Palpitations – Beyond the Cardiology Consult: A Metabolic and Endocrine Perspective

A Review Article for Postgraduate Internal Medicine Trainees

Dr Neeraj Manikath , claude.ai

Abstract

Palpitations represent one of the most common presenting complaints in internal medicine practice, traditionally viewed through a cardiovascular lens. However, a substantial proportion of patients with palpitations harbor underlying endocrine and metabolic disorders that are frequently overlooked in the initial diagnostic workup. This review article provides a systematic approach to identifying endocrine causes of palpitations, emphasizing pattern recognition that can prevent unnecessary cardiology referrals and expedite appropriate treatment. We discuss the distinctive clinical features of thyrotoxic palpitations, the paroxysmal presentation of pheochromocytoma, hypoglycemia-induced catecholamine surges, and provide a rational framework for initial and advanced testing strategies.

Introduction

Palpitations are defined as an unpleasant awareness of one's heartbeat, characterized by sensations of rapid, irregular, forceful, or skipped beats. While cardiologists rightly receive the majority of referrals for this symptom, internists must recognize that the heart is merely the messenger in many cases—the actual pathology often resides in the endocrine system. Studies suggest that approximately 15-30% of patients presenting with palpitations have no identifiable cardiac etiology, and among these, endocrine disorders represent a significant and treatable subset.

The clinical pearl here is straightforward: before reflexively ordering an echocardiogram or referring to cardiology, consider whether the heart is responding normally to an abnormal metabolic milieu. This paradigm shift not only improves diagnostic accuracy but also prevents the cascade of unnecessary invasive testing and patient anxiety associated with presumed cardiac disease.

The "Thyrotoxic" Palpitation: Not Just Fast, But Also Forceful and Persistent

Clinical Characteristics

Thyrotoxicosis remains one of the most common endocrine causes of palpitations, with approximately 60-90% of hyperthyroid patients reporting this symptom. However, the key to recognition lies not in the presence of tachycardia alone—many conditions cause rapid heart rate—but in the distinctive quality of thyrotoxic palpitations.

Pattern Recognition Hack: The thyrotoxic palpitation is characterized by three features:

Persistence: Unlike anxiety-related palpitations that come in discrete episodes, thyrotoxic palpitations tend to be more continuous or nearly continuous throughout the day
Forcefulness: Patients frequently describe a pounding quality, often able to see their precordium moving or feel their pulse in unusual locations (neck, abdomen)
Exercise intolerance: Even mild exertion produces disproportionate tachycardia and dyspnea

Pathophysiology

The cardiovascular manifestations of thyrotoxicosis result from multiple mechanisms. Excess thyroid hormone increases cardiac contractility, heart rate, and cardiac output while simultaneously decreasing systemic vascular resistance. At the molecular level, triiodothyronine (T3) increases beta-adrenergic receptor density in cardiac myocytes and enhances sensitivity to catecholamines. This explains why beta-blockers are so effective as temporizing measures in thyrotoxicosis—they don't address the underlying thyroid dysfunction but dampen the cardiovascular hypersensitivity.

The Diagnostic Oyster

A commonly missed presentation is subclinical hyperthyroidism in elderly patients, where TSH is suppressed but free T4 and T3 remain within normal ranges. These patients may present with isolated atrial fibrillation or palpitations without the classic hypermetabolic features (weight loss, tremor, heat intolerance). The prevalence of atrial fibrillation increases dramatically when TSH falls below 0.1 mIU/L, even in the absence of overt hyperthyroidism.

Clinical Pearl: In any patient over 60 presenting with new-onset atrial fibrillation or persistent palpitations, TSH should be the first test ordered, not after cardiac evaluation proves unrevealing.

Associated Clinical Features

While palpitations may be the presenting complaint, a directed review of systems often reveals additional clues:

Fine tremor (best assessed by placing paper on outstretched hands)
Proximal muscle weakness (difficulty rising from squatting position)
Frequent bowel movements (not necessarily diarrhea)
Heat intolerance and increased perspiration
Anxiety and emotional lability
Weight loss despite preserved or increased appetite

Management Considerations

Once thyrotoxicosis is confirmed, immediate symptomatic relief can be achieved with beta-blockade (typically propranolol 20-40 mg every 6-8 hours or atenolol 25-50 mg daily). However, definitive management requires addressing the underlying cause—Graves' disease, toxic multinodular goiter, toxic adenoma, or thyroiditis—each requiring different treatment strategies.

The Pheochromocytoma Triad: Palpitations + Headache + Diaphoresis – The Paroxysmal Pattern

The Classic Presentation

Pheochromocytomas are catecholamine-secreting tumors arising from chromaffin cells, most commonly in the adrenal medulla. Though rare (annual incidence 2-8 per million), they represent the quintessential "don't miss" diagnosis because they are both life-threatening if unrecognized and potentially curable with surgical resection.

The Diagnostic Triad: The combination of palpitations, headache, and diaphoresis has a specificity exceeding 90% for pheochromocytoma when all three occur together in paroxysmal episodes. This is arguably the most powerful clinical pattern in endocrinology.

Pattern Recognition: The Paroxysmal Nature

Teaching Hack: The hallmark of pheochromocytoma is paroxysmal symptoms—discrete episodes of symptom escalation lasting minutes to hours, followed by complete or near-complete resolution. This pattern immediately distinguishes it from thyrotoxicosis, where symptoms are more persistent and gradually progressive.

During an episode, patients may experience:

Sudden-onset severe palpitations (heart rate often >160 bpm)
Pounding headache (often described as the worst headache of their life)
Profuse diaphoresis (patients may describe being "drenched")
Pallor or flushing
Sense of impending doom or severe anxiety
Tremulousness
Chest or abdominal pain

Between episodes, patients may be entirely asymptomatic or have mild persistent hypertension.

The Hypertension Connection

While not all pheochromocytoma patients are hypertensive, approximately 90% have elevated blood pressure either persistently or during paroxysms. The blood pressure pattern can provide diagnostic clues:

Paroxysmal hypertension (episodic severe elevations) is highly suggestive
Labile hypertension with poor response to standard antihypertensive therapy
Hypertension with orthostatic component (due to volume depletion from pressure natriuresis)

Clinical Oyster: Young patients (<40 years) with hypertension and palpitations deserve screening for pheochromocytoma, particularly if hypertension is difficult to control or associated with paroxysmal symptoms.

The Diagnostic Approach

When clinical suspicion is raised, biochemical confirmation precedes imaging. The preferred initial test is 24-hour urine collection for fractionated metanephrines and catecholamines or plasma free metanephrines. Plasma free metanephrines have sensitivity approaching 99% but slightly lower specificity (85-89%), while 24-hour urine fractionated metanephrines offer excellent balance of sensitivity (90-98%) and specificity (95-98%).

Practical Hack: False positives are common with plasma metanephrines due to stress, exercise, medications, or improper collection technique. Always have patients rest supine for 30 minutes before plasma collection and discontinue interfering medications when possible (tricyclic antidepressants, sympathomimetics, alpha-blockers can all affect results).

Genetic Considerations

Approximately 30-40% of pheochromocytomas occur in the context of hereditary syndromes:

Multiple Endocrine Neoplasia type 2 (MEN2): Associated with medullary thyroid carcinoma and hyperparathyroidism
Von Hippel-Lindau syndrome: Associated with retinal and CNS hemangioblastomas, renal cell carcinoma
Neurofibromatosis type 1: Multiple café-au-lait spots, neurofibromas
Hereditary paraganglioma syndromes: Associated with succinate dehydrogenase mutations

Clinical Pearl: Any patient diagnosed with pheochromocytoma, particularly those under age 50, bilateral tumors, or extra-adrenal location (paragangliomas), should receive genetic counseling and testing.

The Hypoglycemia Connection: How Lows Trigger Catecholamine-Driven Palpitations

The Counter-Regulatory Response

Hypoglycemia induces a physiologic stress response characterized by catecholamine release (both epinephrine and norepinephrine), resulting in a predictable constellation of autonomic symptoms. This counter-regulatory mechanism evolved to mobilize glucose stores and signal the need for food intake when blood glucose falls to potentially dangerous levels.

Pathophysiologic Insight: When blood glucose drops below approximately 55-60 mg/dL, the adrenal medulla releases epinephrine, which stimulates hepatic glucose production and inhibits peripheral glucose utilization. This epinephrine surge produces the classic autonomic symptoms including palpitations, tremulousness, diaphoresis, and anxiety—Whipple's triad components.

Clinical Presentations

Hypoglycemia-induced palpitations occur in several clinical contexts:

Iatrogenic hypoglycemia in diabetes: The most common scenario, occurring in patients on insulin or sulfonylureas. Patients often develop hypoglycemia unawareness with longstanding diabetes and autonomic neuropathy, making palpitations a less reliable warning sign.
Post-bariatric surgery hypoglycemia: An increasingly recognized phenomenon occurring months to years after Roux-en-Y gastric bypass. Patients experience severe postprandial hypoglycemia due to exaggerated GLP-1 response and beta-cell hyperplasia (nesidioblastosis).
Insulinoma: A rare neuroendocrine tumor causing inappropriate insulin secretion. Classic presentation involves Whipple's triad: symptoms of hypoglycemia, documented low blood glucose, and relief with glucose administration. Symptoms typically occur in the fasting state or with exercise.
Non-diabetic reactive hypoglycemia: A controversial entity characterized by postprandial hypoglycemia in patients without diabetes or prior gastric surgery. Diagnosis requires documentation of symptoms concurrent with blood glucose <55 mg/dL during a mixed meal tolerance test.

Distinguishing Features

Teaching Point: Unlike thyrotoxicosis or pheochromocytoma, hypoglycemia-induced palpitations are:

Temporally related to meals (postprandial in reactive hypoglycemia, fasting in insulinoma)
Associated with cognitive symptoms (confusion, difficulty concentrating)
Rapidly relieved by carbohydrate intake
Often accompanied by prominent hunger

Diagnostic Strategy

For patients with suspected hypoglycemia-induced palpitations:

Document glucose during symptomatic episodes (home glucose monitoring)
Obtain HbA1c to assess chronic glycemic control in diabetic patients
Consider supervised 72-hour fast for suspected insulinoma (gold standard test)
Mixed meal tolerance test for suspected postprandial hypoglycemia

Clinical Hack: Have patients carry glucose tablets and check blood glucose during every symptomatic episode. If symptoms consistently occur with glucose >70 mg/dL, hypoglycemia is effectively ruled out as the cause.

The First Three Tests: TSH, Free T4, and Fasting Glucose/HbA1c

A Rational Approach to Initial Evaluation

After thorough history and physical examination, the initial laboratory workup for palpitations with suspected endocrine etiology should be simple, cost-effective, and high-yield. Three tests form the foundation:

1. Thyroid-Stimulating Hormone (TSH)

Rationale: TSH is the single most sensitive screening test for thyroid dysfunction. A normal TSH (typically 0.4-4.0 mIU/L) effectively excludes primary thyroid disease in the vast majority of cases.

Interpretation Pearls:

Suppressed TSH (<0.1 mIU/L) warrants free T4 and T3 measurement to confirm hyperthyroidism
Mildly suppressed TSH (0.1-0.4 mIU/L) in elderly patients may still warrant cardiac monitoring due to increased atrial fibrillation risk
Elevated TSH generally suggests hypothyroidism, which rarely causes palpitations but can cause them when associated with anemia or when treatment is initiated too aggressively

2. Free T4 (Thyroxine)

Rationale: When TSH is abnormal, free T4 helps distinguish subclinical from overt thyroid dysfunction and guides treatment urgency.

Interpretation Framework:

Suppressed TSH + elevated free T4 = overt hyperthyroidism (requires prompt treatment)
Suppressed TSH + normal free T4 = subclinical hyperthyroidism (measure T3, consider treatment especially if TSH <0.1)
Normal TSH + normal free T4 = thyroid dysfunction excluded

Clinical Oyster: Approximately 5% of hyperthyroid patients have isolated T3 toxicosis (elevated T3 with normal T4). If clinical suspicion remains high despite normal TSH and T4, measure free T3.

3. Fasting Glucose and/or HbA1c

Rationale: These tests serve dual purposes—identifying diabetes (which predisposes to autonomic neuropathy and hypoglycemia from treatment) and providing baseline assessment of glycemic control.

Interpretation Strategy:

Fasting glucose >126 mg/dL or HbA1c >6.5% establishes diabetes diagnosis
Fasting glucose <70 mg/dL suggests propensity for hypoglycemia
Normal values don't exclude reactive hypoglycemia (requires symptom-glucose correlation)

Practical Approach: For most patients, HbA1c alone suffices as it reflects 3-month average glucose and doesn't require fasting. However, for suspected hypoglycemia, fasting glucose provides additional information about basal glucose homeostasis.

Additional Baseline Tests to Consider

While not part of the essential three, consider these tests based on clinical context:

Complete blood count: Anemia can cause or exacerbate palpitations
Comprehensive metabolic panel: Electrolyte abnormalities (particularly potassium, magnesium, calcium) affect cardiac rhythm
ECG: Essential for ruling out primary cardiac arrhythmias and establishing baseline QT interval

When to Dig Deeper: Advanced Testing Strategies

Ordering 24-Hour Urine Metanephrines

Indications for testing:

Paroxysmal triad (palpitations + headache + diaphoresis) present
Hypertension with paroxysmal worsening or poor control on multiple agents
Hypertension in young patients (<40 years)
Incidentally discovered adrenal mass with any symptoms
Family history of pheochromocytoma or hereditary syndrome (MEN2, VHL, NF1)
Previous episode of hypertensive crisis with anesthesia or surgery

Collection Instructions (Critical for Accuracy):

Discontinue interfering medications 2 weeks prior if possible (acetaminophen is safe)
Avoid stressful situations during collection period
Collect entire 24-hour output (provide clear instructions to prevent incomplete collection)
Keep specimen refrigerated throughout collection
Document total urine volume (validates completeness of collection)

Interpretation Framework:

Values >2 times upper limit of normal are highly specific for pheochromocytoma
Mild elevations (1-2 times upper limit) may reflect stress, medications, or other conditions—consider repeat testing
Normal values on two separate occasions effectively exclude pheochromocytoma (>95% sensitivity)

Plasma Metanephrines: An Alternative Approach

Plasma free metanephrines offer higher sensitivity (97-99%) than urine testing but lower specificity, resulting in more false positives. Use this test when:

Patient compliance with 24-hour urine collection is uncertain
Rapid turnaround is needed
High clinical suspicion despite normal urine metanephrines

Critical Collection Technique:

Patient must rest supine for 30 minutes before venipuncture
Use forearm vein (avoid excessive tourniquet time)
Morning collection preferred
Stress reduction essential (false positives common with anxiety)

Cortisol Evaluation: When to Suspect Cushing's Syndrome

While less commonly associated with isolated palpitations, Cushing's syndrome should be considered when palpitations occur with:

Central obesity with relatively thin extremities
Wide purple striae (>1 cm)
Proximal muscle weakness
Easy bruising
Hypertension and hyperglycemia
Psychiatric symptoms (depression, anxiety, mania)

Initial Screening Tests (Choose One):

24-hour urine free cortisol: Sensitivity 90-95%, requires complete collection
Late-night salivary cortisol: Convenient, high sensitivity (92-96%), useful for outpatients
1 mg overnight dexamethasone suppression test: Widely available, but higher false-positive rate

Teaching Hack: If Cushing's syndrome is suspected, order at least two different screening tests to improve diagnostic accuracy, as all have limitations.

Hyperparathyroidism Screening: The Calcium Connection

Hypercalcemia from primary hyperparathyroidism occasionally presents with palpitations due to:

Direct effects of calcium on cardiac conduction
Shortened QT interval
Associated anxiety and fatigue

When to Screen:

Unexplained palpitations with fatigue, bone pain, kidney stones, or psychiatric symptoms ("stones, bones, groans, and psychiatric overtones")
Incidentally discovered hypercalcemia on routine labs
History of osteoporosis in younger patients

Testing Strategy:

Serum calcium and albumin (or ionized calcium)
Parathyroid hormone (PTH)
Classic finding: elevated or inappropriately normal PTH in the setting of hypercalcemia

Clinical Algorithm: A Systematic Approach

Step 1: Comprehensive History

Character of palpitations (rapid, forceful, irregular, skipped beats)
Temporal pattern (persistent vs. paroxysmal, duration of episodes)
Associated symptoms (diaphoresis, tremor, headache, anxiety, weight change)
Provoking factors (exercise, meals, stress, supine vs. standing)
Medication review (particularly stimulants, bronchodilators, decongestants)

Step 2: Physical Examination

Vital signs including orthostatic blood pressure
Thyroid examination (size, nodules, bruit)
Cardiovascular examination (murmurs, extra sounds, peripheral edema)
Skin examination (hyperpigmentation, striae, neurofibromas, café-au-lait spots)
Neuromuscular examination (tremor, proximal weakness, hyperreflexia)

Step 3: Initial Laboratory Testing

TSH and free T4
Fasting glucose or HbA1c
Complete blood count
Comprehensive metabolic panel
ECG

Step 4: Targeted Advanced Testing (Based on Clinical Suspicion)

Thyrotoxicosis suspected → Free T3, thyroid antibodies, consider radioiodine uptake scan
Pheochromocytoma suspected → 24-hour urine metanephrines or plasma free metanephrines
Hypoglycemia suspected → Documented glucose during symptoms, consider 72-hour fast or mixed meal test
Cushing's suspected → 24-hour urine free cortisol, late-night salivary cortisol, or dexamethasone suppression
Hyperparathyroidism suspected → Serum calcium, albumin, PTH, vitamin D

Pearls and Pitfalls

Diagnostic Pearls

The "Situational" Pearl: Palpitations occurring specifically during or immediately after meals suggest postprandial hypoglycemia or, less commonly, carcinoid syndrome (if associated with flushing).
The "Medication" Pearl: Always review over-the-counter medications and supplements. Pseudoephedrine, excessive caffeine, weight loss supplements, and even some herbal preparations can cause palpitations mimicking endocrine disease.
The "Anxiety" Pearl: While anxiety disorders commonly cause palpitations, the presence of anxiety doesn't exclude organic disease. Endocrine disorders (particularly thyrotoxicosis and hypoglycemia) frequently cause secondary anxiety that resolves with treatment of the underlying condition.
The "Age" Pearl: New-onset palpitations in patients >60 years warrant aggressive evaluation for atrial fibrillation and thyroid disease regardless of associated symptoms.
The "Pregnancy" Pearl: Palpitations are common in normal pregnancy due to physiologic changes, but also screen for peripartum thyroid dysfunction (postpartum thyroiditis, Graves' disease).

Common Pitfalls

Premature Cardiac Referral: Referring to cardiology before basic endocrine screening wastes resources and delays diagnosis. Complete the initial three tests first.
Over-reliance on Symptoms: Classic symptoms may be absent. Up to 15% of hyperthyroid patients lack classic features; pheochromocytomas occasionally present with atypical patterns.
Single Normal Test Misinterpretation: One normal glucose reading doesn't exclude hypoglycemia (temporal relationship is key); one normal metanephrine level in a patient not having symptoms doesn't exclude pheochromocytoma (consider repeat during symptomatic episode).
Ignoring Medication Effects: Beta-blockers can mask tachycardia from thyrotoxicosis, creating false reassurance; similarly, they can precipitate hypoglycemia in diabetic patients.
Failing to Consider Multiple Diagnoses: Patients can have both cardiac disease and endocrine dysfunction. Atrial fibrillation in a thyrotoxic patient still requires anticoagulation consideration.

Conclusion

Palpitations represent a common symptom at the intersection of cardiology and endocrinology. By recognizing distinctive patterns—the persistent, forceful quality of thyrotoxic palpitations, the paroxysmal triad of pheochromocytoma, and the meal-related timing of hypoglycemic episodes—clinicians can efficiently identify endocrine causes and avoid unnecessary cardiac testing.

The systematic approach outlined here, beginning with the essential three tests (TSH, free T4, and fasting glucose/HbA1c) and proceeding to advanced testing based on clinical patterns, provides a rational framework for evaluation. Remember that the heart is often the messenger, not the culprit, and that many patients with "cardiac" symptoms harbor treatable endocrine disorders awaiting diagnosis.

As internists, we must serve as diagnostic integrators, considering the patient holistically rather than reflexively referring to subspecialists. Mastering the endocrine approach to palpitations not only improves patient outcomes but also enhances our diagnostic acumen and professional satisfaction.

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