Coincident Thyrotoxic Hypokalemic Periodic Paralysis and Cardiomyopathy

Abstract

Thyrotoxic periodic paralysis (TPP) and thyrotoxic cardiomyopathy (TCMP) are potentially lethal complications of thyrotoxicosis that require emergent recognition and management to attenuate significant morbidity and mortality. We present the case of a 23-year-old Asian male with no prior medical history who developed TPP with coincident TCMP, which was successfully managed with antithyroid and heart failure therapies. The clinician should be aware of the diagnosis and treatment of these 2 life-threatening conditions in a hyperthyroid state.

Introduction

Thyrotoxic periodic paralysis (TPP) is a potentially fatal condition associated with muscle weakness and hypokalemia due to a massive intracellular shift of potassium. ¹ It is characterized by a triad of thyrotoxicosis with muscle paralysis and acute hypokalemia without a total body potassium deficit. ² Thyrotoxicosis can also be implicated with deleterious cardiac conditions such as atrial fibrillation (AF) and cardiomyopathy (CMP). ³ Prompt recognition and management of these sequelae is imperative to mitigate potentially devastating outcomes.

We present the case of a 23-year-old Asian male with no prior medical history who developed TPP with coincident thyrotoxic cardiomyopathy (TCMP), which was successfully managed with antithyroid and heart failure (HF) therapies.

Case Report

A 23-year-old Chinese male without any significant medical history presented to the emergency department with a 1-day history of angina, dyspnea, and abrupt paralysis after a vigorous exercise regimen in the gym. His symptoms appeared at approximately 6 am, for which he was alarmed and immediately sought emergency medical care. He described having 5 similar episodes in the past 4 years, which all swiftly resolved without medical intervention. He was a lifelong nonsmoker and denied any use of alcohol and illicit substances. He did not have any family history of neurological disease, recent ill contacts, travel, or pet history.

His vital signs on admission were blood pressure of 137/82 mm Hg, heart rate of 136 beats per minute, pulse-oximetry of 95% on room air, random blood glucose of 138 mg/dL, and a temperature of 36.1°C. On physical examination, he was alert, oriented, and coherent. He was examined to have ⅗ power in the upper limbs and ⅖ power in the lower limbs with downgoing plantar reflexes. His heart sounds were normal, with vesicular breath sounds bilaterally and no peripheral edema. His abdomen was nontender with no palpable masses. There was no palpable thyroid goiter.

His laboratory investigations revealed a mild leukocytosis of 11.2 × 10³/uL (normal range 4-10 × 10³/µL) with a normal hemoglobin and platelet count. His potassium level was 1.7 mmol/L (normal range: 3.5-5.1 mmol/L). The remainder of his comprehensive metabolic panel was within normal limits, including calcium, magnesium, and phosphorus levels. His chest radiograph revealed mild pulmonary edema without cardiomegaly. An admission 12-lead electrocardiogram showed atrial fibrillation (AF) with occasional premature ventricular contractions at 94 beats per minute (Figure 1A). This patient was immediately initiated with slow intravenous potassium chloride (KCl) repletion along with noninvasive continuous positive airway pressure ventilation, which led to swift resolution of his symptoms and mild improvement in his aberrant electrocardiography (ECG; Figure 1B). With respect to our patient, he was administered a total of 40 milliequivalents/liter KCl (mEq/L) over 4 hours, which corresponded to a matched increase in serum potassium (K+) level, using the following K+ deficit formula: K+_deficit (in mmol) = (K+_{normal lower limit} − K+ _measured) × body weight in kilograms × 0.4. ⁴ His serum K+ was vigilantly monitored every 8 hours for rebound hyperkalemia during his emergency room care (2.1 mmol/L). During his ensuing hospitalization to the cardiac care unit, his high-sensitivity cardiac troponin I returned at 2.49 ng/mL (normal range: 0.00-0.080 ng/mL), and the following day, his serum K+ was again repleted with the aforementioned protocol (2.5 mmol/L). His thyroid function tests revealed a thyroid stimulating hormone (TSH) of 0.055 mIU/L (normal range: 0.4-4 mIU/L). A 2-dimensional transthoracic echocardiogram (2D-TTE) demonstrated mild, global left ventricular hypokinesis with an estimated ejection fraction (EF) of 40% to 45% function, mildly elevated right ventricular systolic pressure of 41 mm Hg and no overt valvular dysfunction. He was managed with antithyroid therapies, including carbimazole and the beta-blocker, propranolol, as well comprehensive, guideline-directed anti-HF therapies (CGDMT) of angiotensin-receptor blocker/neprilysin inhibitor (valsartan/sacubitril), nonsteroidal mineralocorticoid receptor antagonist (finerenone) and sodium-glucose transport protein-2 inhibitor (empagliflozin). ⁵

Figure 1.

The patient’s 12-lead electrocardiograms (ECGs). (A) The patient’s admission ECG indicated atrial fibrillation with a rapid ventricular response, intraventricular conduction delay, and secondary ST-T changes. (B) The patient’s hospitalization ECG demonstrating borderline left ventricular hypertrophy. There is also increased p-wave amplitude, PR segment prolongation, ST depression, T-wave flattening, prominent U-waves and QT prolongation.

Further investigations included ultrasonography of the thyroid gland, which was unremarkable, with a normal color flow signal and no thyroid lesions. A computed tomography-pulmonary embolism protocol did not reveal any massive pulmonary embolism, and a cardiac computed tomography angiogram scan indicated a calcium score of 0 without any radiologically evident coronary artery disease. The remainder of his hospital course was uneventful, and his 12-lead electrocardiograms improved (borderline left ventricular hypertrophy with secondary ST-T changes) following judicious potassium repletion, now 3.8 mmol/L without any rebound hyperkalemia. His symptoms gradually improved, and he was discharged with a cardiology and endocrinology outpatient follow-up in 1 month. His CGDMT specifically comprised carbimazole 10 mg every 8 hours, propranolol 20 mg every 8 hours, valsartan/sacubitril 25 mg once daily, finerenone 5 mg once daily and empagliflozin 10 mg once daily. A bedside 2D-TTE demonstrated normalization of his EF at his interval ambulatory visit.

Discussion

Hyperthyroidism can profoundly affect the cardiovascular system (CVS) with respect to electrophysiology, atherogenesis, and myocardial contractility.^6-8 Thyrotoxicosis can induce hypertension, tachyarrhythmias, acute coronary syndromes and CMP. ³ Thyrotoxicosis primarily impacts the CVS via T₃-mediated effects. Some of these effects include attenuated systemic vascular resistance, accentuated heart rate, blood volume, and myocardial contractility, resulting in an overall augmented cardiac output. ⁹ Approximately 6% of thyrotoxic patients experience HF symptomatology; however, dilated CMP with myopathic left ventricular function is rare (<1%). Thyrotoxic HF pathophysiology is ascribed to increased diastolic cytosolic calcium and impaired diastolic dysfunction with a resultant decrement in EF. There is also a complex thrombophilic milieu due to increased endogenous coagulation factors. ⁹ The mechanistic effects of AF have not been clearly established; however, excess thyroid hormone accentuates the propensity for atrial excitation. Pulmonary hypertension is also emerging as a cause of right-sided HF in this subgroup.^7,9-11

TPP is a reversible neuromuscular condition that is typically associated with Graves’ disease and is most common in Asian populations. Despite a predilection of thyrotoxicosis in women, TPP predominantly affects young males. ¹ It usually manifests as recurrent episodes of transient muscle weakness and is usually precipitated by strenuous exercise or carbohydrate-rich meals. The severity ranges from mild weakness to complete flaccid paralysis, with preservation of sensory, bowel, and bladder function. ¹ The pathogenesis of TPP is not well elucidated; however, it involves increased skeletal muscle sodium-potassium ATPase pump activity, which is upregulated by catecholamines, insulin and thyroid hormone. There has also been a recent association with loss-of-function mutations in the Kir2.6 channel, a skeletal muscle-specific inward rectifier K+ channel and thyroiditis.^2,12,13 Hypokalemia can worsen major adverse cardiovascular events by paradoxically increasing the excitability of cardiomyocytes, precipitating arrhythmias and possibly, sudden cardiac death.^14,15 Management typically includes potassium replacement, non-selective beta-blockade to suppress hyperadrenergic effects, and definitive therapy for underlying hyperthyroidism to mitigate recurrence.

Our patient presented after a vigorous gym routine. Other conditions that may present similarly include familial periodic paralysis, Guillain-Barré syndrome, and acute intermittent porphyria. The diagnosis of TPP was clinched with the combination of clinical features such as gender and ethnicity, co-existing hyperthyroid state, and severe hypokalemia. In addition, he was also diagnosed with a Non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) and CMP, with an estimated left ventricular ejection fraction (LVEF) of 40% to 45%. Possible mechanisms for these diagnoses include direct metabolic effects of thyroid hormone with acute HF with reduced EF, coronary artery vasospasm secondary to thyrotoxic-induced vasoconstriction, or a thyrotoxic-mediated arrhythmia as AF with a rapid ventricular response. ¹³ There is a paucity of data with respect to having these 2 conditions simultaneously. ¹⁵ Definitive management entails achieving a euthyroid state; however, urgent potassium repletion with caution for potential rebound hyperkalemia is also imperative to prevent deleterious cardiopulmonary and neuromuscular complications. ¹⁶ In our patient, a combined strategy targeting immediate potassium repletion, nonselective β-blockade, definitive antithyroid therapy, and HF therapies resulted in swift resolution of his clinical presentation as well as mitigated further episodes.

With respect to our patient, he was administered a total of 80 mEq/L of KCL over 8 hours in a 48-hour window (2 tranches of 40 mEq, 4 hours each), with initial serum K+ levels of 2.1, 2.5 mmol/L to avert rebound hyperkalemia from homeostatic redistribution. ⁴ Eventually, his steady-state serum K+ level equilibrated at 3.8 mmol/L, which was acceptable considering the fact that he was also on angiotensin-receptor neprilysin inhibitor (ARNi) and mineralocorticoid receptor antagonist (MRA) therapies, which can also exacerbate this effect. One study demonstrated rebound hyperkalemia (K+ > 5.0 mEq/L) in nearly 40% of patients with TPP who received ≥ 90 mEq/L K+ within 24 hours and recommended monitoring levels after an initial administration of 50 mEq/L.,^12,17 Abnormal K+ distribution is implicated in TPP as opposed to an actual potassium deficiency; hence, the concern is with potassium supplementation unless the patient is experiencing life-threatening arrhythmias or respiratory failure. The risk-benefit ratio of lethal arrhythmias precipitated by the potential of rebound hyperkalemia outweighs transient paralysis. ¹⁸ If K+ supplementation is required in unstable arrhythmias, very low doses should be given (≤10 mEq/hour) with close monitoring of the K+ level to attenuate this effect. ¹⁷

According to recent societal guidelines for the management of HF, all patients should receive treatment with 1 of 3 β-blockers that have been shown to reduce mortality, namely bisoprolol, carvedilol, or metoprolol succinate extended-release. ⁵ Despite these agents being U.S. Food and Drug Administration (FDA)-approved, propranolol is the preferred β-blocker due to its effect on blocking the activity of T₄ conversion to active T₃ and, as such, blocking its effect on cardiac myocytes, terminating reentrant atrial excitation. ¹⁹ However, caution should be exercised when instituting this therapy, as patients can abruptly spiral into cardiogenic shock. Ultra-short-acting β-blockers are easily titratable and may prove more useful in this subgroup due to favorable pharmacokinetic and dynamic properties. ²⁰

Dyskalemia can be fatal metabolic derangement, and a serum K+ level <3.5 to 4.0 mmol/L may portend a similar mortality as a K+ level > 5.5 to 6.0 mmol/L. ²¹ Serum K+ dynamics play a crucial role in HF patients, and the greater the risk of a lethal arrhythmia and sudden cardiac death a patient is, critical attention should be focused on K+ homeostasis. ²² Our team’s clinical acumen and gestalt were to safely but swiftly replete the patient’s K+, given his HF and respiratory distress, considering the complex interplay of a potential rebound effect, overcorrection for presumed K+ deficit, as well as additional potassium-sparing HF therapies.

Conclusion

We present the case of a 23-year-old Asian male with no prior medical history who developed TPP with coincident TCMP, which was successfully managed with antithyroid and HF therapies. A combined strategy targeting immediate potassium repletion, nonselective β-blockade, definitive antithyroid therapy and HF therapies resulted in swift resolution of his clinical presentation as well as mitigated further episodes. The clinician should be aware of the diagnosis and treatment of these 2 life-threatening conditions occurring in a hyperthyroid state.