Ulcers not related to Helicobacter pylori and anti-inflammatories (NSAIDs): how to proceed?

Infection with H. pylori and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are widely accepted as the main causes of peptic ulcer. However, with more effective eradication, better sanitary conditions and widespread use of antibiotics, the prevalence of H. pylori is falling and, consequently, there is an increase in the diagnosis of non-H. pylori ulcers.

The proportion of non-H. pylori and non-NSAID/aspirin ulcers varies quite a bit (from 2 to 35%) according to the time, country and methodology of different studies:

  • A multicenter prospective French study published a decade ago included 713 patients and concluded that 1 in 5 ulcers was not related to either H. pylori or the use of NSAIDs/aspirin.
  • A retrospective Brazilian study published in 2015 (De Carli, DM et al), in turn, identified that, from 1997 to 2000, 73.3% of peptic ulcers were due to positive H. pylori, 3.5% due to NSAIDs, 12.8% due to H. pylori + NSAIDs and 10.4% idiopathic, while, from 2007 to 2010, this proportion became, respectively, 46.4%, 13.3%, 19.9% and 20.5%.

But what would be the other possible etiologies for gastric and duodenal ulcers?

Table 1: Possible etiologies for gastric and duodenal ulcers not associated with Helicobacter pylori and the use of NSAID

Etiology Comment
Neoplasia (Adenocarcinoma, Lymphoma, GIST, Leiomyosarcoma) The possibility of malignancy should always be considered in the case of gastric ulcers (including for this reason we should always biopsy gastric ulcers and always perform an examination to confirm their healing). Adenocarcinoma is the most prevalent (95% of cases). More suspicious characteristics are: necrotic background and raised and irregular edges.
Zollinger-Ellison Syndrome Secondary to gastrinoma (single or multifocal, located in pancreas or small intestine). Patient presents with abdominal pain + diarrhea, with multiple ulcers usually refractory or recurrent. 25 to 30% of patients who develop gastrinoma have multiple endocrine neoplasia type 1 (MEN1 – multifocal primary hyperparathyroidism, pancreatic islet tumors and pituitary adenomas).
Non-NSAID medications (Bisphosphonates, Corticosteroids, Clopidogrel, selective serotonin reuptake inhibitors, potassium chloride) The isolated association of these medications with ulcer disease is controversial, but they certainly have a synergistic action with the use of NSAIDs
Infections – Duodenal colonization by H. pylori- Non-pylori Helicobacter: the most common is Helicobacter heilmannii- Virus (herpes simplex type I, Cytomegalovirus, EBV): the biopsy will be definitive for the diagnosis. – Syphilis- Tuberculosis
Systemic mastocytosis Characterized by infiltration of mast cells in many tissues and symptoms of flushing, itching, tachycardia, abdominal pain and diarrhea. Dyspepsia, ulcers and duodenitis occur in 30 to 50% of cases. It is considered that the production of histamine by mast cells results in excessive stimulation of acid production. Serum tryptase may be increased. In the ulcer biopsy, infiltration of the mucosa by mast cells can be identified.
Ischemic (Arterial or venous disease / Vasculitis) Ischemic ulcers can result from vascular insufficiency secondary to hypotension, vasculitis or thromboembolism. However, they are rare, as there is a rich collateral circulation in the region. Biopsies may suggest ischemia and, in case of suspicion, an abdominal angiotomography may assist.
Drug use Cocaine, crack and amphetamines cause tissue ischemia by vasoconstriction
Post-surgical After subtotal gastrectomy (anastomotic edge ulcer). The etiology can be multifactorial:- Local ischemia- Anastomotic tension- Retained gastric antrum syndrome: when a small portion of the antral mucosa containing G cells remains in the proximal portion of the duodenum. This gastric antrum mucosa at the end of the duodenal loop is then stimulated by the alkaline duodenal environment to continuously secrete gastrin.
Granulomatous diseases (Crohn, Sarcoidosis) – Only 0.3% to 5% of cases of Crohn’s disease involve the upper gastrointestinal tract.
– Gastrointestinal involvement is very rare in sarcoidosis, but when it occurs it mainly affects the stomach. Gastric sarcoidosis can present as an ulcer or as diffuse involvement (similar to plastic linitis).
Hyperparathyroidism Calcium stimulates the release of gastrin, but the clinical relevance of this effect is not certain.
Eosinophilic gastroenteritis It is a rare and heterogeneous clinical condition, which can involve any segment of the gastrointestinal tract. The pathogenesis is not yet well established, but there is an association with atopic conditions, such as asthma, rhinitis and eczema. Laboratory tests show peripheral blood eosinophilia in 70 to 80% of cases and increased serum IgE in up to two thirds of patients. The identification of dense infiltration of eosinophils in the biopsy is a major diagnostic marker.
Stress ulcer Ulcer that occurs due to hospitalization, mainly in patients in the intensive care unit.
Chronic diseases (Cirrhosis, chronic kidney disease, diabetes) These patients generally have lower H. pylori eradication success rates and lower PPI efficacy than those without chronic diseases
Radiotherapy The stomach and duodenum are sometimes involved in the radiation field during the treatment of some tumors. Radiation-induced ulcers are difficult to treat and usually do not heal with conventional anti-acid secretory agents, surgical procedures may be necessary.
Idiopathic –

How to investigate, then, the etiology of the ulcer?

1. Confirm that there really is no H. pylori:

it is necessary to make sure that H. pylori was properly researched. It is considered that the main cause of negative H. pylori ulcer is actually the error in detecting the microorganism. We should check:

  • Was the exam performed in the context of bleeding? If so, it is ideal to repeat. Hemorrhagic peptic ulcer can produce up to 25% false negative results in the urease test;
  • Did the patient stop PPI and antibiotics before endoscopy? For practical purposes, diagnostic tests for H. pylori should be delayed for 4 weeks after the use of antibiotics, bismuth preparations, PPI and H2 blockers.
  • What method used for research? If possible, it is interesting to perform at least two simultaneous tests to increase sensitivity. Histological research should include at least two biopsies of antrum and body.

2. Confirm that the patient really did not use NSAIDs:

Often, the patient forgets that they may have used or does not associate the class with the medication. It is important to actively ask for the medications (name them) and if they did not use treatments, for example, for headache, arthralgia, dental treatment or menstrual cramps. Chinese herbal medicines, compounded medications and alternative therapy products may contain anti-inflammatory compounds, which are not recognized by patients. Also check for the use of ASA, even at low doses.

If we really do not confirm that H. pylori was negative and that there is no report of NSAIDs, we should reinforce some important points in the clinical history:

  • Use of other medications;
  • Use of drugs;
  • History of immunosuppression;
  • History of gastric surgeries or radiation;
  • History of comorbidities, such as Crohn’s Disease, sarcoidosis, systemic mastocytosis, MEN 1 (multifocal primary hyperparathyroidism, pancreatic islet tumors and pituitary adenomas)
  • Associated symptoms, mainly diarrhea (which can be associated with Crohn’s Disease, Zollinger-Ellison Syndrome or systemic mastocytosis);
  • Family history of ulcer or MEN 1.

3. Ulcer biopsy

Although often unspecific, the biopsy of the ulcer (especially gastric) is fundamental for the investigation of less usual etiologies. Immunohistochemical analysis can bring important additional information.

Additional complementary exams should be performed according to clinical suspicion, such as:
– Serum gastrin: If suspicion of Zollinger-Ellison;
– PTH and calcium: Investigation of hyperparathyroidism;
– VDRL: If suspicion of infectious ulcer;
– Serum tryptase: Can assist in the suspicion of systemic mastocytosis.

In patients with an ulcer without a well-established etiology, it is recommended to repeat endoscopy 8 to 12 weeks after treatment, with new biopsies if the ulcer is still present. It may also be interesting to biopsy the duodenum to detect isolated duodenal colonization of HP.

Conclusion

False negative test for H. pylori and failure to detect NSAID use are probably the most common causes of ulcers that apparently have no defined etiology. Once these possibilities are excluded, we should focus on a detailed anamnesis and a careful evaluation of the anatomopathological.

References

  1. Chung CS, Chiang TH, Lee YC. A systematic approach for the diagnosis and treatment of idiopathic peptic ulcers. Korean J Intern Med 2015;30:559–70. doi:10.3904/kjim.2015.30.5.559.
  2. Kim HU. Diagnostic and treatment approaches for refractory peptic ulcers. Clin Endosc 2015;48:285–90. doi:10.5946/ce.2015.48.4.285.
  3. Charpignon C, Lesgourgues B, Pariente A, Nahon S, Pelaquier A, Gatineau-Sailliant G, et al. Peptic ulcer disease: One in five is related to neither Helicobacter pylori nor aspirin/NSAID intake. Aliment Pharmacol Ther 2013;38:946–54. doi:10.1111/apt.12465.
  4. de Carli DM, Pires RC, Rohde SL, Kavalco CM, Fagundes RB. Different frequencies of peptic ulcer related to H. pylori or NSAIDs. Arq Gastroenterol 2015;52:46–9. doi:10.1590/S0004-28032015000100010.
  5. Lanas A, Chan FKL. Peptic ulcer disease. Lancet 2017;390:613–24. doi:10.1016/S0140-6736(16)32404-7.

How to cite this article

Lages RB. Ulcers not related to Helicobacter pylori and anti-inflammatory drugs (NSAIDs): how to proceed? Gastropedia 2023, Vol 1. Available at: https://gastropedia.com.br/gastroenterology/ulcers-not-related-to-helicobacter-pylori-and-anti-inflammatory-drugs-nsaids-how-to-proceed/



How to treat Helicobacter pylori? Understanding how to choose the first-line scheme

The Helicobacter pylori (H. pylori) is the most prevalent chronic bacterial infection in the world, affecting more than half of the population. It is associated with chronic gastritis, which can progress to serious complications such as peptic ulcer, adenocarcinoma, and MALT lymphoma.

Based on current evidence, its eradication has been more broadly recommended, even in the absence of symptoms in many situations. The main references that guide the conduct of H. pylori in Brazil are:

  • IV Brazilian Consensus (2018)
  • Maastricht VI / Florence Consensus (2022)

One of the most important causes of failure to eradicate H. pylori is the increase in resistance to clarithromycin and levofloxacin. Resistance to nitroimidazoles is also common. On the other hand, resistance to amoxicillin and tetracycline is low and stable. These concepts are important both when we think about first-line schemes and retreatment schemes.

The choice of the initial treatment scheme for H pylori considers two main aspects:

  • Local rate of resistance to clarithromycin
  • History of drug allergy

It would be interesting to perform a susceptibility test (molecular or culture) before prescribing antibiotics, but we know that these methods are still extremely scarce (or even almost non-existent) in our daily Brazilian practice.

In areas where there is low resistance to clarithromycin (< 15%), the first-line empirical treatment should be triple therapy with clarithromycin or quadruple therapy with bismuth. A few studies have evaluated the resistance profile of H. pylori in Brazil, identifying resistance of 2.5 to 16.9% to clarithromycin, 5 to 23% to fluoroquinolones, approximately 50% to metronidazole and double resistance to clarithromycin and metronidazole from 7.5 to 10%. Given this, the trend of the Brazilian Consensus is still to consider Brazil as a low resistance area to clarithromycin.

Since Maastricht V (2017) and the IV Brazilian Consensus (2018), an important change in treatment recommendations for H. pylori was the increase in duration from 7 to 14 days in an attempt to increase the eradication rate in the face of the growing increase in bacterial resistance.

The first-line schemes proposed in our country, therefore, are the following:

  • Recommended scheme: OAC – Standard triple therapy with clarithromycin
  • Alternative scheme: BOTM – Quadruple therapy with bismuth
  • Another alternative scheme: OACM – Concomitant quadruple therapy without bismuth. It is an option in areas of higher proven resistance to clarithromycin when bismuth is not available.

Speaking of the availability of colloidal bismuth subcitrate, this medication has been very little available in our country. Currently, it can only be obtained through compounding (and even then with some difficulty). This reminds us of furazolidone, which has been widely used in schemes for the treatment of H. pylori, but which has not been marketed for years in our country.

Penicillin allergy

The eradication of H. pylori in patients with penicillin allergy (reported in up to 3 to 10% of people) is a challenge. Ideally, this allergy should really be proven to have the schemes with amoxicillin available.

According to the Brazilian Consensus, there are two main schemes:

  • Triple therapy with levofloxacin in substitution for amoxicillin (OCL)
  • Quadruple therapy with bismuth (BOTM), as previously mentioned

Adverse effects

Unfortunately, up to 50% of patients experience side effects with H. pylori treatment. In less than 10%, these effects are limiting and lead to therapy interruption. It is therefore always important to properly inform patients about the most common side effects to increase adherence:

  • Amoxicillin: Diarrhea, skin rash
  • Clarithromycin: Nausea, vomiting, abdominal pain, metallic taste, rarely QT prolongation

Do probiotics help?

Probiotics (such as Lactobacilli and Saccharomyces boulardii) reduce the side effects associated with eradication therapy and, with this, can increase adherence. There are studies on direct effects on H. pylori, but more data are still needed.

It is necessary to check curability? When?

Yes. It should be performed at least 4 weeks after treatment. Ideally, non-invasive methods should be preferred, reserving endoscopy only if indicated for another reason (e.g., gastric ulcer cure control).

Conclusion

The H. pylori is extremely common and its eradication can often be a challenge. The standard triple therapy (OAC) in Brazil provides cure rates above 80% and is still the most used. However, we must be aware of the growing levels of bacterial resistance to constantly update our recommendations.

How to cite this article

Lages RB. How to treat Helicobacter pylori? Understanding how to choose the first-line scheme. Gastropedia 2022. Available at https://gastropedia.pub/en/gastroenterology/how-to-treat-helicobacter-pylori-understanding-how-to-choose-the-first-line-scheme

References

[1] Malfertheiner P, Megraud F, Rokkas T, Gisbert JP, Liou JM, Schulz C, et al. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut 2022;71:1724–62. doi:10.1136/gutjnl-2022-327745.
[2] Coelho LGV, Marinho JR, Genta R, Ribeiro LT, Passos M CF, Zaterka S, et al. IVth Brazilian Consensus Conference on Helicobacter pylori infection. Arq Gastroenterol 2018;55:97–121. doi:10.1590/s0004-2803.201800000-20.



Endoluminal Functional Lumen Imaging Probe (EndoflipTM): understanding the technology and its potential uses

The EndoflipTM is an innovative technique that uses impedance planimetry technology to assess the distensibility of gastrointestinal organs.

Despite being developed in 2009, its use is still restricted to research environments due to high costs and the need for more evidence for better standardization of the method.

It consists of a catheter that has at its distal end a distensible balloon of 8 or 16 cm (Figures 1 and 2). In this balloon, there are 16 pairs of impedance planimetry sensors, which are capable of measuring the cross-sectional area of a plane of the organ (planimetry) using the electrical resistance (impedance) of the fluid in the balloon.

At the distal end of the catheter, there is also a pressure transducer, which is responsible for measuring the pressure inside the balloon. Thus, by dividing the cross-sectional area by the pressure, we can determine the Distensibility Index in response to volume-controlled distension.

Figure 1: Representation of the EndoflipTM monitor (Su B et al, 2020).
Figure 2: Representation of the EndoflipTM catheter taking measurements in the lower esophageal sphincter (Hirano et al, 2017).

Most of the studies with EndoflipTM have been carried out for esophageal evaluation. For this, the catheter is introduced with the patient sedated, usually after upper digestive endoscopy.

With the introduction of EndoflipTM 2.0 in 2017, a topography system was also associated, which allows the evaluation of esophageal motility (whether absence of waves, whether abnormal retrograde contractions or normal anterograde contractions) – Figure 3.

Figure 3: Unaltered exam, presenting esophagogastric junction with normal distensibility and normal anterograde contractions (Dorsey YC et al, 2020).
Figure 3: Unaltered exam, presenting esophagogastric junction with normal distensibility and normal anterograde contractions (Dorsey YC et al, 2020).

The potential applications of the method are:

1. Evaluation of dysphagia and achalasia

  • Highlight in those patients with clinical suspicion of achalasia, but diagnostic doubt due to normal relaxation of the esophagogastric junction (EGJ) in manometry exam;
  • Usefulness in patients who cannot perform manometry due to not tolerating the discomfort of the probe (EndoflipTM is performed sedated);
  • Distensibility index of the EGJ > 3 mm2/mmHg and anterograde contractions suggest normality (Figure 3);
  • Distensibility index £ 1.6 mm2/mmHg of the EGJ, as well as absence of contractions (figure 4) or repetitive retrograde contractions (figure 5) suggest achalasia.
  • In cases of manometric diagnosis of EGJ flow obstruction, the Distensibility Index of the EGJ < 2 mm2/mmHg is associated with better symptomatic response to therapies similar to achalasia, while values > 3 mm2/mmHg are favorable to conservative follow-up.
Figure 4: Esophagogastric junction with reduced distensibility and absence of contractions, suggesting Type I Achalasia (Dorsey YC et al, 2020).
esophagogastric-junction-with-reduced-distensibility-type-3-achalasia.jpg
Figure 5: Esophagogastric junction with reduced distensibility and repetitive retrograde contractions, suggesting Type III Achalasia (Dorsey YC et al, 2020).

2. Intraoperative use to guide adjustments in myotomies and fundoplications

  • In myotomies, values of Distensibility Index of the EGJ between 4.5 and 8.5 mm2/mmHg suggest better results (Figure 6);
  • In fundoplications, values of Distensibility Index of the EGJ between 2 and 3.5 mm2/mmHg were associated with lower index of dysphagia and reflux after procedure.
Figure 6: Distensibility Index of the Esophagogastric Junction before and after myotomy in a patient with achalasia (Su B et al, 2020)

3. Evaluation in eosinophilic esophagitis

  • Identify esophageal distensibility, in order to identify fibrostenotic narrowings that are not always well evaluated by endoscopy.
  • Potential benefit in patients who persist with dysphagia despite histological remission, possibly guiding possible dilations.

4. Other potential uses

  • Evaluate pyloric distensibility in patients suspected of gastroparesis
  • Evaluate anal canal in patients with incontinence.

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How to cite this article

Lages RB., Endoluminal Functional Lumen Imaging Probe (EndoflipTM): getting to know the technology and its potential uses. Gastropedia, 2022. Available at: https://gastropedia.com.br/gastroenterologia/esofago/endoluminal-functional-lumen-imaging-probe-endofliptm-conhecendo-tecnologia-e-seus-potenciais-usos/

Bibliographic References

  1. Dorsey YC, Posner S, Patel A. Esophageal Functional Lumen Imaging Probe (FLIP): How Can FLIP Enhance Your Clinical Practice? Dig Dis Sci 2020. Online ahead of print. doi:10.1007/s10620-020-06443-8.
  2. Hirano I, Pandolfino JE, Boeckxstaens GE. Functional Lumen Imaging Probe for the Management of Esophageal Disorders: Expert Review From the Clinical Practice Updates Committee of the AGA Institute. Clin Gastroenterol Hepatol 2017;15:325–34. doi:10.1016/j.cgh.2016.10.022.
  3. Su B, Novak S, Callahan ZM, Kuchta K, Carbray JA, Ujiki MB. Using impedance planimetry (EndoFLIPTM) in the operating room to assess gastroesophageal junction distensibility and predict patient outcomes following fundoplication. Surg Endosc 2020;34:1761–8. doi:10.1007/s00464-019-06925-5.
  4. Su B, Dunst C, Gould J, Jobe B, Severson P, Newhams K, et al. Experience-based expert consensus on the intra-operative usage of the endoflip impedance planimetry system. Surg Endosc 2020. doi:10.1007/s00464-020-07704-3.