What are the etiologies of hiccups (singultus)?

Etiology of Hiccups (Singultus)

Hiccups result from involuntary, spasmodic contractions of the diaphragm and intercostal muscles followed by abrupt glottic closure, mediated through a reflex arc involving the vagus and phrenic nerves, with the central connection located in the brainstem respiratory centers, phrenic nerve nuclei, medullary reticular formation, and hypothalamus. 1, 2, 3

Pathophysiological Mechanism

The hiccup reflex arc consists of three key components that must be understood to identify potential etiologies 4, 3:

• Afferent limb: Sensory branches of the phrenic nerve, vagus nerve, and dorsal sympathetic afferents 3
• Central processing: Brainstem respiratory centers, phrenic nerve nuclei, medullary reticular formation, and hypothalamus 3
• Efferent limb: Motor fibers of the phrenic nerve causing diaphragmatic spasms, with simultaneous glottic closure 3

Categories of Etiologies

Central Nervous System Disorders

Hiccups may represent brainstem seizures or result from CNS abnormalities affecting the medullary respiratory centers 5, 3:

• Brainstem lesions or dysfunction 3
• Central nervous system abnormalities 5
• Disorders affecting the hypothalamus or medullary reticular formation 3

Peripheral Nerve Irritation

Any condition stimulating the vagus or phrenic nerves can trigger the hiccup reflex 4, 3:

• Mechanical stimulation of laryngeal mucosa (similar to laryngospasm mechanisms, though hiccups involve the diaphragm rather than vocal fold adduction) 6
• Direct irritation of phrenic or vagus nerve pathways 4
• Suboccipital muscle tension causing nerve compression 4

Gastrointestinal Causes

Gastrointestinal disorders are among the most common organic causes 5:

• Gastric distension or irritation 5
• Esophageal disorders 5
• Other gastrointestinal pathology 5

Cardiovascular Disorders

Cardiovascular conditions can trigger hiccups through vagal stimulation 5:

• Cardiac pathology affecting vagal tone 5
• Pericardial irritation 5

Metabolic and Endocrine Disorders

Metabolic derangements can precipitate hiccups 5:

• Electrolyte imbalances 5
• Endocrine abnormalities 5

Respiratory and ENT Conditions

Pulmonary and ear-nose-throat pathology may trigger the reflex 5:

• Pneumological problems 5
• ENT conditions affecting the vagus nerve 5

Infectious Causes

Systemic or localized infections can induce hiccups 5:

• Various infectious processes affecting the reflex arc 5

Iatrogenic and Drug-Induced Causes

Pharmacological agents, particularly those affecting dopaminergic pathways, can induce hiccups 5:

• Aripiprazole (second-generation antipsychotic): Acts as a dopamine agonist at low doses (<7.5 mg/day), stimulating D2 and D3 receptors at the "hiccup center" in the brainstem 5
• Laryngeal mask airway placement: Intraoperative hiccups related to LMA insertion present unique diagnostic challenges 2
• Anesthetic agents and airway manipulation 2

Psychogenic Causes

Psychological disorders can manifest as persistent hiccups 1, 5:

• Psychogenic disorders 5
• Stress-related mechanisms 1

Exogenous Factors

Various external triggers can provoke hiccups 1:

• Multiple provoking exogenous factors 1
• Environmental or behavioral triggers 1

Clinical Significance

Persistent or intractable hiccups warrant detailed investigation as they often represent an epiphenomenon of underlying medical conditions rather than a benign, self-limited phenomenon 1, 5. The presence of prolonged hiccups can cause 1, 2:

• Significant decline in quality of life 1
• Increased aspiration risk 2
• Interference with wound healing and hemodynamic stability 2
• Potential morbidity and even mortality in severe cases 4

Important Clinical Caveat

While most hiccup episodes are benign and self-limited, any patient presenting with persistent hiccups (lasting >48 hours) or intractable hiccups (lasting >1 month) requires systematic evaluation to identify the underlying organic, metabolic, infectious, or psychogenic cause 1, 5. The wide array of potential etiologies necessitates a thorough assessment targeting each component of the hiccup reflex arc 2, 4.