Atrioventricular block in patients with hyperthyroidism: a narrative review

Abstract

Atrioventricular block (AVB) is a rare cardiac manifestation of hyperthyroidism (HTH). The scientific literature contains multiple reports of AVB in patients with HTH, ranging from subclinical to overt HTH and even thyroid storm. However, much remains unknown about the true prevalence, clinical course, optimal management, and outcomes of AVB in patients with HTH. Such patients are possibly overtreated with pacemakers because of a lack of understanding that AVB might be secondary to the hyperthyroid state and thus reversible. This narrative review discusses the pathophysiology of AVB in patients with HTH in the context of the available evidence.

Introduction

Atrioventricular block: Background

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, resulting in up to 32% of all deaths. ¹ The major causes of mortality secondary to acute and chronic CVD are myocardial infarction and stroke, leading to 80% of all CVD-related deaths. ¹ In contrast to more chronic mechanisms of mortality, sudden cardiac death (SCD) leads to rapid mortality within hours. ² SCD represents a substantial threat to human life, having caused approximately 400,000 deaths annually in the United States in the 1990s; global figures are much higher. ² There are many established causes of SCD, and they vary in prevalence. An estimated 86% of all cases of SCD are secondary to ischemic heart disease. ³ Non-ischemic causes of SCD include inherited channelopathies such as Brugada syndrome and long QT syndrome, cardiomyopathies, heart failure, valvular heart disease, and congenital structural heart defects. ⁴ One of the less thoroughly studied and rare causes of SCD is atrioventricular block (AVB).^2,5 In a normal, healthy heart, impulses are generated from the sinoatrial node. These impulses are conducted through a channeled pathway from the atria to the ventricles, resulting in synchronized contractions in the myocardium. ⁶ Anatomical or functional disruptions in this process can result in delayed or blocked conduction, leading to AVB. The severity and duration of these disruptions vary, ranging from benign or severe and from temporary to permanent. The level of the block in the conduction pathway and the underlying etiology determine the nature of the disruptions. ⁷

Types of AVB

There are three main types of AVB, mainly depending on the affected region of the conduction pathway. ⁸

First-degree AVB

First-degree AVB is due to delayed conduction from the atrium to the ventricle. On an electrocardiogram (ECG), this manifests as a prolonged P-R interval of >200 ms. ⁸

Second-degree AVB

Second-degree AVB is characterized by discontinuous impulse transmission from the atria to the ventricles, usually in a regular pattern (e.g., 2:1, 3:1). ⁸ It is further subdivided into Mobitz types I and II. On an ECG, Mobitz type I AVB manifests as progressive prolongation of the P-R interval until a beat is dropped, whereas Mobitz type II AVB is characterized by a constant P-R interval followed by a missed beat. ⁹

Third-degree or complete AVB

Third-degree AVB, also called complete heart block (CHB), is due to complete desynchronization of impulse conduction from the atria to the ventricles. This results in complete dissociation between the atria and ventricles and is characterized on an ECG by regular P-P and R-R intervals with an irregular P-R interval. ¹⁰

The global prevalence of AVB is unknown. A nationwide analysis of 15 million people in China revealed a 7.06% overall prevalence of all types of AVB. Most of these were first-degree AVB (6.84%), followed by second-degree AVB (0.18%); CHB was the least common (0.04%). ¹¹ Differentiation among the degrees of AVB is clinically important because the treatment and prognosis are significantly different. First-degree AVB and Mobitz type I AVB generally follow a benign course, whereas Mobitz type II AVB and CHB pose a risk of severe complications such as SCD. ⁷ Although CHB is commonly considered the most dangerous form of AVB, accumulating evidence shows that P-R prolongation is itself a risk factor for atrial fibrillation (A.fib), heart failure, and death. ¹¹

Treatment of AVB mainly relies upon managing the underlying etiology when a reversible cause is identified and implanting a temporary pacemaker (PM) or permanent PM (PPM) when the AVB is of higher degree (Mobitz type II and CHB) with no reversible cause. ⁷ Although PMs significantly reduce the risk of SCD, they are not free of potential complications. Some common complications associated with PM implantation include hematoma formation, lead dislodgement, infection, lead perforation, and dysrhythmia. ¹²

AVB in the context of hyperthyroidism

Cardiac involvement in hyperthyroidism

Cardiac complications are common in patients with hyperthyroidism (HTH), and such complications may take many forms. A.fib is the most common CVD in patients with HTH, showing an incidence of up to 25% among these patients. ¹³ A.fib in patients with HTH has been a focus of research in the past decade. Its clinical significance lies in its role as an independent risk factor for CVD-related events. ¹⁴ The mechanisms underlying the development of A.fib in patients with HTH are multifactorial and include increased left atrial pressure, ischemic changes secondary to persistent tachycardia, and potentiation of atrial ectopic activity. ¹⁵ In their prospective trial, Wustmann et al. ¹⁶ showed that increased supraventricular ectopic activity in patients with HTH is associated with the hyperthyroid state. This association was further strengthened by complete resolution of the ectopic activity once the patients had become euthyroid. ¹⁶ Extensive data indicate that beyond overt HTH, subclinical or silent HTH is strongly associated with deranged cardiac electric activity. The most significant correlation has been observed with A.fib, which can be seen in up to 68% of patients with subclinical HTH at follow-up who did not initially have A.fib. ¹⁷

High-output cardiac failure, dilated cardiomyopathy, right heart failure, and pulmonary hypertension are other uncommon cardiac complications of HTH.^18,19 When HTH results in these complications or when these comorbid conditions are coupled with HTH, the risk of mortality significantly increases. Patients with HTH who develop cardiac failure have a mortality rate of up to 60% higher than that of patients with euthyroidism. ²⁰ This heightened risk is also applicable to patients with subclinical HTH. One study showed that compared with euthyroid patients, the incidence rate ratio of all-cause mortality was 1.25 in patients with overt HTH and 1.23 in those with subclinical HTH. ²¹

The rarest and probably the most under-studied cardiac complication of HTH is AVB. Despite small case series and reports dating back to 1928 ²² as well as ongoing reporting of patients who developed AVB secondary to HTH, ²³ there is still a lack of prospective studies analyzing the clinical course, mechanisms, and management of AVB in patients with HTH.

Mechanism of action of thyroid hormone within the myocardium at the molecular level

Thyroid hormones exert their genomic effects via upregulation of various molecular targets such as major histocompatibility complex α, sarcoendoplasmic reticulum calcium ATPase, cardiac troponin I, sodium–potassium ATPase, voltage-gated potassium channels, potassium channels, and β1 adrenergic receptors, among others. The cumulative effect is increased activation of myocardial muscle fibers, more efficient cardiac contractility, deranged action potential durations, vasodilation with reduced peripheral vascular resistance, increased heart rate, and decreased pulse pressures. ¹³ Thyroid hormone also has non-genomic effects on the heart. Rapid oxygen utilization, enhanced production of metabolic end products, and relaxation of smooth muscles in the arteries collectively contribute to decreased peripheral vascular resistance. This leads to hemodynamic instability in patients with HTH, in whom all these functions are exaggerated. ¹³

HTH and AVB

Hypothyroidism is more commonly associated with AVB than are other thyroid disorders. Because of the deficiency of thyroid hormone in the body, the hypermetabolic effects of this hormone on the heart are lost, resulting in decreased contractility and potential heart failure. ²⁴ Some researchers have postulated that through this mechanism, hypothyroidism also can lead to bradycardia and eventual AVB. ²⁵ According to another theory, autonomic nervous system derangements and sinoatrial node remodeling in patients with hypothyroidism result in bradycardia and AVB. ²⁶ The exact mechanism remains unclear because the prevalence of this condition is too low for the performance of prospective studies, which would produce more valuable and reliable results.

Similarly, how HTH can cause AVB amid increased cardiac activity remains unknown. ¹³ Overactive myocardium secondary to a persistent hyperthyroid state can eventually lead to cardiac failure in the presence of high cardiac output. ¹⁸ A similar theory can be proposed for AVB: increased electrical activity secondary to the hyperactive effects of thyroid hormone can cause exhaustion or depletion of electrical impulses, leading to eventual disruption or blockage of the impulses and subsequent AVB.

Although the mechanism underlying the development of AVB in patients with HTH is unknown, and although there are few extensive studies to support the presence of causality between HTH and AVB, numerous cases have been reported. Possible roles of a coexisting heart condition, infection, or drug treatment have been mentioned in some cases. However, many reports have described patients with HTH and AVB who were otherwise healthy and not taking any drugs with AVB as a known adverse effect. Moreover, there are multiple reports of patients with AVB as the first presentation of thyrotoxicosis.^27–29 Such variable presentations suggest a link between HTH and AVB. This link appears to be independent of antithyroid medications or other drugs given for treatment of HTH (such as beta blockers (BBs)), and it is not contingent on the presence of concurrent illness. Figure 1 shows some existing theories on the possible mechanisms of AVB development in patients with HTH. One of these theories is exaggeration of pre-existing latent hypervagotonia by the autonomic nervous system secondary to the excess thyroid hormone in the body. ³⁰ Another possible mechanism is thyroid hormone-induced myocarditis and associated inflammation. ³¹ Almange et al. ³² proposed the possibility of a direct thyrotoxic effect of HTH on cardiac tissue. Singer and Shvartzman ³³ proposed an autoimmune reaction against the cardiac nodal tissue as another mechanism underlying the development of AVB in patients with HTH.

Figure 1.

Flow chart denoting the hypothesized mechanisms of the occurrence of atrioventricular block in hyperthyroidism.^30–33 AVB, atrioventricular block; HTH, hyperthyroidism.

Despite these multiple theories, the literature lacks preclinical or clinical studies that could elucidate the more detailed pathophysiology of AVB in HTH. Therefore, we performed a literature search via several electronic databases (PubMed, Embase, Scopus, and Google Scholar) using the following keywords to collate previously published literature relevant to this narrative review: “heart block” OR “atrioventricular block” OR “AV block” OR “AVB” AND “thyroid gland” OR “thyroid” OR “thyroids” OR “thyroidal” OR “hyperthyroidism” OR “thyroiditis” OR “Grave’s disease” OR “hyperthyroid” OR “multinodular.” In total, 56 studies detailing patients with AVB in the context of HTH were collected and analyzed to generate this narrative review. The primary objective of this narrative review was to examine the occurrence of various types of AVB in the context of HTH, explore the pathophysiological mechanisms elucidated in existing studies, evaluate the management strategies employed, and assess the outcomes.

Discussion

Patients with HTH and varying degrees of AVB have been reported since as early as the 18th century. ³⁴ However, the most readily available literature began to appear in the 19th century.^34–36 The first case of AVB in association with HTH was reported in a 34-year-old woman in 1927. ²² The patient underwent treatment for Grave’s disease (GD) in 1921; however, her disease recurred with comorbid influenza 6 years later. In addition to the conventional symptoms of thyrotoxicosis, she also exhibited second-degree AVB. The AVB was eventually ameliorated with adrenaline. ²² Cameron and Hill ³⁵ reported AVB in two women with HTH admitted with tonsilitis in 1932. The first patient, a 33-year-old woman with GD, was found to have second-degree AVB (2:1) followed by A.fib. The second patient, an 18-year-old woman with GD, developed second-degree AVB (3:2) 4 days post-tonsillectomy. Treatment using Lugol’s iodine and ergotamine tartrate was attempted with no improvement in the AVB. Thyroidectomy was eventually performed, after which the AVB resolved and did not recur. ³⁵

The earliest evidence of CHB in the setting of HTH comes from a case series published in 1933 by the Mayo Clinic in the United States. Five of the six patients in the series were women, and the patients’ ages ranged from 22 to 65 years. The patients were otherwise free of comorbidities. Interestingly, all patients had GD with ophthalmopathies. One of the patients, a 53-year-old woman who developed CHB with infection in the setting of GD, died in the hospital. The autopsy findings showed normal myocardial tissue. However, the atrioventricular node and bundle exhibited excessive polymorphonuclear cell infiltration with inflammation. Further analysis revealed gram-positive bacterial infiltration. Other than one patient who died in the early days of hospitalization, all other patients underwent thyroidectomy with successful resolution of the CHB and no recurrence. ³⁴ Given the occurrence of infection in four of the six patients, the authors concluded that the AVB was a direct consequence of the infection in most cases, with HTH indirectly predisposing the patients to develop CHB due to myocardial involvement secondary to excess thyroid hormone circulation. ³⁴

Maher et al. ³⁶ reported four cases involving young men with AVB in the setting of HTH and rheumatic fever. The first patient had first-degree AVB that progressed to second-degree AVB (2:1). The second patient had CHB. Neither patient showed improvement in the AVB with iodine solution; however, the AVB in both patients improved after subtotal thyroidectomy. The third patient had variable degrees of AVB with P-R prolongation alone and occasional dropped beats. This patient showed no improvement in the AVB even after thyroidectomy and continued to have P-R prolongation years after the surgery. The last patient had first-degree AVB that persisted for 2 weeks. This patient was also treated by thyroidectomy with no recurrence of the AVB. Because all of these patients had underlying rheumatic heart disease, the authors concluded that the AVB in each case was associated with rheumatic disease and unrelated to GD. ³⁶

In 1990, Sriussadaporn et al. ³⁷ reported a case of CHB in a patient with HTH. This patient was a 29-year-old man who presented with fever and CHB; he had no other comorbidities. An endomyocardial biopsy ruled out features of carditis, and further investigations revealed no infectious cause of the fever. The patient’s fever was therefore associated with his underlying HTH, and the CHB was deemed a complication of HTH with no other provoking factors. ³⁷ Ho et al. ³⁸ appear to be the first to report a case of thyroid storm that was further complicated by CHB. This atypical presentation of thyroid storm led to delayed identification of the storm. The CHB resolved completely with carbimazole, intravenous iodide, and dexamethasone. This case highlights the significance of recognizing AVB as a manifestation of severe thyrotoxicosis for prompt diagnosis of patients. ³⁸ The most recently reported case of HTH with AVB was published in the 20th century. The patient died of fatal arrhythmia, and the autopsy revealed that the atrioventricular node and bundle branches were filled with granulocytes, histiocytes, and lymphocytes. Interestingly, the sinoatrial node was normal. The inflammation seen in the cardiac conduction system suggested myocarditis. However, because the inflammation was confined to the cardiac conduction system and did not involve the adjacent areas of the myocardium, the authors considered it less likely due to a concomitant viral illness and instead attributed it to hyperthyroid heart changes. ³⁹

By the end of the 19th century, researchers had formed the basis for associating AVB with HTH. However, many reported cases had an inciting factor for AVB (usually infection) in addition to a hyperthyroid state. Furthermore, extensive research to identify the presence of causation between HTH and AVB could not be performed. Nevertheless, all types of AVB from first-degree AVB to CHB were reported in the setting of HTH, with CHB being the most common. Among the 37 patients in cases reported from 1927 to 1999, 46% had CHB. Interestingly, most AVB occurred in young patients who were otherwise healthy and free of chronic disease. With respect to treatment, most patients’ AVB resolved with the management of HTH. However, four patients required pacing (transcutaneous in two and transvenous in two).^31,40–42

In 2000, Moustaghfir et al. ⁴³ published a case series of 30 patients with cardio-thyrotoxicosis. Cardiac arrhythmia, mainly A.fib, was the most common manifestation. Interestingly, the second most common cardiac complication was AVB. Most patients (n = 7) had first-degree AVB, one had second-degree AVB, and two had sinus bradycardia. ⁴³

The first case in which CHB in the setting of HTH required a cardiac device was published in 2001. Osman et al. ⁴⁴ described a 60-year-old woman with GD who presented with syncope and was found to have thyrotoxicosis. Because she had bradycardia (heart rate of 40 beats/minute), an ECG was obtained, confirming the presence of CHB. Treatment with carbimazole achieved a euthyroid state, but the CHB persisted and ultimately required a dual-chamber PPM. ⁴⁴ The authors reported another case of subacute thyroiditis in a 30-year-old woman who developed Mobitz type I AVB. Treatment with steroids improved the thyroiditis and resolved the AVB. However, after the steroid dose reduction, thyrotoxicosis ensued with recurrence and progression of the AVB to CHB. The patient ultimately underwent implantation of a dual-chamber PPM. ⁴⁴ Kuo et al. ⁴⁵ described a 67-year-old man who presented with syncope and was found to have thyrotoxicosis. His ECG tracings revealed episodes of intermittent CHB. The patient had received one 10-mg dose of propranolol since admission; however, the CHB persisted. This led the authors to suspect that the CHB was secondary to HTH-associated high vagal tone. ⁴⁵ The patient ultimately required a dual-chamber PPM. The authors discussed several possible mechanisms underlying the development of AVB in patients with HTH. Based on previously published data, two theories were proposed: direct thyrotoxic effects of HTH on cardiac contractility and indirect induction of AVB by known triggers such as infection, medications, or hyperkalemia. ⁴⁵ The authors provided a basis for the theory of hypervagotonia secondary to HTH as a cause of AVB in their patient. The patient’s AVB improved with atropine, which is a vagolytic agent, and his fluctuating heart rate showed increased vagal tone prior to initiation of the CHB. The authors pointed out potential risks of giving atrioventricular node blockers in patients with a baseline prolonged P-R (<0.24 seconds) because these patients are reportedly at high risk for the development of CHB in the presence of HTH.^45,46 Patients who have HTH with thyrotoxicosis usually require BBs; hence, examination of the P-R interval on a baseline ECG can help identify patients potentially at risk of AVB.

Dave and Ross ⁴⁷ published a case of CHB in a patient with GD. The patient was a 28-year-old woman with no other comorbid conditions. She had developed a flu-like illness a few weeks before presentation. However, her reason for presentation was a syncopal episode. Her CHB resolved with treatment of HTH using carbimazole (60 mg daily) and Lugol’s iodine (5 drops orally every 8 hours). However, first-degree AVB persisted. ⁴⁷ The authors discussed the potential mechanisms underlying the development of HTH-induced AVB. They proposed that hyperadrenergic changes are present in patients with HTH, leading to cardiac complications. This is supported by the fact that although the presentation of HTH is similar to that of catecholamine excess, the catecholamine levels in patients with HTH are normal or even low.^48,49 Notably, however, the theory of the hyperthyroid state being mainly driven by hyperadrenergic changes is not supported by strong evidence. Moreover, a preclinical study showed that mice with and without the three known beta-adrenergic receptors had a similar cardiovascular response to increased amounts of exogenous thyroid hormone. The authors proposed that the cardiac effects of thyroid hormone are therefore independent of beta-adrenergic activity. ⁵⁰ Interestingly, the maximum heart rate in the thyroid hormone-treated wild-type mice was much lower than that in the thyroid hormone-treated experimental mice with deficient adrenergic receptors, ⁵⁰ indicating at least a potentiating role of beta-adrenergic receptors in achieving maximum effects of the thyroid hormone on the heart. Likewise, it can be postulated that the AVB seen in patients with HTH might be related to mechanisms other than those associated with the adrenergic system. However, no preclinical or clinical studies have shown any evidence of this.

Krishnamoorthy et al. ²⁷ described a patient with HTH who presented with CHB and renal failure. The patient was a 59-year-old man who presented with lethargy and weight loss. Investigations revealed thyrotoxicosis, a multinodular goiter on ultrasound, and negative antibodies. His ECG showed CHB with underlying A.fib. The patient received temporary pacing and carbimazole, resulting in euthyroidism and sinus rhythm restoration. He also had acute renal failure on presentation, which resolved with management of the HTH. The authors attributed the renal failure and CHB to thyrotoxicosis based on the complete resolution of both through achievement of euthyroidism. ²⁷

Sampana and Jasul ⁵¹ reported a case of GD in which discontinuation of antithyroid medications resulted in recurrence of thyrotoxicosis, which primarily manifested as CHB. The patient required temporary pacing, which was removed once euthyroidism was attained. The authors emphasized the significance of recognizing CHB as a manifestation of HTH because the treatment mainly lies in managing the thyrotoxicosis with only temporary external pacing instead of PPM implantation, which is associated with more complications. ⁵¹ This argument was strengthened in a publication by Atri et al. ⁵² in 2011. They described a 60-year-old woman who presented with thyroid storm secondary to multinodular goiter. The patient’s ECG showed evidence of a 2:1 AV block alternating with CHB. She received treatment with steroids, antithyroid medications, and fluids. The patient was discharged against medical advice and did not comply with the recommendation to undergo temporary pacing; she only continued the antithyroid drugs. Nevertheless, a follow-up visit 4 weeks later revealed a normal ECG with no residual symptoms. ⁵²

Accumulating evidence shows that even subclinical HTH can manifest with AVB. Kausel et al. ²⁸ reported a case of subclinical HTH in a 71-year-old woman who presented with an isolated syncopal episode in 2011. Her examination did not show thyrotoxicosis. However, laboratory investigations revealed subclinical HTH, and an ECG revealed variable AVB. The etiology of HTH was found to be a toxic adenoma, and her symptoms improved after radioactive iodine therapy. Treatment of the adenoma converted the variable AVB to fixed first-degree AVB, which then persisted throughout further follow-up. ²⁸ Because the patient had no underlying heart disease and was taking no medications that could have caused AVB, the authors associated the variable AVB with subclinical HTH, especially given the dramatic improvement in the AVB after radiotherapy. The theory that subclinical HTH can involve the cardiac conduction system is not refutable because A.fib is a well-established manifestation of subclinical HTH. ¹⁷ Similarly, AVB can be thought to manifest in subclinical HTH as well. However, further research into the mechanism underlying such conduction abnormalities is needed because thyroid hormone excess might not be the only etiology of the dysfunction.

BBs are an important part of management in patients with overt thyrotoxicosis. They are mainly administered to control adrenergic symptoms (such as tachycardia, palpitations, heat intolerance, and agitation, among others) and have been used in patients with HTH for more than 20 years. ⁵³ BB therapy rarely leads to AVB; however, among the various types of drug-induced AVB, BB is the most common cause (up to 54% of cases). ⁵⁴ Although most of the patients discussed in the literature to date had AVB in the setting of HTH, their AVB developed either before or immediately after starting treatment (which included BB therapy in many patients). Thus, it is very unlikely that all cases of AVB are drug-induced. Furthermore, an interesting case was reported by Meles ⁵⁵ in 2011, in which a 52-year-old woman presented with loss of consciousness. The patient had sinus tachycardia alternating with bradycardia. She was diagnosed with GD and began treatment with methimazole. During hospitalization, she developed severe bradycardia necessitating insertion of a temporary transvenous PM. This was followed by recurrence of sinus tachycardia. The patient was then started on propranolol, which was gradually optimized to 80 mg three times daily. Interestingly, the alternating tachycardia with bradycardia completely resolved, eliminating the need for the PM. ⁵⁵ This case further highlights that AVB in patients with HTH should not be attributed only to BB therapy; there is likely a primary mechanism underlying the development of AVB in such patients, and the AVB might even respond to BB therapy instead of worsening. Importantly, however, larger and more reliable data are required to make accurate conclusions regarding the response of HTH-induced AVB to BB therapy. Careful case-by-case evaluation is critical in making treatment decisions for such patients.

With the advent of more literature, AVB is becoming a recognized complication of thyroid storm, although it remains rare. Since the publication of a single case in 1998, ³⁸ multiple reports have described patients with thyroid storm along with various degrees of AVB.^52,56–58 Thyroid storm is a life-threatening endocrine emergency. High clinical suspicion is required to identify patients presenting with thyroid storm. ⁵⁹ The mortality rate associated with thyroid storm can be as high as 25%, even with advances in diagnostic and treatment methods. The Burch–Wartofsky point scale, introduced in the 1990s, represented a turning point in the management of thyroid storm. ⁶⁰ This scale allows categorization of patients as having either low or high risk of thyroid storm. One of the limitations of the scale, however, is that the score is calculated based on the most common presentation of thyroid storm. The dilemma in diagnosing thyroid storm is twofold. First, many other diseases can present similarly to thyroid storm. Second, thyroid storm itself can present in many ways. Moreover, the levels of thyroid hormones do not appear to have a linear relationship with the probability of thyroid storm. Thyroid storm can be suspected in patients with normal or near-normal thyroid hormone levels, especially if they have a history of HTH. ⁶¹ Presentation of thyroid storm with atypical and unusual complications not recognized with HTH, such as AVB, can further complicate the diagnosis, and physicians may deviate from promptly addressing the storm itself. Some evidence shows that even patients with complicated thyroid storms presenting with AVB, if diagnosed in a timely manner and managed with antithyroid treatment and steroids, can effectively recover without pacing. Therefore, in addition to applying the Burch–Wartofsky point scale, clinicians should consider atypical presentations when diagnosing and treating thyroid storm presenting with AVB if there is strong clinical suspicion.

Immune checkpoint inhibitors (ICIs) are among the latest advancements in cancer therapy. Initially introduced and approved for melanomas, ICIs are now used for more than 17 types of cancer.^62,63 ICIs have significantly reduced mortality in patients with certain cancers.^64–66 However, endocrine-related adverse effects associated with ICI therapy are being increasingly reported. Because of the limitations in the global use of ICIs secondary to cost and logistic issues, data related to endocrinopathies are still emerging. This area remains a research focus among endocrinologists and oncologists. Practice guidelines are being developed to safely and effectively manage ICI-induced endocrinopathies. ⁶⁷ Thyrotoxicosis is among the emerging endocrine complications of ICI therapy.^68–71 In 2018, Roy et al. ⁵⁷ reported a case of nivolumab-induced thyroid storm in which the patient’s clinical course was further complicated by CHB. The patient received antithyroid treatment and a PPM; however, cardiac shock and multiorgan failure eventually occurred. ⁵⁷

Conclusion

Considering advances in science related to thyrotoxicosis, its various presentations, and multiple atypical manifestations, AVB deserves to be recognized as an established complication of HTH. Its prevalence remains unknown, and given the rarity of its occurrence, it does not seem easy to design studies that can calculate the incidence of AVB in HTH cohorts. Science has yet to witness extensive studies designed to validate the proposed mechanisms of AVBs in the context of HTH. Whether pacing is required or antithyroid treatment will suffice to resolve the AVB also remains uncertain, and current evidence suggests the need for a case-by-case approach in decision-making. However, with greater acceptability of AVB being secondary to the hyperthyroid state, physicians are expected to become more comfortable attempting conservative management before PPM insertion.