AFGALALY محمد عبد الفتاح جلال

Peptic Ulcer Diseases
　

Anatomy of the Upper G-I Tract
　
Histological Review of The Gastric Mucosa

Peptic ulcer may result from:

Unbalance of aggressive and defensive factors due to:

Increased aggressive factors (acid-pepsin), or decreased mucosal defensive factors.

	Gastric ulcer (except antral ulcer) appear to dependent more on reduced mucosal defense (resistance).
	Duodenal ulcers are more dependent on increasing aggressive factors.

The defensive & aggressive factors related to peptic ulcer disease

A. Mucosal Defensive Factors

Mucosal Barrier

Two-Component Mucous Barrier

Mucus acts in the defense against injury of G-I mucosa.

1st line of defense: the layer of mucus secretion

	Tenacious adherence to the underlying tissue
	Impermeability to destructive chemical agent
	Impermeability to pepsin (adsorptive properties & buffering action)

2nd line of defense:

	The layer of columnar & cuboidal cells of the surface & crypts of the mucosa.
	Amazing rate of reconstitution

Mucosal Resistance -- Nutrition

High protein diet -- increase mucosal resistance to acid-pepsin digestion.

Local Mucosal Blood Flow

Small nutrient vessels in the mucosa or submucosa --- occlusion (spasm, thrombosis, embolism or endarteritis) -- localized necreosis -- ulceration

* Factors contributing to vascular occlusion:

	Fat, large amount of epinephrine, vasopressin, serotonin
	Venous stasis secondary to liver-spleen disease or circulatory disorders.
	Arteriosclerosis.

Intrinsic Mechanisms That Inhibit Gastric Secretion

Antral inhibition of gastric secretion when its mucosa is bathed by acid of sufficient concentration

Duodenal brake

Active enterogastrone from duodenum inh. histamine- & gastrin-stimulated gastric secretion

Secretin: inh. gastrin- but not histamine-stimulated gastric secretion.

CCK-PZ: inh. gastrin-stimulated gastric secretion, ? Competitive inhibitor of gastrin

B. Aggressive Factors

1. Acid-pepsin secretion

Vagal activity

Gastrin

Parietal cell mass

2. Helicobacter pylori

3. Free Radicals (superoxide, etc.)

Vagal Activity - promote acid, pepsin, and mucus secretion

Action:

1. Directly operates upon the fundic glands.

2. Through the mediation of antral or small bowel gastrin

Stimulated by:

Hunger, anger, pleasant food odors, hypoglycemia, and histamine.

Inhibited by:

Satiety (full stomach), fear, anticholinergics, normal or elevated blood sugar, & vagotomy.

Gastrin

Secreted by antral mucosa (pyloric gl., G cell)

Action:

Heavy secretion of HCl
Moderate secretion of pepsin
Increase hepatic biliary flow, pancreatic enzymes, and volume and bicarbonate of pancreatic juice.
Large amount -- stimulate and then inh. the motility of small bowel.

Inhibited by: lower mucosal pH

local anesthesia of the antrum

vagotomy or anticholinergics

active enterogastrone, secretin, & CCK-PZ

Stimulated by: Antral distension

Alkaline pH (gastric mucosa)

Polypeptide solution

Hypercalcemia

Vagal stimulation

Presence of bile in the antrum

Parietal Cell Mass (Oi)

-- The number of parietal cells contained in the gastric mucosa.

The same secretory stimulus will evoke different amount of acid from different subjects.
A point of maximal response to histamine stimulation
Maximal dosage of histamine: 40 mg/kg, s.c.
Parietal cell mass is decreased by removal of the pyloric gl. area, the adrenal gl., & the pituitary gl.
Parietal cell mass is a dynamic feature of the gastric mucosa, capable of gradual variation from time to time as stimuli are altered.

Helicobacter pylori (H. pylori)

H. pylori is extraordinary in that it is able to exist in the stomach for the entire lifetime of the host, a hostile environment that all other bacteria find intolerable.

1983 Marshall & Warren: Announced the culture of a spiral-shaped bacterium

1984 Marshall & Warren: Campylobacter-like organism

1984 Marshall et. al. : Campylobacter pyloridis

1987 Marshall & Goodwin: Campylobacter pylori

1989 Goodwin et. al. : Helicobacter pylori (H. pylori)

No acid, no ulcer (Schwarz, 1910)

No Helicobacter pylori, no ulcer (1989)

Characteristics of H. pylori

H. pylori is a short (0.2 to 0.5 mm in length), spiral-shaped, microaerophilic gram-negative bacillus with multiple flagella.
H. pylori are found in the deep portions of the mucus gel layer that coats the gastric mucosa and between the mucus gel layer and the apical surfaces of the gastric mucosal epithelial cells. They also located in the regions of the tight junctions between adjacent mucosal epithelial cells.
H. pylori may adhere to the luminal surfaces of gastric epithelial cells, but they do not invade the gastric mucosa.
Colonization of H. pylori in the duodenum is restricted to areas of gastric metaplasia and is found in metaplastic gastric epithelium in the duodenal bulb of most patients with duodenal ulcer.

Prevalence of H. pylori

	Gastric colonization with H. pylori has been reported : in 90 to 95 % of patients with D.U. in 60 to 70 % of patients with gastric ulcer. in 10% of healthy persons less than 30 year-old.
	Gastric colonization increases with age, with those over age 60 having colonization rates approximating their age.

The Possible Role of H. pylori in Gastric Disorder

The Possible Role of H. pylori in Duodenal Ulceration

Endocrine effects on gastric secretion

Hypothalamico-Pituitary-Adrenal Concept

Adrenalectomy reduced the concentration of acid but not the volume of secretion.

Adrenal or pituitary insufficiency -- secretion of acid & pepsin is very low

Incidence of peptic ulcer in patients with hyperparathyroidism is much higher than in population (20-25% vs 5-7%)

Hypercalcemia -- increased concentrations of acid & pepsin and
increased volumes of gastric secretion quickly.

Increased secretory activity of the thyroid gl. augments sympathetic response.

The incidence of peptic ulcer in associated with hyperthyroidism is lower than in the population at large.

ADH -- transient reduced the volume of gastric secretion

Stress and gastric secretion

	Stress -- post. hypothalamus -- pituitary stalk -- ant. pituitary -- adrenal cortex -- gastric secretion
	Stress -- ant. hypothalamus -- vagal nucleus -- vagus n.-- gastric secretion.

Psychosomatic relationship

"Ulcer personality"

Sustained anxiety, resentment, guilt, insecurity, & hostility are associated with vascular engorgement of the gastric mucosa -- hypersecretion of HCl.

Heredity & Constitution

	Ulcer in both members of monozygotic twin
	Familiar tendency (2 - 2.5x than normal population)
	Blood type "0", non-secretor of ABH substance.

Classification of Peptic Ulcer:

	Gastric ulcer (above angle) -- normal or lower acid secretion (antrum or pre-pyloric) --increase acid seeretion
	Duodenal ulcer -- increase acid seeretion
	Post-bulbar ulcer -- extremely high secretion of acid-pepsin
	Esophageal ulcer -- Acid-pepsic irritation consequent to gastro-esophageal reflux.

"Gastrin ulcer":

D.U. -- slow gastric emptying -- distension of antrum - continuous production of gastrin -- antral ulcer.

Stress ulcer:

Severe injury or during illness -- hypotension or shock -- opening of submucosal A-V shunt (stomach) -- blood to bypass the mucosa (ischemia) -- increased permeability of the mucosa to H⁺ ion -- gastric erosions.
　
Stages of Gastric Ulcer: Active Stage Healing Stage
A1 Stage A2 Stage H1 Stage H2 Stage
Scar Stage: S1 Stage (red scar) S2 Stage (white scar)
　
Life Circle of Gastric Ulcer

Gastric Ulcer vs Duodenal Ulcer

D.U./G.U. = 4/1

M/F D.U: 4-8 :1

G.U: 2 :1

Peak age incidence

D.U. : 20-30 y-o

G.U. : 50-60 y-o

Location

D.U. : 0.5cm below P.R., ant. wall > post. wall

G.U. : along L.C., angle (antrum)

Multiplicity, size, & shape

D.U. : Kissing, 1 cm in d., round, linear

G.U. : Single, round or ovoid, 1-2.5 cm in d.

Symptoms

D.U. : typical

G.U. : atypical, or even symptomless

Blood type

D.U. : "0" type

G.U. : not related to blood type

Symptoms of uncomplicated peptic ulcer

Characteristics of ulcer symptoms:

	Chronic: off & on for years
	Periodic: exacerbated at winter, spring
	Rhythmic: 2 or 3 hrs after meals and during the night (1-2 A.M.)

PAIN is the outstanding symptom

	Quality: deep, steady, visceral pain, burning sensation
	Relieved by: food, milk, or alkali within a few min.
	Aggrerated by: alcohol, caffeine, vinegar, or subs. which may injure the mucosa (ASA, etc.)

Localization: upper or mid-epigastrium,

D.U. more on rt side,

G.U. more on lt. side;

radiates to back occasionally.

Usually accompanied with tenderness

Nausea & vomiting associated with severe pain and gastroduodenal spasm.

Atypical symptoms:

Colonic symptom:

1. Irritable bowel manifested by constipation & lower abd.pain

2. Diarrhea

G.U. is more likely with "atypical" pain:

Post-meal pain, pain not relieved by food or alkali

Complications

1. Bleeding

Ulcer penetrate the vascular compartment -- bleeding

75% of peptic ulcers bleed at sometime during their course

Significant blood loss -- less than 30% of patients.

S/S:

Hematemesis -- Coffee ground materials

Melena -- Black shiny stool (tarry stool)

Dark reddish stool

Strong foul odor

S/S of significant blood loss:

	Tachycardia, oral dryness, cold sweating
	Shock (vascular collapse) -- Acute or massive bleeding Elevation of systolic pressure -- Widening of pulse pressure (indicate significant blood loss) -- Hypotention -- shock
	Changes of Hct: Normal Hct initially -- Hct fall a few hrs later - An excellent index of slow bleeding
	Elevation of BUN * Cerebral, cardiac, and renal complications: aged patients

2. Perforation (3 - 5%)

Free perforation -- Chest P-A

Posterior penetration -- UGI Barium meal study.

Free perforation:

Ant. wall, L.C., or G.C. of the stomach or bulb -- perforated into peritoneal cavity

-- Acute chemical peritonitis

-- Bacterial contamination (within 12 hrs.)

-- Walling off by greater omentum

S/S:

Sudden onset of intense and steady pain (upper abd.)

Board-like rigidity of abd. mm.

Posterior penetration (chronic perforation):

D.U.-- retroperitoneum

G.U.-- lesser sac -- localized peritonitis

Penetrating to pancreas, back muscles

S/S:

Previous pain replaced by a more intense, continuous, sharply localized pain in the back.

Much less responsive to food or alkali.

Intractable pain

3. Obstruction (Gastric retension): 10 - 20%

Location of ulcer is very close to the pylorus: D.U., pyloric canal ulcer, or prepyloric ulcer

Transient obstruction:

Mucosal edema + spasm of sm.m. in pyloroduodenal area

Permanent obstruction:
Scarring -- fibrotic stricture -- narrowing of the pyloroduodenal segment ( less than 5 mm in d.)

S/S:

	Vomiting, several hrs following meal or immediately after-eating
	Vomitus contains only food (ingested recontly)
	Splashing sound (+)
	Dehydration & electrolyte inbalance
	Alkalosis -- tetany, confusion or even coma
	Hypokalemia

Treatment:

Decompression

Replacement of fluid and electrolyte

Diagnosis of Peptic Ulcer

1. Symptoms & signs (History taking & physical examination).

2. Upper G-I barium meal study.

3. Endoscopic Examination.

Therapeutic Mechanisms in Peptic Ulcer

A. Improve mucosal resistance to ulceration

B. Eliminate drugs which facilitate ulceration

Salicylates, corticosteroid

Tabacco,esp. cigarette smoking -- delay the healing

C. Reduce acid secretory stimui

	Reduce vagal stimulation:
	Avoid hunger (well fed)
	Minimize emotional stress -- stress of business life, familiar pressure
	Attempt to moderate temper
	Anticholinergics (medical vagotomy)
	Sedetives
	Reduce gastrin secretion:
	Avoid antral distension -- ?small feeding, frequently
	Avoid dilute ethyl alcohol
	Avoid caffeine, seasonings( pepper, ginger, cloves) -- which directly stimulate the parietal cells.

D. Raise intragastric pH ( >3.2)

-- above the optimal levels for protease activity

Alkalinizing Agents

1. Antacids

Absorbable antacids (NaHCO3 etc.) -- systemic alkalosis

Poorly or non-absorbed antacids:

Calcium carbonate, MgO -- intragastric pH up to 5 or 6.
Aluminum hydroxide and Mg trisilicate suspensions

Antacid Tab. less effective than their suspension

Small amounts of antacids (esp. Ca.carbonate) -- absorbed -- mild urinary alkalosis.

If large amounts of dietary Ca (milk & cheese) are also being ingested
- excess Ca precipitate in renal tubules
-- progressive renal dysfunction: "milk-alkali syndrome".

Hypercalcemia -- muscular weakness, fatigue, increased gastric HCl secretion.

2. Muscarinic-receptor Antagonist

3. Gastrin-receptor Antagonist

4. Histamine-2 receptor Anatgonist.

5. Proton-pump (H⁺/K⁺ ATPase) inhibitor

Treatment of uncomplicated peptic ulcer

A. Cytoprotection or Mucosally Active Agents

1. Site Protection Agents

Sucralfate 1 gm q.i.d/ac1h & hs

Colloidal Bismuth Subcitrate (CBS) 120mg q.i.d/ac & hs

(equivalent to DeNol 300 mg q.i.d.)

2. Cytoprotection Agents

Prostaglandin E1 (Cytotec) 200 mg t.i.d. or q.i.d.

B. Acid Neutralization or Inhibition

1. Antacids

	Al-Mg Hydroxide Compound or other poorly absorbed antacids
	After treatment with 7 doses regimen of antacid (1.2 gm of Al-Mg hydroxide compound) for 6 wks, the healing rate of DU achieve 76%

2. Histamine-2 Antagonist

	Cimetidine (Tagamet) 400 mg b.i.d
	Ranitidine (Zantac) 150 mg b.i.d or 300 mg q.d.
	Famotidine (Gaster) 40 mg b.i.d or 80 mg q.d.

After 4~6 wks' treatment, the healing rate of DU achieve 75~80%

3. Gastrin-receptor Antagonist

4. Muscarinic-receptor Antagonist

Pirenzepin 50 mg bid

5. Proton-pump (H⁺/K⁺ ATPase) inhibitor (PPI)

	Omeprazole (Losec) 20 mg q.d. or b.i.d.
	Lansoprazole (Takeprone) 30 mg q.d.

After 4 wks' treatment, the healing rate of DU achieve 90% or more

C. Others

Sedatives

Anticholinergics

Factors reported to increase ulcer recurrence

	Cigarette smoking
	Male gender
	Age at onset
	Long ulcer history
	Use of aspirin/NSAIDs
	Gastric acid hypersecretion
	Treatment of initial ulcer
	Helicobacter pylori (H. pylori)

* H. pylori infection:

The key factor that related to recurrence of duodenal ulcer.

Treatment of peptic ulcer with eradication of H. pylori

I. Triple therapy:

A) The 1st line triple therapy (1+2)

1. Amoxicillin 500 mg + Metronidazole (Flagyl) 250 mg qid for 2 wks

2. One of the followings for 6 wks

	Colloidal bismuth (CBS) 120 mg qid / ac 30' & hs
	Cimetidine 400 mg bid
	Ranitidine 150 mg bid
	Famotidine 20 mg bid

B) Amoxicillin 1 gm bid + Clarithromycin 500mg bid + Omeprazloe 20 mg bid
for 1 wk. follwed by PPI or H2-antagonist therapy

II. Dual therapy:

Amoxicillin 500 mg qid for 2 wks + Omeprazole 20~40 mg q.d. for 4 wks

Recurrence of Peptic Ulcer

	Before the anti-microbial therapy to be introduced, the recurrence rate of DU had been reported to be 50 to 80 % within one year.
	While, using triple therapy or dual therapy, the recurrence rate of DU was markedly reduced to around 10~20% within one yr, after successful eradication of H. pylori.
	However, some problems on the healing & recurrence of DU still remain as follows.

Why the ulcer still recur after a successful eradication of H. pylori?

Is there any factor other than H. pylori related to ulcer recurrence ?

Is the quality of ulcer scar good enough to prevent ulcer recurrence. ?

How to prevent re-infection of H. pylori?

The factors that may contribute to recurrence of the peptic ulcer:

Besides H. pylori infection, the factors that may contribute to recurrence of the DU are:

Lower intragastric pH of healed ulcer.
Marked deformity of the duodenal bulb.
Poor maturity of regenerating mucosa (poor quality) of ulcer scar.
High grade of gastric metaplasia of regenerating duodenal mucosa.
Others.

For problems or questions regarding this web contact [afgalaly@yahoo.com].
Last updated: 07/01/06.

	D.U. more on rt side,
	G.U. more on lt. side;
	radiates to back occasionally.

	Antacid Tab. less effective than their suspension
	Small amounts of antacids (esp. Ca.carbonate) -- absorbed -- mild urinary alkalosis.
	If large amounts of dietary Ca (milk & cheese) are also being ingested - excess Ca precipitate in renal tubules -- progressive renal dysfunction: "milk-alkali syndrome".
	Hypercalcemia -- muscular weakness, fatigue, increased gastric HCl secretion.