What are the pathophysiological mechanisms by which hyperthyroidism, myocardial infarction (MI), and pheochromocytoma precipitate anxiety?

Pathophysiological Mechanisms of Anxiety in Hyperthyroidism, Myocardial Infarction, and Pheochromocytoma

Hyperthyroidism

Hyperthyroidism precipitates anxiety through direct thyroid hormone effects on brain neurotransmitter systems and widespread activation of peripheral adrenergic receptors, creating both central nervous system dysregulation and somatic symptoms that mimic and trigger anxiety states. 1

Central Mechanisms

• Thyroid hormone receptors are widely expressed throughout the limbic system (including the amygdala and hippocampus), directly modulating mood regulation centers 2, 1
• The central thyroid system cross-communicates with noradrenergic and serotonergic pathways, disrupting the neurochemical balance essential for emotional stability 2
• Blunted TSH responses to TRH stimulation in hyperthyroid patients suggest altered hypothalamic-pituitary feedback that may independently contribute to anxiety symptoms 2

Peripheral Mechanisms

• Excess thyroid hormones increase beta-adrenergic receptor sensitivity throughout the body, amplifying sympathetic nervous system activity 1
• This creates cardiovascular manifestations (palpitations, tachycardia), respiratory symptoms (shortness of breath), and autonomic hyperactivity (increased perspiration, tremor) that are indistinguishable from panic attacks 2, 3
• The number of anxiety symptoms directly parallels the number of hyperthyroid symptoms, suggesting a dose-dependent relationship 4

Clinical Pitfall

• Hyperthyroidism symptoms overlap so extensively with primary anxiety disorders that misdiagnosis is common—psychomotor agitation, weight loss, and insomnia are the key discriminating features favoring hyperthyroidism over primary anxiety 3, 4

Pheochromocytoma

Pheochromocytomas cause anxiety through massive, paroxysmal catecholamine release that directly activates the body's "fight or flight" response, creating indistinguishable physiological and psychological manifestations of severe panic attacks. 5

Direct Catecholamine Effects

• Tumors secrete excess epinephrine and norepinephrine, which bind to alpha and beta-adrenergic receptors throughout the central and peripheral nervous systems 5
• This triggers the complete sympathetic stress response: severe hypertension, tachycardia, diaphoresis, tremor, and the subjective experience of terror or impending doom 5, 6
• Anxiety attacks occur as a direct clinical manifestation of catecholamine surges, not as a secondary psychological reaction 5

Cardiovascular Complications

• Catecholamine excess causes coronary vasospasm, direct myocardial toxicity from catecholamine oxidation products, and beta-receptor-mediated myofibril dysfunction 6, 7
• These mechanisms can precipitate myocardial infarction even in patients with non-obstructive coronary arteries, creating a medical emergency that further amplifies anxiety 7, 8

Critical Diagnostic Pitfall

• Pheochromocytomas are frequently misdiagnosed as primary anxiety disorders, leading to dangerous treatment delays—only 24% present with the classic triad of headache, palpitations, and sweating 5, 7
• Beta-blocker administration without alpha-blockade can precipitate severe hypertensive crisis by allowing unopposed alpha-receptor stimulation 6

Myocardial Infarction

Myocardial infarction precipitates anxiety through multiple converging mechanisms: direct neurohormonal activation from cardiac injury, psychological trauma from life-threatening illness, and ongoing autonomic dysregulation during the acute and recovery phases.

Acute Neurohormonal Response

• Myocardial ischemia and infarction trigger massive sympathetic nervous system activation as a compensatory response to maintain cardiac output 6
• This releases endogenous catecholamines that create the same adrenergic symptoms as pheochromocytoma: palpitations, diaphoresis, tremor, and subjective anxiety 6, 7
• Pain and dyspnea activate the amygdala and other fear-processing centers, creating an integrated stress response 7

Cardiovascular-Anxiety Feedback Loop

• Chest pain, arrhythmias, and hemodynamic instability create interoceptive signals that the brain interprets as life-threatening danger 2
• Patients with heightened interoceptive sensitivity (common in anxiety-prone individuals) experience amplified anxiety responses to these cardiac symptoms 2
• The uncertainty of prognosis and fear of recurrent events perpetuates chronic anxiety even after the acute event resolves 2

Special Consideration: MINOCA

• Myocardial infarction with non-obstructive coronary arteries (MINOCA) should raise suspicion for pheochromocytoma as an underlying cause, particularly when accompanied by erratic blood pressure 7, 8
• In these cases, the anxiety is both a symptom of the underlying pheochromocytoma and a response to the cardiac event itself 8