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Micrograph of Barrett’s esophagus

Bild: “Micrograph of Barrett’s esophagus” von Nephron. Lizenz: CC BY-SA 3.0


Definitions

Gastroesophageal reflux

Gastroesophageal reflux is the temporary reflux of gastric content into the esophagus. This condition may also occur in healthy individuals. To a certain degree, it is a physiological response, particularly after the consumption of a fatty meal or wine.

Gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is sometimes called (acid) reflux disease. GERD leads to a diminished quality of life and/or puts the individual’s health at risk. GERD is divided into:

  • NERD (non-erosive reflux disease): Here, patients suffer from asymptomatic reflux. However, reflux esophagitis cannot be macroscopically or histologically ascertained.
  • ERD (erosive reflux disease) or Reflux esophagitis: In this condition, endoscopy reveals mucosal lesions, either macroscopically or during a histopathological examination. This finding is indicative of reflux esophagitis.
  • Barrett’s esophagus: This is potential epithelial dysplasia that can occur in the esophagus during the course of GERD, which constitutes a precancerous stage of esophageal adenocarcinoma.

Epidemiology

Up to 20% of people in western countries are affected by acid reflux disease, and the incidence is increasing; 60% of these patients display no lesions (NERD). The remaining 40% display reflux esophagitis (ERD).

Etiology

Depending on its etiopathogenesis, reflux disease is divided into 2 categories:

  • Primary reflux disease (most common type, about 80–90%)
  • Secondary reflux disease

Causes of primary reflux disease

The prevalent causes of primary reflux disease include a primary insufficiency of the lower esophageal sphincter and the increased production of gastric acid, often of unknown origin.

Factors encouraging the development of reflux disease:

  • Coffee, smoking, alcohol, heavy evening meal
  • Obesity (increased intra-abdominal pressure due to obesity)
  • Stress
  • Insufficiency of the diaphragmatic crura
GERD

Image: GERD. By: BruceBlaus. License: CC BY-SA 4.0

Patients often suffer from an axial hiatal hernia at the same time. From another viewpoint, among patients with a hiatal hernia, the number of those who simultaneously suffer from reflux disease is not significantly higher when compared to patients without a hiatal hernia; that is why the latter seems to play no causal role. However, a hiatal hernia seems to encourage the progression of gastroesophageal reflux to GERD.

Causes of secondary reflux disease

A secondary reflux disease arises when there is a determinable underlying condition that causes an esophageal sphincter disorder or aggressive reflux. For example:

  • During the last months of pregnancy (increased intra-abdominal pressure)
  • After surgery for achalasia
  • Pyloric stenosis
  • Scleroderma

Pathophysiology

Different factors promote the onset of reflux disease

In the majority of the cases, various etiological factors primarily result in lower esophageal sphincter insufficiency. Normally, the sphincter functions as a reflux barrier. Physiologically, the resting pressure in the lower esophageal sphincter approximately is 20 mm Hg. As this pressure is higher than the intragastric pressure, it prevents the potential backflow of the stomach’s contents into the esophagus. The only time when the esophageal sphincter is temporarily loose is during the swallowing process. Insufficiency can manifest in 2 ways:

  • Inadequate sphincter relaxation (during the swallowing process)
  • Generally decreased resting pressure

In addition to these, a dysfunctional self-purification of the esophagus (decreased esophageal clearance) also leads to prolonged contact of the reflux with the esophagus.

Finally, another fact that is related to the disease’s pathophysiology and which is crucial, is that the esophageal mucosa is subject to damage caused by acidic gastric juices. Alkaline biliary reflux is very rarely the reason behind reflux disease.

Note: From a pathophysiological view, lower esophageal sphincter insufficiency is a crucial component of reflux disease.

Symptoms

Heartburn affects 75% of patients

The cardinal symptoms of gastroesophageal reflux disease include:

  • Heartburn (75% of patients)
  • Burping (60% of the patients), also accompanied by bloating
  • Regurgitation of food residue, which leaves a sour taste
  • Dysphagia

Many patients also describe a certain thoracic pain (differential diagnosis: myocardial infarction). Paroxysmal retrosternal pain is caused by a spasm of esophageal muscle, which can occur in cases of recurrent reflux. A reflux-induced vagal stimulation can cause a dry cough, whereas some patients also complain of weakness and vomiting.

Note: Symptoms deteriorate with lying, pressure, bending, effort, and stress.

Complications

In GERD, mucosal lesions can become ulcerated and form strictures and peptic stenoses in the lower esophagus; such circular strictures are also known as ‘Schatzki’s Rings’.

A potential nocturnal aspiration of gastric contents can lead to pneumonia or chronic bronchitis; asthma can also be provoked or can worsen if already present. The nocturnal intensified backflow of acid can also lead to laryngitis with hoarseness, especially in the morning.

Barrett’s esophagus

A lethal complication of reflux disease is Barret’s esophagus. The multilayered, non-cornified squamous epithelium of the terminal esophagus is damaged by the constant, non-physiologic contact with gastric acids, ultimately resulting in an intestinal-type columnar epithelium with goblet cells.

These transformed segments of columnar epithelium follow a proximal, tongue-like course. If less than 3 cm of the esophagus is affected, it is known as short-segment Barret’s esophagus. If more than 3 cm is affected, long-segment Barrett’s esophagus results. This classification is of vital prognostic importance.

Barrett’s esophagus appears in endoscopy as in the images below:

Endoscopy

Picture: (A) Conventional endoscopic view of Barrett’s esophagus with concomitant esophagitis. (B) Positive staining of Barrett’s epithelium after absorption chromoendoscopy with methylene blue (1%, 10 mL). (C) Villous cerebroid pits with finger-like projections seen with magnification endoscopy (pattern 5 according to Endo’s classification). (D) Histological section of (C) showing intestinal metaplasia with glands of different sizes and shapes and numerous goblet cells. By: Openi. License: CC BY 4.0

Mucosal lesions run out in a tongue-like manner in an irregular Z-line. Histology confirms the suspicion.

Barrett’s esophagus and the associated epithelial dysplasia are considered precancerous since adenocarcinomas can subsequently develop (about 10% of the cases).

Note: The risk of malignant degeneration particularly increases in cases of long-segment Barrett’s esophagus.

Differential Diagnosis

Differentiating reflux disease from other esophageal conditions

The differential diagnosis first takes into consideration other esophageal conditions, e.g., esophagitis, esophageal cancer, diverticulitis, achalasia, or other motility disorders.

Another cause of mucosal esophageal ulcerations is medication (NSAIDs, doxycycline, etc).

Other conditions whose symptoms may resemble those of reflux disease include myocardial infarction, coronary heart disease, and gastroduodenal ulcers.

Diagnosis

Medical history and the use of proton pump inhibitors (PPI) for reflux disease

When a patient describes symptoms possibly related to a mild acid reflux disease, first-line treatment with PPI can be attempted. If the patient responds to the treatment, the diagnosis of reflux disease will be corroborated.

Esophagoscopy with biopsy

Endoscopy should be performed to confirm reflux esophagitis and inspect the patient for a possible Barrett’s esophagus. This should be followed by biopsy (‘Four-Quadrant biopsy’). The endoscopic findings facilitate the classification of reflux esophagitis into categories, depending on the degree of severity (see below).

Endoscopy also helps to exclude other conditions otherwise included in the differential diagnosis: esophageal thrush (yeast infection) has a whitish appearance. Eosinophilic esophagitis (unknown etiology, but often associated with diseases of the atopic spectrum) stands out with bloody mucosa (‘crêpe-paper’ mucosa) and ring-shaped erosions, sometimes called “feline-esophagus”, because of its resemblance to the esophagus of a cat.

Concentric rings in the distal esophagus, consistent with eosinophilic esophagitis

Image: Concentric rings in the distal esophagus, consistent with eosinophilic esophagitis. By: Openi. License: CC BY 2.0

In addition to endoscopy with four-quadrant biopsy, methods such as chromoendoscopy with methylene blue, fluorescence studies, and magnification endoscopy can also be performed to diagnose and monitor the disease.

Histology

The tissue extracted during endoscopy is investigated for features of reflux esophagitis. After that, additional information that may be obtained include leukocyte infiltration, squamous epithelium proliferation, ulcerations, and cornification.

Histological assessment of the esophageal mucosa

Picture: Histological assessment of the esophageal mucosa (hematoxylin and eosin ×200) from sham-operated rats (A) and GER model rats (B, C). Normal esophageal mucosa is shown in A (controls). The absence of esophageal mucosal inflammation is shown in B (NERD). Basal layer thickening, vascular congestion, and the infiltration of inflammatory cells, such as eosinophils, are shown in C (reflux esophagitis). By: Openi. License: CC BY 2.0

Micrograph of Barrett’s esophagus

Picture: Micrograph of Barrett’s esophagus. By: Nephron. License: CC BY-SA 3.0

The existence of Barrett’s esophagus is indicated by the conversion of the squamous epithelium into a columnar epithelium with goblet cells.

Histology also makes a further division of Barrett-related findings possible:

  • Low-Grade Intraepithelial Dysplasia (LGID)
  • High-Grade Intraepithelial Dysplasia (HGID)

24-hour pH monitoring with a nasal tube

This method is particularly applied to patients with NERD. The esophageal pH is monitored for 24 hours through a nasal esophageal tube, and a pH of ≤ 4 corresponds to the reflux of acidic gastric content. In healthy individuals, such episodes are only seen postprandially (after a meal) and just for up to 5 minutes. In patients with acid reflux disease, reflux episodes are particularly observed at night and after midnight.

Classification of Reflux Esophagitis

As mentioned in the section about esophagoscopy, there are many useful classifications of GERD, depending on the endoscopic findings. Two of them will be discussed here since they are fairly common exam questions:

Savary-Miller classification

Stage Endoscopic finding
0 Reflux complaints, but no mucosal erosions
I Single mucosal erosions (IA: superficial – ‘red spots’, IB: deep, coated with fibrin – ‘white spots’)
II Longitudinal mucosal erosions along the mucosal folds (IIA: superficial – ‘red spots’, IIB: deep, coated with fibrin – ‘white spots’)
III Circular confluent mucosal erosions
IV Existent complications. e.g., ulcerations, stenoses, epithelial dysplasia, etc.

Los Angeles classification

Stage Endoscopic finding
A Erosions have a diameter <5 mm and are limited to one mucosal fold
B Like A but with a diameter >5 mm
C Erosions extend to more mucosal folds but involve <75% of the circumference
D Confluent erosions > 75% of the circumference

GERD Therapy

General measures for treating reflux disease

Generally, the therapy for reflux disease should encompass the following supportive measures:

  • Adjustment of dietary habits: weight loss, avoiding the consumption of sour and alcoholic drinks and food (e.g., coffee, salt, wine, tomato sauce, garlic, etc.), avoiding late meals, avoiding meals containing much fat or sugar, avoiding reclining directly after eating.
  • Avoiding substances that provoke reflux disease: nicotine, alcohol, sphincter-relaxing medication (e.g., anticholinergics, calcium antagonists, and theophylline).
  • Adjustment of sleep habits: sleeping with the upper part of the body elevated, lying on one’s right side.

Treatment with medication: PPIs

The combination of frequent complaints and esophagitis makes the use of medications necessary. First-choice medications include PPIs, e.g., omeprazole or pantoprazole, which suppress gastric acid secretion and help regenerate the mucosa.

Initially, therapy starts with a high dose (so that existent erosions will heal more quickly). Maintenance therapy is continued with half the therapeutic dose (step-down-treatment). If the patient relapses after the end of the treatment, the long-term prophylactic administration of PPIs comprising half the standard dosage is applied. For occasional relapses, a patient can take PPIs on demand.

H2-receptor antagonists and antacids are recommended only in mild cases without signs of inflammation.

Note: PPIs are the first-choice therapeutic treatment for acid reflux disease.

Surgical therapy for reflux disease: Nissen fundoplication

Fundoplication Nissen

Nissen Fundoplication

A laparoscopic Nissen fundoplication is indicated for stage IV disease when conservative methods fail to succeed, when there is an intolerance to PPIs, or when complications persist (e.g., aspiration pneumonia). Surgical therapy can also be applied to younger individuals who reject long-term PPI treatment.

In a Nissen fundoplication, a cuff is laparoscopically laid around the lower esophageal sphincter to narrow the cardia and prevent reflux. In order to form the ‘cuff’, the fundus must be mobilized. Eventually, the mobilized fundus is pulled dorsally to the esophagus and is ventrally sewn in place with loose sutures. This method can achieve subjective freedom from symptoms in up to 80% of the cases.

A complication that is relatively common and possibly the one asked most often in the exams, is the ‘gas-bloat syndrome’. Patients with reflux disease, who used to swallow air before the operation, continue to do so postoperatively (the disorder is referred to as aerophagia). However, a successful fundoplication does not allow for the air to be vented, since the gastroesophageal passage is subjected to a proper pressure ratio. This can lead to nausea, feelings of pressure, and even arrhythmias, and a second operation is indicated in order to loosen the cuff.

Control pattern in Barrett’s esophagus

Because of the increased risk of malignant degeneration in Barrett’s esophagus, patients are consistently treated and are also frequently monitored endoscopically with multiple biopsies.

In the case of Barrett’s esophagus without intraepithelial dysplasia, the patient undergoes 2 endoscopic examinations in 1 year. If the results continue to show no degeneration, an interval of 3 (long-segment-Barrett) and 4 (short-segment-Barrett) years is considered to suffice.

In the case of Barrett’s esophagus with LGID, the patient undergoes 2 endoscopic examinations within the first 6 months. Thereafter, follow-ups are performed once a year.

For Barrett’s esophagus with HGIDendoscopic mucosal resection or local radiofrequency ablation (RFA) is indicated.

Prognosis of GERD

Reflux disease is curable

In 90% of the cases, reflux esophagitis resolves with PPI therapy. However, if treatment is stopped, up to 50% of patients relapse.

Ten percent of patients with reflux disease develop ulcerative esophagitis. Barrett’s esophagus occurs in up to 5% of GERD patients and up to 10% of these patients develop an adenocarcinoma.

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