obesity and atypical Achilles reflexes. He was then transferred to the emergency department at a community children’s hospital.On physical examination, he has a heart rate of 62 beats/min, respiratory rate of 15 breaths/min, and blood pressure of 107/63 mm Hg. The patient’s height is 165.1 cm (sixth percentile), weight is 105.2 kg (99th percentile), and body mass index is 38.59 kg/m2 (99th percentile). His cardiac examination results are normal. He has a typical gait, 5/5 strength in his upper and lower extremities, delayed relaxation phase of his Achilles reflexes bilaterally, and normal muscle bulk and tone without tenderness to palpation. He does not have peripheral edema, flank pain, or a goiter.The differential diagnosis for a patient presenting with muscle fatigue, cramping, and palpitations includes excessive exercise resulting in rhabdomyolysis, autoimmune, infectious, or inflammatory myositis, substance induced myopathy, or electrolyte derangements such as hypokalemia leading to cramping. Other less likely diagnoses, given the patient’s age at presentation, include inherited causes of myopathy such as mitochondrial myopathies, muscular dystrophy, and glycogen storage disease. Rhabdomyolysis from muscle damage of any etiology can lead to acute kidney injury (AKI) and—if severe—can cause derangements in electrolyte levels, resulting in palpitations. Other considerations for muscle weakness include myasthenia gravis and hypothyroidism. The presence of palpitations indicates the need to rule out a potentially dangerous arrhythmia resulting from cardiac ischemia or cardiomyopathy.At the community children’s hospital emergency department, repeat CK is 3917 U/L (65.28 μkat/L; reference range: 0.917–2.83 μkat/L). The creatinine, troponin, and urine studies are also repeated and are unchanged. His sodium is 141 mmol/L (reference range: 135–145 mmol/L), potassium is 4 mmol/L (reference range: 3.5–5 mmol/L), and estimated glomerular filtration rate (eGFR) is 48 mL/min/1.73 m2 (reference range for age/sex: >90 mL/min/1.73 m2) per the revised Schwartz equation. Calcium is 9.3 mg/dL (2320 μmol/L: reference range: 2130–2620 μmol/L) and Vitamin D 25OH is 23 ng/mL (57.31 nmol/L; reference range: 50–100 nmol/L). The EKG results show no evidence of myocardial ischemia, cardiomyopathy, or tachyarrhythmia, but they are notable for sinus bradycardia with a heart rate in the 50s. He is given 3 1L normal saline boluses and is started on 200 mL/h normal saline to treat rhabdomyolysis. Additional laboratory studies following admission are notable for an undetectable free thyroxine (T4) and thyrotropin of 403 mIU/L (reference range 0.8–1.4 mIU/L). The patient’s condition was diagnosed as hypothyroidism, later found to be secondary to Hashimoto’s disease, also known as chronic lymphocytic thyroiditis.The patient’s condition was found to have a primary diagnosis of severe hypothyroidism that led to his secondary diagnoses of myopathy, rhabdomyolysis, AKI, and bradycardia. Myopathy is a common presentation of severe hypothyroidism and can be accompanied by rhabdomyolysis.1 The CK level is reflective of the extent of muscle injury but does not necessarily reflect the degree of hypothyroidism.2The pathogenesis of hypothyroid-induced myopathy and rhabdomyolysis is not entirely known. The thyroid hormone is necessary for normal cellular metabolic function. A deficiency in T4 leads to a deficiency in mitochondrial function, atypical glycogenolysis, and increased insulin resistance. This causes the atrophy of type 2 (fast-twitch) muscle fibers and alteration to type 1 (slow-twitch) fibers, which lead to slowed muscle contraction. As a compensatory response, the muscles undergo hypertrophy. Muscle carnitine levels also decrease, which contributes to the symptoms of myopathy. There is also deposition of glycosaminoglycans, poor contractility of actin-myosin units, and low adenosine triphosphate turnover, leading to low muscle energy stores.1Low levels of thyroid hormone can lead to bradycardia, sometimes resulting in sick sinus syndrome and progressing to heart block. Of note, preventricular complexes (PVC) are not a symptom of hypothyroidism.Severe hypothyroidism can be associated with AKI, but this is uncommon. There are 2 main mechanisms of action, the first being in the setting of severe rhabdomyolysis. Myoglobin released from damaged muscles during rhabdomyolysis causes kidney injury in 3 ways: (1) increased vascular permeability causing decreased intravascular volume, (2) increased amount of directly toxic reactive oxygen species, and (3) the formation of obstructive casts in the renal tubules.3,4 The second method in which hypothyroidism results in AKI is through the direct effect of thyroid hormone on the GFR and—by extension—on creatinine clearance. Hypothyroidism leads to a lower GFR, which means that serum creatinine levels will gradually increase if left untreated.3,4 This mechanism is more likely the reason for our patient’s AKI, given that hydration did not improve his creatinine as would be expected had rhabdomyolysis been the primary driver.If left untreated, severe hypothyroidism can very rarely lead to myxedema coma in children. This is a complication that affects multiple organs, is usually precipitated by stressors such as infection, and is potentially fatal. Mortality rates are reported to range from 20% to as high as 60%.The patient was admitted for intravenous (IV) hydration and cardiac monitoring given his bradycardia. After his laboratory work returned, the endocrinology service was consulted, and he was started on IV levothyroxine for the severity of his hypothyroidism and concern that enteral absorption would be impaired as a result of his overall slowed metabolism. IV liothyronine, a synthetic form of triiodothyronine (T3), was added the following day for persistent bradycardia. T3 was used for a more immediate response because it does not need to be converted to an active form to be effective, as compared with T4, which must undergo peripheral conversion to T3, potentially causing a delay in response. Thyrotropin and free T4 were monitored every 12 hours, and the patient was maintained on a cardiac monitor.The patient’s muscle cramps improved as his thyroid hormone levels slowly improved with treatment. His bradycardia gradually resolved, and he was discharged on oral levothyroxine with follow-up in endocrinology clinic. His telemetry monitoring during admission showed predominantly sinus rhythm with occasional PVC, which was presumed to be the source of his palpitations and was directly related to his bradycardia. The PVC decreased in frequency as the patient’s heart rate normalized. However, after discharge, the patient continued to report occasional palpitations even after normalization of his thyroid hormone levels and heart rate and was referred to cardiology for further workup. As an outpatient, he had a Holter study done, the results of which showed no abnormalities, and the predominant rhythm during his reported palpitations was normal sinus rhythm with no PVC captured. The exact etiology of his palpitations remains unknown. It is possible that the patient’s palpitations on initial presentation could be explained by bradycardia-related PVC, but it is unlikely that the continued palpitations are related to the patient’s now-treated hypothyroidism. His persistent palpitations on Holter monitoring in the absence of PVC may indicate hyperawareness of the body or panic attacks. The chest “cramping” noted on presentation was likely owing to skeletal muscle breakdown from rhabdomyolysis and was not cardiac in nature. His creatinine did not improve with IV hydration, and it was thought that this could be an underlying chronic kidney disease instead of an AKI. However, after a few weeks of treatment of his long-standing hypothyroidism, his elevated creatinine normalized. He experienced a 20-kg weight loss in the 5 months after starting treatment.
Mahendran et al. (Sun,) studied this question.