Peptic ulcer diseaseSpeaker : 顏宇寬

Outline

� Introduction of peptic ulcer

� Epidemiology and etiology

� Clinical manifestations and diagnosis

� Management of peptic ulcer

� Summary

Introduction of peptic ulcer

disease

Peptic ulcer disease (PUD)

� A defect in the gastric or duodenal mucosa that extends through

the muscularis mucosa into deeper layers of the wall.

� Breaks of mucosal surface

� > 5 mm in size

� Depth till submucosa

� Could be acute or chronic

Peptic ulcer disease (PUD)

� Peptic ulcers encompasses ：

� Gastric ulcers (GUs)

� Duodenal ulcers (DUs)

� Esophageal ulcers (less)

Peptic ulcer disease (PUD)

� Comparison of gastric ulcer and duodenal ulcer

Gastric ulcer Duodenal ulcer

Site often occurs lesser curvature(胃小彎) Near pyloric channel

Food intake Pain accentuated Pain relived

Epidemiology of peptic ulcer

disease

Epidemiology of peptic ulcer disease

� Time trends

� The pathology of gastric ulcer was first defined in 1835, and the duodenal

ulcer was rare until about 1900.

� Gus and Dus have been steadily falling over the past several decades.

� Ulcer incidence increased with age for both GUs and DUs

� Bleeding from PUD is 13-fold higher in individuals >70years versus <40years.

Etiology of peptic ulcer disease

Etiology of peptic ulcer disease

� Peptic ulcer is associated with two major factors：

� Helicobacter pylori infection

� The consumption of nonsteroidal anti- inflammatory drugs(NSAIDs)

� Unusual causes of peptic ulcer disease

Helicobacter pylori infection

Helicobacter pylori infection

� 台灣地區幽門螺旋桿菌的感染率約為50%(人口高達一千多萬人)，而且感染率和年齡有明顯的相關性。

� 十歲以下的感染率約為20% ，二十歲以下的感染率約為35~40%，二十~三十歲的感染率約為50%，三十~四十歲的感染率約為60%，四十歲以上的感染率則超過75%。

� 台灣地區閩南人的感染率較客家人高出許多，原住民則最高。

� Although many people are infected with H. pylori bacteria, only a few get

ulcers.

� The ulcer incidence is about 1 percent per year , a rate that is 6-10-fold higher

than for uninfected subjects.

NSAIDs cause peptic ulcer

� Mechanisms of gastroduodenal protection by endogenous：

� Prostaglandins(PGs) — Many mucosal functions are altered by endogenous prostaglandins and by exogenously administered PGs.

� Some of the cytoprotective mechanisms of PGs include:

� Stimulation of glycoprotein (mucin) secretion by epithelial cells

� Stimulation of bicarbonate secretion by epithelial cells

� Stimulation of phospholipid secretion by epithelial cells

� Enhancement of mucosal blood flow and oxygen delivery to epithelial cells via local vasodilation

� Enhanced epithelial cell proliferation

NSAIDs cause peptic ulcer

� Topical injury (直接傷害)

� NSAIDs 呈弱酸性，可直接對消化道黏膜造成傷害

� 減少胃黏膜之厭水性(hydrophobicity)，因此胃酸及胃蛋白脢可輕易穿透胃黏膜造成傷害

� Systemic injury (全身系統影響)

� 抑制COX-1活性，減少胃黏膜prostaglandins而造成傷害

NSAIDs cause peptic ulcer

� NSAID can injure the gastric and duodenal mucosa, with considerable

morbidity and mortality.

� Aspirin 10 mg/day inhibit gastric PG generation and can damage the stomach,

325 mg QOD increased the risk of duodenal ulcer.

� Ibuprofen, naproxen, indomethacin and ketorolac etc.

NSAIDs cause peptic ulcer

� 在台灣約有25.6%的門診患者使用除了aspirin以外的其他非類固醇類消炎藥(NSAID)；在內視鏡的追蹤下：

� 使用NSAID藥物有20%病患會有消化道潰瘍發生，特別是胃潰瘍。

� 大部分患者沒有臨床症狀產生。

� 其中1~4％會因消化道潰瘍而產生併發症，如出血或胃穿孔。

J intern Med Taiwan 2009 ；20 203-208

Etiology of peptic ulcer disease

�Other etiologies of PUD

� It is important to carefully exclude H. pylori infection and NSAID use.

�There are also a number of other defined mechanisms for peptic

ulcer disease that are much less common but becoming more

evident as the prevalence of H. pylori declines in developed

countries

Unusual cause of PUD

�Drugs other than NSAIDs

�Acetaminophen – dosage up to 2-3 g/day or higher

�Glucocorticoids – increased the risk, and exacerbate NSAID-induced PUD

�Clopidogrel – a significant risk for GI bleeding

�Sirolimus – inhibit wound healing and has been associated with bowel ulceration

�Chemotherapy

Unusual cause of PUD

� Smoking and alcohol

� Zollinger-Ellison syndrome

� A non-beta islet cell tumor secreting gastrin in association with acid hypersecretion

and severe PUD

� Other infection – Herpes simplex virus type I

� Gastric tumors

Clinical manifestations of PUD

Clinical manifestations of PUD

� Asymptomatic

� Peptic ulcer are commonly asymptomatic (70 ％ )

�May later present with ulcer related complications

�Older adults on NSAIDs are more likely to be asymptomatic.

Clinical manifestations of PUD

� Dyspepsia

� Upper abdominal pain is the most prominent symptom in patients with peptic ulcer.

�May have food-provoked symptoms due to gastroduodenal dysmotility：

� Epigastric pain with eating

� Postprandial belching

� Epigastric fullness

� Early satisfy, fatty food intolence

� Nausea and occasional vomiting.

Complications of peptic ulcer

� Bleeding

� Gastric outlet obstructions

� Ulcer related to pyloric channel and duodenum

� Penetration into a solid organ

� Fistulization into a hollow viscus

� Free perforation

Clinical manifestations of PUD

Diagnosis of peptic ulcer disease

Diagnosis of peptic ulcer disease

� The diagnosis of peptic ulcer disease is suspected in patients with dyspepsia,

especially in the setting of

� Nonsteroidal anti-inflammatory drug (NSAID) use

� A history of Helicobacter pylori infection.

� The diagnosis of peptic ulcer disease is definitively established by direct

visualization of the ulcer on upper endoscopy.

Diagnosis of PUD – Upper endoscopy

� On upper endoscopy, benign gastric and duodenal ulcers have smooth,

regular, rounded edges, with a flat, smooth ulcer base often filled with

exudate.

Diagnosis of PUD – Upper endoscopy

� Some endoscopic features that suggest that an ulcer may be malignant

include:

� An ulcerated mass protruding into the lumen

� Folds surrounding the ulcer crater are nodular, clubbed, fused, or stop short of

the ulcer margin

� Overhanging, irregular, or thickened ulcer margins

� All ulcers with malignant features should be biopsied.

� Routine biopsy of benign-appearing duodenal ulcers is not recommended,

as they are unlikely to be malignant.

Diagnosis of PUD – Imaging

� Barium radiography (鋇劑Ｘ光攝影)

� 因為消化道為肉質組織，一般Ｘ光放線攝影無法將它照出來，所以須借助外物使消化道顯影。

� 鋇劑會短暫附著在消化道的黏膜上但不被人體吸收，而Ｘ光無法穿透鋇劑，它在Ｘ光片上呈白色；再配合導入空氣(在Ｘ光片上呈黑色)，可照出雙重對比影像，進而偵測消化道的病灶。

Diagnosis of PUD – Imaging

� Barium radiography

� Infrequently used for the diagnosis of peptic ulcer disease

� The desire to limit radiation exposure to patients

� Limitations inherent to radiography, such as the inability to biopsy for H.

pylori testing and histopathology.

Testing for Helicobacter pylori

Testing for H. pylori – Biopsy urease test

� The basis of the test is the ability of H. pylori to secrete the urease enzyme,

which catalyzes the conversion of urea to ammonia and carbon dioxide.

� Under gastroscopy, a biopsy of mucosa is taken from the antrum of the

stomach, and is placed into a medium containing urea and an indicator

such as phenol red.

Testing for H. pylori – C14 urease breath test

� C14呼吸測試主要是偵測由幽門螺旋桿菌產生的尿素酶（urease），由於尿素酶並不會出現在正常的人類組織上，其它會產生的細菌的尿素酶也不會出現於胃部，所以當尿素酶存在於胃部則可視為幽門螺旋桿菌感染。

� 當有尿素酶存在時，經口服的C14尿素將會被水解成氨（ammonia）與14CO2 ，14CO2 被吸收進入血液循環後再由肺部排出。因此，當呼出氣體中出現大量的14CO2時，就代表是幽門螺旋桿菌的感染。

Testing for H. pylori – Urease breath test

� 病患事前準備: 病患應該停止服用以下藥物：

� 檢查前的30天內停止服用抗生素及鉍製劑（bismuth compounds）。

� 檢查前的兩星期內停止服用Sucralfate與質子幫浦抑制劑（proton pump inhibitors）例如：omeprazole、esomeprazole、lansoprazole、rabeprazole、pantoprazole。

� 2. 病患於檢查前必須禁食六小時以上。

Testing for H. pylori – Stool antigen test

� Stool antigen test

� To check if substance that trigger the immune system to fight an H.

pylori infection (H. pylori antigens) are present in faces.

� Support a diagnosis of H. pylori infection

� Whether the treatment for an H. pylori infection has been successful

Management of PUD

Management of Peptic ulcer disease

� Initial management

� H. Pylori-positive ulcer - eradication of H. pylori

� NSAID-induced ulcer - patients with peptic ulcers should be

advised to avoid NSAIDs.

� Antisecretory therapy - All patients with peptic ulcers should

receive antisecretory therapy to facilitate ulcer healing

H. Pylori-positive ulcer

� Eradication of H. pylori

� All patients with PUD should be tested for infections with H. pylori and

treated

� Eradication of H. pylori even without concurrent acid suppression therapy

heals >90 percent of duodenal ulcers

� A meta-analysis of 24 randomized trials revealed that the 12-month

ulcer remission rates for GUs and DUs were significantly higher in

patients successfully eradicated of H. pylori infection as compared

with those with a persistent infection (97 and 98 % versus 61 and 65 %,

respectively) Aliment Pharmacol Ther 2001; 15:1949.

Treatment regimens for H. pylori

� Initial therapy

� Triple therapy regimen most commonly recommended for first line in treatment

of H. pylori is a therapy with PPI for 7 to14 days.

Triple therapy

Amoxicillin 1g BID

Metronidazole 500 mg BID

Clarithromycin 500 mg BID Lansoprazole 30 mg BID

Omeprazole 20 mg BID

Pantoprazole 40 mg BID

Rabeprazole20 mg BID

Esomeprazole 40 mg QD

Treatment regimens for H. pylori

� Triple therapy

� A meta-analysis suggested that extension of PPI-based triple therapy

from 7 to 14 days was associated with a 5 ~12 % increase in eradication

rates.

� Increasing the doses of PPIs has small effects on eradication rates.

� 在台灣，使用7天標準三合療法的除菌率已可高達82%~94%；7天之標準三合療法在台灣在台灣是適當的。 Gut 2010; 59: 572-8.

Treatment regimens for H. pylori

� Quadruple therapy

� Quadruple therapy consists of a PPI, combined with bismuth

subsalicylate and two antibiotics for 10 to 14 days.

� Non-bismuth containing quadruple therapy for 7 days

Quadruple therapy

PPI Bismuth subsalicylate

524mg QID

Metronidazole 250mg

QID

Tetracycline 500mg QID

or

Doxycycline 100mg TID

Non-bismuth quadruple therapy

PPI Clarithromycin 500mg

BID

Metronidazole 500mg

BID

Amoxicillin 1g BID

Treatment regimens for H. pylori

� Sequential therapy for 10 days

� Multiple randomized trials have demonstrated that sequential therapy

and concomitant quadruple therapy are equally effective for

eradication of H. pylori

5 Days5 Days 5 Days5 Days

PPI BID

+ Amoxicillin 1g BID

PPI BID

+ Clarithromycin 500mg BID

+ Metronidazole 500mg BID

Treatment regimens for H. pylori

�Sequential therapy for 10 days

� 滅菌成功率高達94%，優於7天或10天的標準三合療法。

� 有效根除對clarithromycin有抗藥性的菌株，其對具clarithromycin抗藥性之H. pylori的除菌率高達80%，而目前常用之標準三合療法對clarithromycin抗藥性菌株的除菌率則約只有30%。

Aliment Pharmacol Ther 2000; 14: 715-8.

Treatment regimens for H. pylori

� 高雄地區進行一多中心研究， 收集了232位病人， 隨機給予以esomeprazole為基礎的天連續性治療或以esomeprazole、amoxicillin、clarithromycin和metronidazole組成的7天四合滅菌治療。

� 結果顯示：10天之系列性治療和7天之四合一治療的滅菌成功率相似，都高達92%以上病人之藥物順從性都很好。因此，不含鉍劑之四合療法似乎極具潛力 且使用上也較系列性治療方便。

Clin Gastroenterol Hepatol 2010; 8:36

Treatment regimens for H. pylori

� Levofloxacin based triple therapy for 7-14 days

� Levofloxacin based Quadruple therapy for 10-14days

Levofloxacin containingTriple therapy

PPI BID Amoxicillin 1g BID Levofloxacin 500mg QD

Quadruple therapy

PPI Bismuth subsalicylate

524mg QID

Amoxicillin 500mg BID Levofloxacin 500mg QD

Treatment regimens for H. pylori

第一線治療第一線治療第一線治療第一線治療 使用時間使用時間使用時間使用時間 H. Pylori 清除率清除率清除率清除率 (ACG)

Triple therapy 7~14 days 70~85%

Sequential therapy 10 days > 90%

Non-bismuth containing

quadruple therapy

7 days ~92%

第二線治療第二線治療第二線治療第二線治療 使用時間使用時間使用時間使用時間 H. Pylori 清除率清除率清除率清除率

Quadruple therapy 10~14 days 75~90%

Levofloxacin based triple

therapy

7~14 days 82~92%

第三線治療第三線治療第三線治療第三線治療 使用時間使用時間使用時間使用時間 H. Pylori 清除率清除率清除率清除率

以抗生素敏感性試驗為指引之除菌治療

PPI+ bismuth+

levofloxacin+ amoxicillin

10~14 days ~84%

Eradication confirmation

� Eradication may be confirmed by a urea breath test, fecal antigen test, or

upper endoscopy performed four weeks or more after completion of

therapy

� Eradication should be confirmed in the following situations :

� Patients who have persistent symptoms after H. pylori treatment for dyspepsia

� Patients who had an H. pylori-associated ulcer

� Patients who had gastric mucosa-associated lymphoid tissue (MALT) lymphoma

� Patients who had resection for early gastric cancer

H. Pylori eradication failure

� (1) 抗生素之抗藥性

� 在台北、台中、台南及高雄地區，H. pylori對amoxicillin的抗藥菌株比率是0%1，但是在花東地區，幽門螺旋桿菌對amoxicillin的抗藥菌株比率則高達36%；同時，花東地區，幽門螺旋桿菌對clarithromycin及metronidazole的抗藥菌株比率也比西部地區為高20%。

Clin Gastroenterol Hepatol 2010; 8:36-41. J Gastroenterol Hepatol 2007; 22: 720-3.

� (2) 病人對藥物之順從性不良

� 藥物之副作用 (如clarithromycin有腹痛、腹瀉、嘔吐的副作用；metronidazole有味覺異常、噁心、嘔吐、頭痛、頭暈的副作用)

� 對服藥總量攸關除菌成敗的瞭解不足。

H. Pylori eradication failure

� Proton pump inhibitors play the role of：

� (1)增加抗生素在胃中的穩定度，

� (2)提升胃內pH值，以增加了抗生素對幽門螺旋桿菌之敏感度

� (3)直接抑制細菌生長。當胃內pH值由5.5提升至6.0及7.5時，amoxicillin之MIC90

濃度可自0.5 mg/L降低至0.25mg/L及0.06 mg/L；而clarithromycin之MIC90濃度則可自0.25 mg/L分別降低至0.06 mg/L及0.03 mg/L。

J Intern Med Taiwan 2010; 21:252

� PPI主要由肝臟之CytochromeP450之CYP2C19酵素代謝，CYP2C19具三種基因型，其代謝質子幫浦阻斷劑的能力有所不同。

� 具有「代謝速率快基因型」者，因PPI可持續作用之時間較短，除菌率往往較低

NSAID-induced ulcer

� Patients with NSAID-associated ulcers should be treated with a PPI

for a minimum of eight weeks.

� In patients with peptic ulcers who need to remain on NSAIDs or

aspirin

� Maintenance antisecretory therapy with a PPI should be considered to

reduce the risk of ulcer complications or recurrence.

NSAID-induced ulcer - Antisecretory

therapy

http://www.uspharmacist.com/

http://www.uspharmacist.com/

Treatment during pregnancy and

lactation

� When peptic ulcer disease is diagnosed in a woman who is pregnant, the

focus of treatment is typically acid suppression with PPI, if H. pylori is present,

treatment is typically deferred until after delivery.

� There is some evidence that H. pylori can cause severe nausea/vomiting in

pregnancy, including hyperemesis gravidarum.

Treatment during pregnancy and

lactation

� With the exception of bismuth and tetracycline, the other medications

used for H. pylori eradication are low risk in pregnancy, especially after 14

weeks. This includes ：

� Clarithromycin

� Amoxicillin

� Metronidazole.

Maintenance therapy of peptic ulcer

� Continue maintenance antisecretory therapy with a proton pump inhibitor

in the following high-risk subgroups of patients with peptic ulcer disease

� Giant (>2 cm) ulcer and age >50 years or multiple co-morbidities

� H. pylori-negative, nonsteroidal anti-inflammatory drug (NSAID)-negative ulcer

disease

� Refractory peptic ulcer

� Failure to eradicate H. pylori

� Frequently recurrent peptic ulcers (>2 documented recurrences a year)

� Continued NSAID use

Summary of peptic ulcer disease

Summary of peptic ulcer disease

� Peptic ulcer is associated with two major factors：

� Helicobacter pylori infection

� The consumption of nonsteroidal anti- inflammatory

drugs(NSAIDs)

� Asymptomatic

� Peptic ulcer are commonly asymptomatic (70 ％ )

Summary of peptic ulcer disease

第一線治療第一線治療第一線治療第一線治療 使用時間使用時間使用時間使用時間 H. Pylori 清除率清除率清除率清除率 (ACG)

Triple therapy 7~14 days 70~85%

Sequential therapy 10 days > 90%

Non-bismuth containing

quadruple therapy

7 days ~92%

第二線治療第二線治療第二線治療第二線治療 使用時間使用時間使用時間使用時間 H. Pylori 清除率清除率清除率清除率 (ACG)

Quadruple therapy 10~14 days 75~90%

Levofloxacin based triple

therapy

7~14 days 82~92%

第三線治療第三線治療第三線治療第三線治療 使用時間使用時間使用時間使用時間 H. Pylori 清除率清除率清除率清除率 (ACG)

以抗生素敏感性試驗為指引之除菌治療

PPI+ bismuth+

levofloxacin+ amoxicillin

10~14 days ~84%

Summary of peptic ulcer disease

http://www.uspharmacist.com/

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