Etiology

The etiology of hiccups is not fully understood.

Benign hiccups can be caused by gastric distension from aerophagia, excessive food and alcohol consumption, and drinking carbonated beverages.[5] Other causes include sudden changes in ambient or gastrointestinal temperature (e.g., cold showers, drinking hot or cold beverages), sudden excitement, and emotional stress.[5] 

There are various underlying mechanisms that can lead to chronic hiccups. Although more than 100 conditions have been implicated, no causal relationships have been consistently shown.

The causes of hiccups may be classified as: peripheral, central, metabolic, drug-induced, and psychogenic.

Peripheral causes

Peripheral processes involve irritation of the diaphragmatic, phrenic, and vagus nerves.

Diaphragmatic and phrenic nerve irritation may result from: subphrenic abscess, splenomegaly, hepatomegaly, myocardial infarction, pericarditis, a hiatus hernia, esophageal cancer, or an aberrant cardiac pacemaker electrode.

Irritation of the vagus nerve may result from:[6][7][8][9]

  • a foreign body irritating the tympanic membrane

  • pharyngitis, laryngitis, goiter or neck cyst

  • pneumonia, empyema, bronchitis, asthma, pleuritis, tuberculosis, lung cancer

  • esophagitis

  • aortic aneurysm

  • cor pulmonale

  • mediastinitis

  • gastric atony, gastric cancer, gastritis, duodenal ulcer

  • pancreatitis, pancreatic cancer

  • intra-abdominal abscess

  • bowel obstruction

  • cholecystitis, cholelithiasis

  • ulcerative colitis, Crohn disease, gastrointestinal hemorrhage

  • appendicitis

  • hepatitis, or

  • prostatic disease.

Central causes

Central causes of hiccups include:[10][11][12]

  • structural lesions (intracranial neoplasm, syringomyelia, multiple sclerosis, ventriculo-peritoneal shunt)

  • vascular lesions (intracranial hemorrhage or infarction, arterio-venous malformation, vascular insufficiency)

  • infection (meningitis, encephalitis, neurosyphilis, malaria, herpes zoster)

  • trauma, and

  • epilepsy.

Metabolic causes

Metabolic causes include uremia, diabetes mellitus, gout, hyponatremia, hypocalcemia, hypokalemia, and alkalosis. Electrolyte disturbances can decrease the central inhibition of the hiccup reflex arc, leading to chronic hiccups.

Drug-induced hiccups

Alcohol, dexamethasone, diazepam, sulfonamides, anti-epileptics, and alpha-methyldopa may cause hiccups.[13] Cancer chemotherapy may cause episodic hiccups.[14] Hiccups associated with sedation or anesthesia can be considered as a separate subtype. The hiccup reflex is usually inhibited by the cortex, but during sedation and anesthesia this inhibition is decreased, leading to hiccups.[1][15][16]

Psychogenic causes

Psychogenic disorders associated with the development of chronic hiccups are personality disorder, conversion reaction, hysterical neurosis, anorexia nervosa, sudden shock, and grief reaction.[8][17]

Pathophysiology

The exact mechanism underlying hiccups remains unknown.

The afferent limb of the hiccup reflex arc involves the phrenic and vagus nerves, as well as the sympathetic chain. The primary efferent branch is the phrenic nerve; however, efferent nerves to the glottis and accessory muscles (e.g., intercostals, scalenus muscles) are also involved.[5] The central connection involves the third, fourth, and fifth cervical segments and the brainstem.[5][18] The neurotransmitters gamma-aminobutyric acid, dopamine, and serotonin are involved in processing.[18][19] 

Following activation of the hiccup reflex arc, an abrupt inspiration occurs. Hiccups usually involve unilateral diaphragmatic contraction frequently confined to the left hemi-diaphragm. Although bilateral contractions occur, one side usually dominates.[16] The accelerated movement of air leads to a sudden closure of the glottis approximately 35 milliseconds later. This cycle can repeat 4 to 60 times a minute.

The arterial partial pressure of carbon dioxide (PCO₂) level has an impact on the frequency of hiccups.[20] Increasing PCO₂ levels lower the frequency, whereas hyperventilation (leading to reduced CO₂ levels) increases the number of hiccups per minute.

Classification

Clinical classification

Benign hiccups

  • Self-limited with a duration of <48 hours and no associated complications.

Chronic hiccups

  • Not self-limited and with a duration of over 48 hours that can even last up to several years. Associated often with an underlying organic cause, and associated complications may develop.

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