Gastroesophageal reflux disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Gastroesophageal reflux disease is defined as chronic symptoms due to damage to the esophageal mucosa as a result of abnormal reflux of acidic stomach contents into the esophagus^[1]. This is commonly due to transient or permanent changes in the barrier between the esophagus and the stomach. This can be due to incompetence of the lower esophageal sphincter (LES), transient LES relaxation, impaired expulsion of gastric reflux from the esophagus, or a hiatal hernia. Chronic GERD is associated with an increased risk of Barrett’s esophagus which is a premalignant condition of the esophageal mucosa which is in turn associated with an increased risk of adenocarcinoma of the esophagus.

GERD is believed to be first described and treated by the ancient Egyptians according to the papyrus which was discovered by Edwin Smith at Thebes. The esophagus itself was named by the ancient Greeks. Friedenwald and Feldman described the symptoms of GERD in 1925. Robbins and Jankelson used the radiological procedures to observe GERD in 1926.

GERD can be classified based on the endoscopic appearance of the esophageal mucosa and the clinical presentation of the disease.

Pathophysiology of GERD depends on several mechanisms that lead to the retrograde movement of the acidic content of the stomach to the esophagus. These mechanisms include transient lower esophageal sphincter relaxation, hypotensive lower esophageal sphincter, hiatal hernia, and prolongedesophageal acid clearance.

Common causes of GERD include obesity, autonomic neuropathy, systemic sclerosis, esophageal achalasia, and hiatus hernia. Other causes of GERD include hypochlorhydria, hypercalcemia, and Zollinger-Ellison syndrome.

GERD must be differentiated from other diseases like gastritis, peptic ulcer, crohn’s disease, gastric adenocarcinoma, and gastrinoma.

The prevalence of GERD in USA and Europe ranges from 10,000 to 20,000 per 100,000 people. The incidence of GERD increases with age especially above 40 years.

Common risk factors of GERD include smoking, obesity, pregnancy, alcohol binge drinking, and medications like the anticholinergic drugs. Other risk factors include some kinds of food like spicy food and bad eating habits like eating large meals.

There is insufficient evidence to recommend routine screening for GERD.

If left untreated, 20% of patients with GERD may progress to develop esophageal stricture due to excessive acid in the lower esophagus. Complications of GERD include barrett’s esophagus, erosive esophagitis, esophageal ulcer, and esophageal adenocarcinoma. Prognosis of GERD is good with the appropriate treatment. 

Common symptoms of GERD include heart burn, regurgitation, and dysphagia. A positive history of nausea, vomiting, and regurgitation is suggestive of GERD. Other symptoms of GERD include chest pain, cough, and odynophagia.

Patients with GERD usually appear ill due to the pain. Common physical examination include hoarseness of voice, laryngitis, otitis media, and lung wheezes. 

Laboratory findings consistent with diagnosis of GERD is the presence of acidic reflux in the esophagus through the ambulatory reflux monitoring.

There are no EKG findings associated with GERD. However, EKG can be performed to exclude the cardiac causes of chest pain that can be presented in cases of atypical GERD.  

X ray imaging suggestive for associated problems with GERD include free acid reflux, esophagitis with scarring, strictures, and barrett’s esophagus.

There are no CT findings associated with GERD.

There are no MRI findings associated with GERD.

There are no ultrasound findings associated with GERD.

There are no other imaging findings associated with GERD. However, endoscopy may be used in screening for the complications associated with chronic GERD like barrett’s esophagus.

There are no other diagnostic studies associated with GERD.

The mainstay treatment of GERD is lifestyle modifications which include weight loss, elevating head of the bed and no eating before going sleep. The pharmacologic medical therapy is recommended among patients with persistent GERD despite following the lifestyle modifications. Antacids, histamine receptor antagonists, proton pump inhibitors, and prokinetics medications are used in treatment of GERD. 

Surgery is not the first-line treatment option for patients with GERD. Surgery is usually reserved for patients with either chronic GERD, high volume of acid reflux, non-compliant medical therapy, the presence of large hiatal hernia, or with upper respiratory manifestations as hoarseness of voice and laryngitis. The nissen fundoplication is the operation of choice in patients with GERD.

Effective measures for the primary prevention of GERD include avoiding food that worsens the symptoms, smoking cessation, weight loss, eating frequent meals, and head raising of the bed while sleeping.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

GERD is believed to be first described and treated by the ancient Egyptians according to the papyrus which was discovered by Edwin Smith at Thebes. The esophagus itself was named by the ancient Greeks. Friedenwald, and Feldman described the symptoms of GERD in 1925. Robbins and Jankelson used the radiological procedures to observe GERD in 1926.

• The esophagus was first named by the ancient Greeks as “oisophagos” at which “oiso” means carry and “phagema” means food.^[1]
• In 1541, Gyudon put the first description of the esophagus and its function.
• In 1704, Anton Maria Valsalva published an article where he described the lower esophageal sphincter (LES). The LES was first named as cardiac sphincter as it is very near to the heart.
• In 1862, the American Egyptologist Edwin Smith discovered a papyrus at Thebes. This papyrus, which was named after him, contain 48 cases of different illnesses and their treatment. In 1930, the Edwin Smith papyrus was translated by Henry Breasted. Among the 48 cases, the case number 28 was titled with “Instructions concerning a wound in his throat” which was most probably a case of GERD.
• In 1925, Friedenwald and Feldman described the presenting symptoms of GERD. They associated between the symptoms of GERD and the presence of hiatus hernia.
• In 1926, Robbins and Jankelson used the radiological procedures to observe GERD.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

GERD can be classified based on the endoscopic appearance of the esophageal mucosa and the clinical presentation of the disease.

• GERD can be classified based on the endoscopic appearance of the esophageal mucosa into two subtypes:^[1]
  • Erosive GERD
  • Non-erosive GERD

• GERD can be classified based on the clinical presentation into two types:^[2]
  • Typical GERD
  • Atypical GERD

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Pathophysiology of GERD depends on several mechanisms that lead to the retrograde movement of the acidic content of the stomach to the esophagus. These mechanisms include transient lower esophageal sphincter relaxation, hypotensive lower esophageal sphincter, hiatal hernia, and prolonged esophageal acid clearance.

• The esophagus is a part of the gastrointestinal tract which is responsible of moving the food from the mouth to the rectum.^[1]
• The esophagus has anti-reflux barrier which prevents the return of the acidic contentof the stomach back to the esophagus. The anti-reflux barrier consists of the lower esophageal sphincter (LES) and the related part of the diaphragm.
• The lower esophageal sphincter is contracting smooth muscle at the end of the esophagus responsible for the food passage to the stomach. LES has high pressure tone which helps keeping it a strong barrier between the esophagus and the stomach.

• Pathogenesis of GERD depends on various mechanisms that lead to the reflux of the gastric acidic contents into the esophagus.
• Several mechanisms impair the anti-reflux barrier and cause esophageal dysmotility. These mechanisms include the following:^[2][3]
  • Transient lower esophageal sphincter relaxations
  • Hypotensive lower esophageal sphincter
  • Hiatus hernia
  • Impaired esophageal acid clearance
  • Delayed gastric emptying

• Transient lower esophageal sphincter relaxations is considered the main mechanism of GERD development in most of the patients. It occurs alongside a normal LES and more common with obesity. ^[4]
• Distension of the stomach worsens the case of transient lower esophageal sphincter relaxation. The diaphragm is also affected by the sphincter relaxation leading to diaphragm inhibition. ^[5]

• Some of the GERD patients have hypotensive lower esophageal sphincter which leads to retrograde movement of the gastric content into the esophagus.

• A hiatal hernia occurs as part of the stomach is dislocated into the chest. This dislocation leads to placement of the LES above the diaphragm impairing the acid clearance.^[6]
• Increase the exposure of the lower esophagus due to a hiatal hernia plays a big role in the pathogenesis of GERD.

• The esophagus has pre-epithelial and epithelial defensive mechanisms against the acidic components that can lead to esophageal injury. However, these defensive mechanisms are limited and weak to stand against injury in case of excessive acid exposure.
• In case of an excessive increase of the noxious agents more than the ability of the mucosal defensive mechanism to eliminate them, mucosal injury occurs and GERD develops.
• The gastric acid leads to erosion of the esophageal mucosa and destruction of the intercellular junctions which leads to increase cellular permeability. The increase in the cellular permeability is proved by the dilation of the intercellular spaces and explains the typical symptoms (e.g, heartburn) of GERD.

The most important conditions and diseases associated with GERD include the following: ^[7][8]

• laryngitis
• Chronic cough
• pulmonary fibrosis
• earache
• asthma
• Obstructive sleep apnea

Findings in gross pathology of GERD include the following:

• Erythematous esophageal mucosa
• Erosions
• Ulcerations in severe cases

Biopsies can be performed during gastroscopy and these may show:

• Edema and basal hyperplasia (non-specific inflammatory changes)
• Lymphocytic inflammation (non-specific)
• Neutrophilic inflammation (usually due to reflux or Helicobacter gastritis)
• Eosinophilic inflammation (usually due to reflux)
• Goblet cell intestinal metaplasia or Barrett’s esophagus.
• Elongation of the papillae
• Thinning of the squamous cell layer
• Dysplasia or pre-cancer.
• Carcinoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Common causes of GERD include obesity, autonomic neuropathy, systemic sclerosis, esophageal achalasia, and hiatus hernia. Other causes of GERD include hypochlorhydria, hypercalcemia, and Zollinger-Ellison syndrome.

• Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.There are no life-threatening causes of GERD.

Common causes of GERD include the following:^[1]

• Obesity
• Hereditary sensory and autonomic neuropathy type 1B
• Esophageal achalasia
• Ibuprofen lysine
• Hiatus hernia
• Pharyngeal pouch

Less common causes of GERD include the following:

• Hypochlorhydria
• Hypercalcemia, which can increase gastrin production, leading to increased acidity.
• Zollinger-Ellison syndrome, which can be present with increased gastric acidity due to gastrin production.
• Scleroderma and systemic sclerosis, which can feature esophageal dysmotility.

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Apremilast, febuxostat, ibuprofen lysine, naproxen and esomeprazole magnesium, pirfenidone, pramipexole, ritonavir,
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

GERD must be differentiated from other diseases like gastritis, peptic ulcer, crohn’s disease, gastric adenocarcinoma, and gastrinoma.

• GERD must be differentiated from other diseases such as gastritis, peptic ulcer, crohn’s disease, gastric adenocarcinoma, and gastrinoma.^{[1][2][3][4][5][6][7][8][9]}

Differential Diagnosis

Disease

Cause

Symptoms

Diagnosis

Other findings

Pain

Nausea & Vomiting

Heartburn

Belching or Bloating

Weight loss

Loss of Appetite

Stools

Endoscopy findings

Location

Aggravating Factors

Alleviating Factors

GERD

Lower esophageal sphincter abnormalities Hiatal hernia Abnormal esophageal contractions Prolonged emptying of stomach Gastrinomas

Epigastric pain

Spicy food Tight fitting clothing

Antacids Head elevation during sleep

✔ (Suspect delayed gastric emptying)

✔

–

–

–

–

Esophagitis Barrette’s esophagus Strictures

Other symptoms: Dysphagia Regurgitation Nocturnal cough Hoarseness Complications Esophagitis Strictures Barrette esophagus

Acute gastritis

H. pylori NSAIDS Corticosteroids Alcohol Spicy food Viral infections Crohn’s disease Autoimmune diseases Bile reflux Cocaine use Breathing machine or ventilator Ingestion of corrosives

Epigastric pain

Food

Antacids

✔

✔

✔

–

✔

Black stools

Pangastritis or antral gastritis Erosive (Superficial, deep, hemorrhagic) Nonerosive (H. pylori)

–

Chronic gastritis

H. pylori Alcohol Medications Autoimmune diseases Chronic stress

Epigastric pain

Food

Antacids

✔

✔

✔

✔

✔

–

H. pylori gastritis Atrophy Intestinal metaplasia Lymphocytic gastritis Enlarged folds Aphthoid erosions

–

Atrophic gastritis

H. pylori Autoimmune disease

Epigastric pain

–

–

✔

–

✔

✔

–

H. pylori Mucosal atrophy Autoimmune Mucosal atrophy

Iron deficiency anemia Autoimmune gastritis diagnosis includes: Antiparietal and anti-IF antibodies Achlorhydria and hypergastrinemia Low serum cobalamine

Crohn’s disease

Autoimmune disease

Abdominal pain

–

–

–

–

–

✔

✔

Chronic diarrhea often bloody with pus or mucus Rectal bleeding

Mucosal nodularity with cobblestoning Multiple aphthous ulcers Linier or serpiginous ulcerations Thickened antral folds Antral narrowing Hypoperistalsis Duodenal strictures

Fever Fatigue Anemia (pernicious anemia)

Peptic ulcer disease

H. pylori Smoking Alcohol Radiation therapy Medications Zollinger-ellison syndrome

Epigastric pain sometimes extending to back Right upper quadrant pain

Duodenal ulcer Pain aggravates with empty stomach Gastric ulcer Pain aggravates with food

Antacids Duodenal ulcer Pain alleviates with food

✔

✔

–

–

–

Black stools

Gastric ulcers Discrete mucosal lesions with a punched-out smooth ulcer base with whitish fibrinoid base Most ulcers are at the junction of fundus and antrum 0.5-2.5cm Duodenal ulcers Well-demarcated break in the mucosa that may extend into the muscularis propria of the duodenum Found in the first part of duodenum <1cm

Other diagnostic tests Serum gastrin levels Secretin stimulation test Biopsy

Gastrinoma

Associated with MEN type 1

Abdominal pain

–

–

✔ (suspect gastric outlet obstruction)

✔

–

–

–

Black stools

Useful in collecting the tissue for biopsy

May present with symptoms of GERD or peptic ulcer disease Associated with MEN type 1 Diagnostic tests Serum gastrin levels Somatostatin receptor scintigraphy CT and MRI

Gastric Adenocarcinoma

H. pylori infection Smoked and salted food

Abdominal pain

–

–

✔

✔

✔

✔

✔

Black stools, or blood in stools

Esophagogastroduodenoscopy Multiple biopsies are taken to establish the diagnosis

Other symptoms Dysphagia Early satiety Frequent burping

Primary gastric lymphoma

H. pylori infection

Abdominal pain Chest pain

–

–

–

–

–

✔

–

–

Useful in collecting the tissue for biopsy

Other symptoms Painless swollen lymph nodes in neck and armpit Night sweats Fatigue Fever Cough or trouble breathing

• GERD must be differentiated from other causes of dysphagia, odynophagia and food regurgitation such as esophageal adenocarcinoma and esophageal stricture.

	Manifestations	Diagnostic tools
Achalasia	Dyspnea[10] Dysphagia for solids and liquids is the most common feature, being seen in 91 % and 85% of patients respectively[11] Regurgitation of undigested food occurs in 76-91% of patients[11] Cough mainly when lying down in 30%[11]	Esophagogastroduodenoscopy findings include a dilated esophagus with residual food fragments, normal mucosa and occasionally candidiasis (due to the prolonged stasis). Barium swallow shows the characteristic bird’s beak appearance.
GERD	Retrosternal burning chest pain. Cough and hoarseness of voice. May present with complications such as strictures and dysphagia.[5]	Upper GI endoscopy shows the complications such as esophagitis and barret esophagus. Esophageal manometry may show decreased tone of the lower esophageal sphincter. 24-hour esophageal pH monitoring may be done to confirm the diagnosis.
Esophageal carcinoma	Dysphagia Odynophagia– fluids and soft foods are usually tolerated, while hard or bulky substances (such as bread or meat) cause much more difficulty[12] Weight loss Pain, often of a burning nature, may be severe and worsened by swallowing, and can be spasmodic in character Nausea and vomiting[12]	Upper GI endoscopy and esophageal biopsy the gold standard for the diagnosis of esophageal
Corckscrew esophagus	Retrosternal chest pain that presents with or without food intake.[13] The condition is not progressive and not causing complications.[14]	Barium swallow shows the characteristic corckscrew appearance of the esophagus.
Esophageal stricture	Patient may present with the symptoms of the underlying GERD. Dysphagia and odynophagia.[15]	Barium esophagography provides information about the site and the diameter of the stricture before the endoscopic intervention.[16]
Plummer-Vinson syndrome	Common symptoms of Plummer-Vinson syndrome include:[17][18][19] Difficulty swallowing (more for solids) Weakness Pain Burning sensation in mouth Dry tongue Painful cracks in the angles of a dry mouth Pale color of the skin Less cmmon symptoms Cold intolerance Reduced resistance to infection Altered behavior Craving for for unusual items (such as ice or cold vegetables)	Lab tests are consistent with the diagnosis of iron deficiency anemia. Findings on an x-ray (barium esophagogram) suggestive of esophageal web/strictures associated with Plummer-Vinson syndrome appear as either: Thin projections on the anterior esophageal wall. Multiple upper (cervical) esophageal constrictions consistent with esophageal webs.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

The prevalence of GERD in USA and Europe ranges from 10,000 to 20,000 per 100,000 people. The incidence of GERD increases with age especially above 40 years.

• In the USA and Europe, the prevalence of GERD ranges from low of 10,000 per 100,000 persons to high of 20,000 per 100,000 people. ^[1]
• In Asia, the prevalence of GERD is 5,000 per 100,000 people.

• In the USA, the incidence of GERD is 5,400 per 100,000 persons.
• In Europe, the incidence of GERD is 840 per 100,000 persons.

• The prevalence of GERD increases with age.
• GERD affects all age groups but it affects more the people older than 40 years.

• Men and women are affected equally by GERD.

• There is no racial predilection for GERD.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Common risk factors of GERD include smoking, obesity, pregnancy, alcohol binge drinking, and medications like the anticholinergic drugs. Other risk factors include some kinds of food like spicy food and bad eating habits like eating large meals.

Common risk factors of GERD include the following:

• Smoking
• Obesity
• Pregnancy
• Hiatal hernia
• Scleroderma
• Drinking a lot of alcohol
• Consuming drinks that contain caffeine

• Medications:

• Anticholinergics (e.g. for seasickness)
• Beta blockers for high blood pressure or heart disease
• Bronchodilators for asthma
• Calcium channel blockers for high blood pressure
• Dopamine-active drugs for Parkinson’s disease
• Progestin for abnormal menstrual bleeding or birth control
• Sedatives for insomnia or anxiety
• Tricyclic antidepressants

Less common risk factors of GERD include the following:^[1]

• Special kind of diet from below items:
  • Spicy food
  • Fried food
  • Sweets
• Eating habits such as the following:
  • Irregular eating
  • Eating quickly
  • Eating between meals
  • Eating large meals

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

There is insufficient evidence to recommend routine screening for GERD.

There is insufficient evidence to recommend routine screening for GERD.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

If left untreated, 20% of patients with GERD may progress to develop esophageal stricture due to excessive acid in the lower esophagus. Complications of GERD include barrett’s esophagus, erosive esophagitis, esophageal ulcer, and esophageal adenocarcinoma. Prognosis of GERD is good with the appropriate treatment.

• The symptoms of GERD include heart burn, regurgitation, and dysphagia.
• If left untreated, GERD will develop to esophageal stricture which occurs in around 20% of the patients with GERD.^[1]
• Esophageal stricture occur due to excessive acid in the lower of the esophagus which lead to scar formation. This scar causes narrowing of the esophagus and lead to difficulties in swallowing.

Complications that can develop as a result of GERD include the following:^[2]

• Barrett’s esophagus:
  • A type of dysplasia, is a precursor high-grade dysplasia, which is in turn a precursor condition for carcinoma. The risk of progression from Barrett’s to dysplasia is uncertain but is estimated to include 0.1% to 0.5% of cases, and has probably been exaggerated in the past.
  • Due to the risk of chronic heart burn progressing to Barrett’s esophagus, EGD every 5 years is recommended for patients with chronic heartburn, or who take drugs for chronic GERD.
• Erosive esophagitis
• Esophageal ulcer:
  • The excess acid secretion in the esophagus can lead to ulcer formation which increases pain in GERD patients.
• Esophageal adenocarcinoma

• The majority of people respond to nonsurgical measures, with lifestyle changes and medications. However, many patients need to continue to take drugs to control their symptoms.

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