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Updates for the Medical Treatment of Peptic Ulcer Disease (PUD)


Updates for the Medical Treatment of Peptic Ulcer Disease (PUD)

Peptic ulcer disease (PUD) is still one of the most common diseases that are extremely important in almost all medical specialties, especially in gastroenterology and general surgery.

The case of any peptic ulceration may vary from a simple superficial ulcer that can be easily healed by medical treatment, to a surgical catastrophe when it perforates, putting someone's life into serious danger if neglected.


As nowadays most of peptic ulcer diseases  are proved to be bacterial in origin, medical treatment proved to be effective in the vast majority of the patients. However, most of them can't cope with current available treatment regimens, so catching up with what’s new in medical treatment is of great importance that helps making patients compliance to treatment regimens better.

 

Historical Background:

If we took a quick glance at history, we'd find that peptic ulcer disease (PUD), was very rarely recognized as symptoms/complications that may cause death, until the beginning of the 19th century. However, few cases were reported, late in the 18th century.


In the 20th century this disease was well recognized and appreciated. However, surgical treatment dominated the first 6o years with various procedures (Total or subtotal gastrectomy/vagotomy etc…), until histamine-2 blockers emerged in the 1970s, and in 1982 Australian physicians Robin Warren and Barry Marshall first identified the link between Helicobacter pylori (H. pylori) and ulcers, concluding that the bacterium, not stress or diet, causes ulcers.


 In 1996, the FDA approved the first antibiotic for the treatment of PUD,  and in 1997, medical researchers sequenced the H.pylori genome, and this discovery helped scientists find more effective and money saving treatment for PUD.


What are the risk factors for developing peptic ulcer disease?

Lifestyle Factors
  • Some studies suggest that smoking can increase the risk of H. pylori and can slow the healing of peptic ulcers.
  • Drinking acidic beverages such as fruit juices and consuming caffeine-containing foods and beverages can cause gastric irritation and increase production of gastric acid. This can make people more susceptible to H. pylori infection.
  • Alcohol in large quantities can cause gastric irritation leading to increased susceptibility to H. pylori .
  • Alcohol taken while using non-steroidal anti-inflammatory agents can further  increase the chance of developing a peptic ulcer.
  • Even in the absence of alcohol misuse, certain anti-inflammatory medications (including aspirin and most other drugs commonly available over-the-counter or by prescription as “non-steroidals”) can increase the risk of peptic ulcer. These drugs are responsible for at least half of all peptic ulcers in elderly persons.
Helicobacter Pylori Infection

Infection with Helicobacter pylori is the most well-defined risk factor for the development of peptic ulcers. People have an increased risk of being infected with H. pylori if they:

  • Live in crowded conditions
  • Live in unsanitary conditions
  • Use certain medications, including:
  1. Non-steroidal anti-inflammatory medications
  2. COX-2 inhibitors
  3. Corticosteroid drugs (although this connection is less clear than the others)
  • Had prior peptic ulcer disease
  • Had Zollinger-Ellison Syndrome
  • Recently had major surgery
  • Recently suffered severe injury or burns
  • Had head trauma
  • Had radiotherapy
  • Have congenital malformations of the stomach and/or duodenum
  • Have specific malignant diseases such as mastocytosis and basophilic leukemia
Age
  • Duodenal ulcers: More common between ages 30-50 years old
  • Gastric ulcer: More common in people over age 60 years old

Gender
  • Duodenal ulcers: Twice as likely in men
  • Gastric ulcers: More common in women

Genetic Factors

Usually, peptic ulcers have familial backgrounds.


Ethnic Background

African-American or Hispanic background are more susceptible to develop PUD.


Other Risk Factors
  • Stress is no longer believed to actually cause ulcers. However, many researchers still believe that stress can play a role in exacerbating symptoms and slowing the healing of pre-existing peptic ulcers.
  • People who have type O blood may develop PUD, though it was previously thought to happen more in people who have type A blood.

 

Diagnosis Of PUD:

Clinically:
History
  • Epigastric pain (the most common symptom):
  1. Burning sensation
  2. Occurs 2-3 hours after meals
  3. Relieved by food or antacids
  4. Pain awakens Patient at night.
  5. Sometimes radiates to the back
  • Nausea
  • Vomiting, which might be related to partial or complete gastric outlet obstruction
  • Dyspepsia, including: belching, bloating, distention, and fatty food intolerance
  • Heartburn
  • Chest discomfort
  • Anorexia, weight loss
  • Hematemesis or melena resulting from gastrointestinal bleeding
  • Dyspeptic symptoms that might suggest PUD are not specific because only 20-25% of patients with symptoms suggestive of peptic ulceration are found on investigation to have a peptic ulcer.
 
Physically:
  • In uncomplicated PUD, clinical findings are few and nonspecific.
  1. Epigastric tenderness
  2. Guaiac-positive stool resulting from occult blood loss
  3. Melena resulting from acute or sub-acute gastrointestinal bleeding
  4. Succussion splash resulting from partial or complete gastric outlet obstruction

N.B:  The timing of the symptoms in relation to the meal may differentiate between gastric and duodenal ulcers: A gastric ulcer would give epigastric pain during the meal, as gastric acid is secreted, or after the meal, as the alkaline duodenal contents reflux into the stomach. Symptoms of duodenal ulcers would manifest mostly before the meal—when acid (production stimulated by hunger) is passed into the duodenum. However, this is not a reliable sign in clinical practice.

 

Investigations:

  • Full blood count may show evidence of iron deficiency anemia
  • Testing for H. pylori:
  1. Blood antibody test. To detect any preformed antibodies to H. pylori bacteria. And that means the patient is either currently infected or has been infected in the past.
  2. Urea breath test. A urea breath tests the presence of H.Pylori bacterium in the stomach showing if the patient is infected. It's also used to see whether H.Pylori infection is eradicated from the body. Unfortunately, breath test is not always available.
  3. Stool antigen test. Stool antigen testing may be done to help support a diagnosis of H. pylori infection or to determine whether treatment for an H. pylori infection has been successful.
  4. Gastric biopsy: During endoscopy, a biopsy can be taken and  several different tests may be done on the biopsy sample.
  • Endoscopy:

-National Institute for Health and Clinical Excellence (NICE) guidelines state that endoscopy is not required unless the patient is presenting for the first time above the age of 55, or there are warning signs.

-Irrespective of age endoscopy is required if there is:

  1. Iron deficiency anemia.
  2. Chronic blood loss.
  3. Weight loss.
  4. Progressive dysphagia
  5. Persistent vomiting.
  6. An epigastric mass.

-In patients aged over 55 years, referral should also be considered if there is:

  1. Previous gastric ulcer.
  2. Previous gastric surgery.
  3. NSAID use.
  4. Pernicious anemia
  5. Family history of gastric carcinoma.

 

Differential Diagnosis:

Biliary colic, cholecystitis, cholelithiasis, acute and chronic gastritis, mesenteric ischemia, GERD (Gastro-esophageal Reflux Disease), acute or chronic pancreatitis, pancreatic cancer.

 

Facts & Numbers:

In USA:
  • About 1 in 10 Americans develop at least one ulcer during their lifetimes.
  • Ulcers affect about 5 million people each year.
  • More than 40,000 people a year have surgery because of persistent symptoms or problems from ulcers.
  • Each year about 6,000 people die of ulcer-related complications.
  • Ulcers can develop at any age, but they are rare among teenagers and even more uncommon in children.

 

Treatment:

Prevention is the keystone of treating any peptic ulcer, and that comprises, stress reduction and lifestyle modifications, quitting smoking, avoiding alcohol, and above all stopping random use of any drugs involved in peptic ulcer formation especially NSAIDs, those should only be used as directed.


All individuals with a diagnosis of PUD must be evaluated and/or treated for H. pylori.


There are many drugs used for treating PUD, (Proton pump inhibitors, H2 blockers, antacids ,etc..) , and if H. Pylori was proved positive then those drugs could be combined with antibiotics (amoxicillin, clarithromycin, metronidazole and tetracycline).


Drugs that reduce gastric acid include proton pump inhibitors (PPIs) and histamine receptor blockers (H2 blockers). Both acid-reducing medicines help relieve peptic ulcer pain after a few weeks and promote ulcer healing. PPIs and H2 blockers work in different ways:

  • PPIs suppress acid production by halting the mechanism that pumps acid into the stomach.
  • H2 blockers work by blocking histamine, which stimulates acid secretion.

It's well known that PPIs cannot eradicate H. pylori. However, researches show they do help fight the H. pylori infection. Moreover, after 4 weeks of treatment, patients taking PPIs had earlier pain relief and better cure rates than those taking H2 blockers.


Bismuth subsalicylate coats ulcers, protecting them from gastric acid. Although bismuth subsalicylate may eradicate H. pylori, it is used with —not in place of— antibiotics in some treatment regimens.


Antibiotic regimens may differ throughout the world because some strains of H. pylori have become resistant to certain antibiotics.


In the United States, clarithromycin-based triple therapy is the standard treatment for an ulcer caused by H. pylori.  The prescription includes  the antibiotic clarithromycin, a PPI, and the antibiotics amoxicillin or metronidazole for 10 to 14 days as follows:

  • Amoxicillin 1 g plus clarithromycin 500 mg plus either lansoprazole 30 mg or omeprazole 20 mg (all taken twice daily), or
  • Clarithromycin 250 mg plus metronidazole 400 mg plus either lansoprazole 30 mg or omeprazole 20 mg (all taken twice daily)

Meanwhile, in the United Kingdom, the drugs chosen are almost the same,  but with different regimen, which is a 7-day triple therapy course, and it's either clarithromycin or amoxicillin based regimen. Because researches show higher cure rates with 14 days of treatment, some doctors now prescribe triple therapy for this longer period.


Bismuth quadruple therapy is another treatment strategy used in the United States. The patient takes a PPI, bismuth subsalicylate, and the antibiotics tetracycline and metronidazole for 10 to 14 days. Bismuth quadruple therapy is used to treat patients in one of several situations, including if the patient:

  • Is sensitive to penicillin
  • Has been treated before with a macrolide antibiotic, such as clarithromycin
  • As a second round of treatment after triple therapy failed to kill the bacteria

NSAIDs Induced Ulcers:

  1. NSAIDS should be stopped if possible, with substitution of acetaminophen.
  2. H. pylori should be ruled out as a causative agent for PUD in patients receiving NSAIDS.
  3. If NSAIDS must be continued, misoprostol is effective in preventing PUD.

 

H.pylori and NSAIDs ; to treat or not to treat?

THE MAASTRICHT III CONSENSUS REPORT, March 2005 :
The report stated that, "H. Pylori eradication is useful in chronic NSAIDs users, but is insufficient to  prevent ulcer related to NSAIDs completely". It also stated that: "In naïve NSAIDs users, H. Pylori eradication may prevent peptic ulcer and bleeding". The researchers also stressed that in patients receiving long term NSAIDs, and with peptic ulceration and/or bleeding, PPI maintenance therapy is more useful than H. Pylori eradication in preventing ulcer recurrence and/or bleeding. It was also stated that "patients with known long term aspirin therapy and who bleed should be tested for H. Pylori infection, and if positive, should receive eradication therapy".

 

Compliance to treatment in PUD:

One of the major problems that arise from the treatment of PUD, was the poor compliance to drugs regimens by the patients, since committing to a fixed time to consume medication, for a relatively long period, plus the number of medications, made it difficult to many patients, as it was proven that about 10% of PUD patients failed to take 60% of the treatment as "LEE" concluded on 1999.


Other factors that influence compliance are related to doctors, therapy costs, patients awareness and side effects.


Poor compliance, especially to antibiotics, leads to subsequent bacterial resistance to therapy. Hence, incomplete eradication of H. pylori and the scenario unfortunately ends as failure of treatment.


In 2004, "Megraud" found that, H.pylori eradication rates with standard regimen (proton pump inhibitor-amoxicillin-clarithromycin) were around 88% when bacterial strains were sensitive to clarithromycin and  around 18 % when those bacterial strains were resistant to clarithromycin.


One of the strategies suggested to help improving patient compliance to therapy is explaining to them, how effective is the eradication of H. pylori, following the regimen, and this is also important in preventing gastric cancer, as it's sometimes related to H. pylori infection.


 In Japan, more than 50% of population know that PUD and H.pylori are related to each other, and understand well that eradication of H. pylori is important to prevent cancer, as "Inoue" said in 2006.

 

Recent Studies:

  1. The Department of Internal Medicine, American University of Beirut Medical Center  published a study titled “Efficacy of two rabeprazole/gatifloxacin-based triple therapies for Helicobacter pylori infection”.  By  Sharara AI, Chaar HF, Racoubian E, Moukhachen O, Barada KA, Mourad FH, Araj GF, on June 9th 2004. This  study showed that a 7-day regimen of gatifloxacin-rabeprazole-amoxicillin is an effective eradication therapy for H. pylori. The use of rabeprazole twice daily results in superior eradication rates including cases of failed primary therapy. This new regimen is simple, well-tolerated, and may lead to higher compliance and lower costs.
  2. On the other side of the world A study published by LIU Man-Fen Lai Huai Lin Chuqing, (Liu Man-Fen, Lai Huai, and Lin Chuqing) China by the title of  “Gatifloxacin-based triple therapy, efficacy of Helicobacter pylori eradication” on June 2008, stated that Gatifloxacin, metronidazole, lansoprazole combination therapy can be safe and effective eradication of Helicobacter pylori and peptic ulcer treatment.
  3. Again from China, The Digestive Disease Centre of the Third People’s Hospital published a paper under the title “Analysis of different protocols in the treatment of Helicobacter pylori” by LI Jun-ying and YU ling in the Hainan Medical Journal June, 2009. The study claimed that employing the protocol of PPI + Clarithromycin + Amoxicillin can eradicate HP effectively and speed up the healing of digestive stomach ulcers.

 

Conclusions and Recommendation:

As there is a strong relation between H .pylori infection and peptic ulcer, physicians should bear in mind how crucial it is to eradicate this bacterium, even in drug induced ulcers, since this eradication may prevent bleeding/or perforation.


A clarithromycin based triple therapy (amoxicillin - clarithromycin, and PPI), is the most popular and most effective therapy.
Therapy duration is 10 - 14 days, with better cure rates than a 7-day course.


Improving the compliance with H. pylori eradication therapy is rather important and can reduce antibiotic resistance and improve cure rates.


The physician should play a partner role in dealing with patients, as this can help patients in sticking to the treatment regimen and understand that eradication of H. pylori is a step to prevent gastric cancer.


Bismuth quadruple therapy helps in eradicating H. pylori, but only indicated if previous treatment failed, or if the patient is sensitive to penicillins.


We hope, a day comes, and all the medications of PUD turn into a single magical pill that heals any peptic ulcer with a 100% compliance.


اضغط هنا للقراءة باللغة العربية

Prepared by: Dr. Adel M.Al-Haj Saleh


Source :

1-PEPTIC ULCER DISEASE, Dr. Anil Minocha http://www.diagnosishealth.com/ulcer.htm
2-Munnangi S. and Sonnenberg A. Time Trends of Physician Visits and Treatment Patterns of Peptic Ulcer Disease in the United States. Arch Intern Med. vol. 175, July 14, 1997. pp 1489-94.
3-Helicobacter pylori in Peptic Ulcer Disease, National Institutes of Health Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease, Journal of the American Medical Association. Volume 272, no. 1. July 6, 1994, pp 65-69.
http://www.cdc.gov/ulcer/history.htm
4-American College of Gastroenterology website. Available at: http://www.acg.gi.org/ . Accessed March 3, 2006.
5-Cecil RL, Goldman L, Bennett JC. Cecil Textbook of Medicine . 21st ed. Philadelphia, PA: WB Saunders Company; 2000.
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13-http://www.umm.edu/digest/ulcers.htm  January  24, 2008
14-http://digestive.niddk.nih.gov/ddiseases/pubs/hpylori/  American college of Gastroenterology
15-http://www.cks.nhs.uk/dyspepsia_proven_peptic_ulcer/management/detailed_answers/treatment_for_helicobacter_pylori
16-Al-Eidan, F.A., McElnay, J.C., Scott, M.G. and McConnell, J.B. (2002) Management of Helicobacter pylori eradication – the influence of structured counselling and follow-up. Br J Clin Pharmacol 53: 163–171.
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