Pathophysiology of dyspepsia, GERD and PUD

Dyspepsia

• is a symptom not a diagnosis

• collection of upper GI symptoms lasting at least one month (not every day in the month but ongoing over the whole month)

• where epigastric pain is the dominant feature

• other symptoms:

  • NV

  • burping or bloating (upper abdomen)

  • early satiety

  • uncomfortable post-prandial

  • heartburn

Functional dyspepsia

• is a diagnosis of elimination

• rules out everything else through other investigations

  • is not PUD, GERD, esophageal or gastric cancer

Red flags for dyspepsia

• Vomiting

  • frequent and >7 days

• Bleeding

  • hematemesis (vomiting bright red blood)

  • coffee ground emesis

  • dark tarry stools

• Anemia/Anorexia/Abdominal mass

  • unexplained dizziness or fatigue, pale

  • can have subclinical bleeding from ulcer or malignancy

• Dysphagia

  • choking when eating or drinking

  • difficulty swallowing

  • odynophagia - pain with swallowing

• patients >60 years

  • greater risk of malignancies

**severity of dyspepsia does not infer severity of condition

Which patients are able to self-treat for dyspepsia?

• patients without red flags (VBAD

  • could still have GERD, PUD or malignancy but risk is low enough

• called uninvestigated dyspepsia

Esophagogastric junction

• where esophagus meets stomach, not a clear division, will see a change in the tissues that occur

• comprised of:

  • lower esophageal sphincter (LES)

  • squamocolumnar junction (z-line)

Lower esophageal sphincter (LES)

• made of 2 muscle layers

• internal: thickened smooth muscle of distal esophagus (~4cm)

• external: crural part of diaphragm (~2cm)

  • supports the sphincter by applying pressure

Squamocolumnar junctions (z-line)

• transition from one type of epithelium to mucosa

• esophageal mucosa: stratified squamous cells

• gastric mucosa: columnar cells covered by protective layer of mucus

Normal function of LES

• prevents backflow of stomach contents

• some degree of gastroesophageal reflux is normal after meals

  • saliva neutralizes acidic content

  • secondary peristaltic waves help reflux return

• contracted (closed) at rest and relaxes (opens) with swallowing

GERD

• GER becomes pathological when reflux is sustained, leading to symptoms or complications

• generally due to increased frequency of transient LES relaxation

• less significant mechanisms:

  • decreased LES tone at rest

  • delayed gastric emptying

• NOT due to increased gastric acid secretion

Non-modifiable GERD risk factors

• age

  • esophageal tissue less resistant to damage

  • diminished salivation

• pregnancy

  • increased intraabdominal pressure - pushes against diaphragm

  • progesterone decreases LES tone

• family history

  • likely predisposition to decreased LES tone

• scleroderma

  • muscle of LES replaced with connective tissue

• Zollinger-Ellison syndrome

  • tumour (gastrinoma) leads to excessive acid production - overwhelming protective factors

• hiatal hernia

Hiatal hernia

• lower part of esophagus and upper part of stomach push through the diaphragm and into chest cavity

  • loss of external LES support

  • larger angle between esophagus and curve of stomach (angle of His)

• happens from increased intraabdominal pressure

• more common in:

  • >50 years

  • obesity

  • smoking

• can undergo surgery to fix

Modifiable GERD risk factors

• obesity

  • increased intraabdominal pressure

  • increased risk for hiatal hernia

• smoking

  • lowers LES pressure

  • hyposalivation

• medications

  • lowers LES pressure

  • anticholinergic, benzos, CCB, nitrates, opioids, tricyclic antidepressants

• alcohol/caffeine

  • lowers LES pressure

• eating chocolate/peppermint

  • lowers LES pressure

• eating fatty/fried foods

  • delays gastric emptying

• eating large meals

  • increased pressure on LES

  • increased volume for reflux

• sleeping (recumbent position)

  • swallowing occurs less often

  • gravity unable to assist clearance of reflux

GERD symptoms

classic symptoms

• heartburn - throat to upper stomach along midline

  • direct irritation of esophageal mucosa

• regurgitation - gastric contents into back of throat

  • may be sour taste or burning

  • may experience hypersalvation (“water brash”)

other symptoms

• dyspepsia

• dysphagia

  • usually reflects esophageal erosion or stricture (complications)

• extraesophageal symptoms

  • chronic cough or throat clearing

  • tooth erosion

  • asthma (aspiration into bronchial tree)

Complications of GERD

require additional diagnostics for definitive diagnosis

• erosive esophagitis (EE)

• esophageal stricture

• Barrett’s esophagus

Erosive esophagitis (EE)

• exposure of stomach acid on the epithelium causes inflammation (defense mechanism)

• persistent inflammation causes erosion and decreases peristalsis

• 30% of GERD progress to EE

• could have EE and be asymptomatic

Esophageal stricture

• damaged mucosa and musculature from EE is replaced with scar tissue

  • not as flexible as before

  • leads to narrowing of esophagus lumen

• will experience symptoms of choking or pain/difficulty to swallow

  
  

Barrett’s esophagus

• esophageal epithelium is replaced with columnar cell, better able to withstand GER

• primary risk factor for esophageal adenocarcinoma

  • monitoring very important once developed

• 15% GERD progress to Barrett’s esophagus and 6% Barrett’s progress to cancer

• Risk factors developing:

  • male

  • > 50 year

  • Caucasian

  • obesity

  • smoking

  • symptoms of GERD >5 years

Potential exacerbations of GERD

• spicy or acidic food

  • local irritation

• medications that can induce or worsen esophagitis due to direct mucosal injury

  • bisphosphonates

  • Aspirin and NSAIDs

  • potassium and iron salts

  • tetracycline, doxycycline and clindamycin

Diagnosis of GERD

1. classic symptoms that are moderate-to-severe (impacts daily activity) OR occur >2x/week even if mild

   ……OR…….

2. diagnostic evidence of complications, regardless of symptoms

in the absence of classic symptoms, other causes need to be ruled out

Role of additional investigations

• when appropriate:

  • if alarm features present (VBAD)

  • GERD is refractory to therapy

• when not needed:

  • most patients with classic symptoms - if undergo and find no damage called non-erosive reflux disease (NERD)

  • those with risk factors of Barrett’s esophagus for screening purposes

Types of investigations used for GERD

• esophageal manometry

  • measures the pressure in the esophagus during swallowing to measure how well functioning

• 24-hr pH impedance

  • how much acid in esophagus, so if increased frequency or degree of stomach acid reflex

• x-ray with barium contrast

  • swallow barium and watch how moves with x-ray to identify if have stricture - lumen will get smaller while barium is travelling

• endoscopy with biopsy

  • biopsy is only way to diagnose Barrett’s

  • most common

GER in infants

• extremely common but is not a disease

• peaks at 4 months and resolves usually at 1 year

• increased susceptibility due to:

  • very little solid intake (easier to reflux)

  • anatomy predisposes (LES not fully matured and angle of His naturally blunted)

  • often lying down, or semi-recumbent

GERD in infants

• if suspected needs to be referred:

  • refusing to eat

  • irritable

  • not keeping anything down

• multiple mimickers - as long as child seems healthy and gaining weight is okay

Gastric cell types

• surface mucous cells

  • secrete mucous and bicarbonate

• parietal cells

  • secrete H+ and Cl-

  • produce intrinsic factor

• neck mucous cells

  • secrete mucous and bicarbonate

• chief cells

  • secrete pepsinogen and lipase to breakdown the contents of food

• enteroendocrine cells

  • 3 types of cells that secrete regulatory hormones

Enteroendocrine cells

• enterochromaffin-like cells

  • produce histamine (stimulating parietal cells)

• G-cells

  • produce gastrin (stimulates parietal, chief cells, and peristalsis)

• D-cells

  • stimulated by acid presence

  • produce somatostatin (inhibits G-cells, parietal cells, and enterochromaffin cells)

  • the “breaks”

  • negative feedback loop for HCl

How much gastric juice is produced by gastric mucosa?

~1.5L per day

How is the homeostatic causticity maintained?

along with the mucosal defenses

• mucous and bicarbonate production

  • stimulated by prostaglandins

• mucosal blood flow

  • delivers oxygen and bicarbonate

  • facilitates healing of mucosal damage

Peptic ulcer disease (PUD)

• develops in the stomach or in the duodenum when causticity of gastric juices overwhelm mucosal defenses

• causticity damages the GI mucosa goes deep enough through epithelium to the muscularis mucosa underneath

• exposed muscle later (can be few mm or cm deep)

  • if deep enough can cause perforation

• can lead to slow (anemia) or severe (haematosis) bleeding, perforation or obstruction

Causes of PUD

Primary

• NSAID use

  • 4x increased risk

  • particularly gastric ulcers

• Helicobacter pylori infection

  • 6-10x increase risk

  • historically large percentage of ulcers - but now know how to treat

Secondary

• Zollinger-Ellison Syndrome

• other medications especially used alongside NSAIDs

  • directly toxic to the barrier of the stomach

  • on own not generally a risk

  • acetaminophen > 2-3g/day, bisphosphonates, glucocorticoids, clopidogrel, sirolimus, spironolactone, SSRIs, oral potassium

Cause of NSAID-induced ulcers

• systemic effects - inhibition COX

  • COX2 pro-inflammatory prostaglandins (inhibiting decreased pain and inflammation)

  • COX1 gastroprotective prostaglandins (inhibiting disrupts stomach’s balance)

  • dominant

• local effects - direct epithelial irritation

  • NSAIDs = carboxylic acids and unionized in stomach

  • once absorbed across gastric mucosa ionize and cause local toxicity

  • coating tablet not preventative because this is minor pathway

Risk of PUD with NSAID use

• dose

• choice of agent

  • highest risk: ketorolac

  • lower risk: ibuprofen, diclofenac, naproxen

  • lowest risk: COX2 selective agents (but not zero)

• duration of therapy

  • want shortest because less time for ulcer to develop

  • can get back to homeostasis

• Use of combo therapy

• other risk factors:

  • advanced age

  • history of PUD

  • smoking/alcohol

  • family history

  • concurrent med use

  • concomitant infection with H. pylori

Helicobacter pylori infection

• gram-negative

• helical, rod-shaped

• motile

• adapted to survive gastric (acidic) environment

• acquired commonly in childhood because of fecal-oral route

  • leads to colonization of gastric mucosa

  • can have for entire life and does not always cause ulcer

Cause of H. pylori-induced ulcer

• using flagella, moves through mucosa layer and land on epithelial cells

• attach to epithelial cells and start producing urease

• urease combines urea and H2O to make CO2 and ammonia

  • ammonia will neutralize the gastric acid and makes it more suitable for H. pylori to live and proliferate

• during proliferation it produces enzymes that disrupt the integrity of gastric mucosa and toxins that damage local epithelium

• will move along mucosa, and will mucosal damage leads to cellular damage

• creates a gap in protection causing caustic stomach contents to reach mucosa and create ulcer

H. pylori can also lead to?

• chronic gastritis

• gastric adenocarcinoma

• gastric mucosa-associated lymphoid tissue (MALT) lymphoma

NSAID-negative and H. pylori-negative PUD (“stress ulcer”)

• can be caused from critical illness because body is under great stress

• can be causes from MAJOR emotional stress

PUD symptoms

• most are asymptomatic until complications develop

  • anemia symptoms

  • hematemesis or coffee-group emesis

  • black or tarry stools

  • severe acute abdominal pain

• if there are symptoms - generally non-specific and often fluctuate (cycle of spontaneous healing and relapse)

  • dyspepsia

  • nausea

  • bloating

  • early satiety

  • ± GERD symptoms

• some patient may find food worsens and get weight loss

Diagnosis of PUD

• definitive requires visualization

• non-invasive H. pylori testing recommended for patients < 60 years