What Are the Extragastric Manifestations of H pylori Infection?

Helicobacter pylori (H pylori) infection is estimated to affect more than 50% of the global population, with an established causative role in peptic ulcer disease, gastric carcinoma, and other GI disorders. In addition, a range of research findings suggest associations between H pylori and numerous extragastric complications, such as hematologic, dermatologic, cardiovascular, and neurologic diseases.1,2

Studies have also shown that eradication of H pylori can lead to resolution or improvement in some of these extragastric manifestations along with related GI complications.2,3 As H pylori infection is underrecognized and undertreated, especially in historically marginalized populations already at greater risk for gastric cancer and other comorbidities linked to H pylori, such findings reinforce the need for timely screening and adequate treatment of this common disease-causing pathogen.4,5

To learn more about the potential systemic effects of H pylori infection and associated clinical recommendations, we interviewed Joseph J. Jennings, MD, gastroenterologist and hepatologist at MedStar Georgetown University Hospital and assistant professor of medicine at Georgetown University School of Medicine in Washington, DC, and Cynthia L. Sears, MD, professor of medicine and oncology at the Johns Hopkins University School of Medicine and professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health in Baltimore. 

What are some of the most prevalent extragastric effects of H pylori infection, and what are the proposed mechanisms driving these links?

Dr Jennings: H pylori infection has been associated with multiple extragastric complications, including iron deficiency anemia (IDA), immune thrombocytopenic purpura (ITP), and chronic spontaneous urticaria (CSU). IDA is thought to be caused by both H pylori’s impact on iron absorption as well as iron losses from gastritis and ulcer disease caused by H pylori.

The mechanisms for ITP and CSU are even less understood. For ITP, molecular mimicry between antigens from H pylori and antigens located on platelets has been suggested as a possible mechanism: The immune system would see antigens from H pylori and develop antibodies that also interact with antigens on platelets. This would result in the immune system creating antibodies that were intended to fight H pylori but now also interact with and destroy platelets.

For CSU, increased gastric mucosal permeability in the setting of H pylori infection can lead to increased food antigen exposure, which may play a role in development of CSU.

Dr Sears: Unexplained IDA associated with H pylori is thought to be due to slow, hard-to-detect blood loss from H pylori-induced gastric inflammation.

B12 deficiency associated with H pylori leads to extragastric clinical signs and symptoms, such as megaloblastic anemia, neuropathy, and cognitive changes, and may accelerate cardiovascular diseases among others. This complication is probably a result of gastric atrophy due to H pylori and autoimmune antibodies — to gastric parietal cells and intrinsic factor, for example — resulting in pernicious anemia.

A large number of other extragastric effects, including metabolic syndrome, cardiovascular disease, and neurologic and neurodegenerative diseases have been suggested, but in my view, a clear scientific basis for these associations has not yet emerged.2

What are the relevant clinical recommendations regarding these findings? Does H pylori eradication tend to resolve the associated extragastric complications?

Dr Jennings: Physicians should be aware of the associations between H pylori and disease processes such as ITP and CSU, as this may prompt them to remember to check for H pylori infection while investigating the presenting symptoms.

For IDA, identifying the signs of anemia, such as fatigue and decreased exercise tolerance, can prompt investigation of hemoglobin levels and iron stores. The workup for IDA often involves endoscopic evaluation in which H pylori can be easily identified and treated.

ITP typically presents with easy bleeding and bruising, with subsequent labs showing a low platelet count.

CSU presents as wheals and swelling that comes and goes for periods greater than 6 weeks. Unlike with IDA, the initial workups for ITP and CSU may not always include testing that will capture H pylori

H pylori eradication is associated with improvement in IDA, ITP, and CSU. For IDA and ITP, the association between eradication of H pylori and improvement in these conditions is strong enough that evaluation for H pylori infection and subsequent eradication of H pylori are included in the guidelines for management of these disease processes as well as B12 deficiency.6

Dr Sears: Typically, when usual causes for these conditions are not evident or a lack of response to usual therapy occurs, then it is good for a clinician to know that these associations may exist, as treatment of H pylori has been reported to reverse the anemia and ITP. In the case of B12 deficiency, parenteral supplementation is required.

What are some of the most important ongoing needs to address gaps in this area?

Dr Jennings: Further research is needed to investigate the mechanisms involved in the connection between H pylori infection and these extragastric complications.   

Dr Sears: H pylori infection is difficult to treat, and antibiotic resistance is an issue.7 Clinicians tend to be unclear about who should be treated, sequencing of medications, therapy toxicities and their management, timing of test of cure, and the importance of adherence.8,9 Medication adherence for treatment of H pylori is a very difficult issue, considerably more difficult for patients than adherence to regimens for other infectious diseases. This is a very complicated topic, with many remaining needs in terms of physician education.


  1. Baj J, Forma A, Flieger W, et al. Helicobacter pylori Infection and extragastric diseases – A focus on the central nervous system. Cells. 2021;10(9):2191. doi:10.3390/cells10092191
  2. Gravina AG, Priadko K, Ciamarra P, et al. Extra-gastric manifestations of Helicobacter pylori infection. J Clin Med. 2020; 9(12):3887. doi:10.3390/jcm9123887
  3. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017;112(2):212-239. doi:10.1038/ajg.2016.563
  4. Huerta-Franco MR, Banderas JW, Allsworth JE. Ethnic/racial differences in gastrointestinal symptoms and diagnosis associated with the risk of Helicobacter pylori infection in the US. Clin Exp Gastroenterol. 2018;11:39-49. doi:10.2147/CEG.S144967
  5. Reichstein J, Parish A, Garbarino S, et al. Variations and racial disparities in Helicobacter pylori guideline adherence for eradication testing. Am J Gastroenterol. 2020;115:S670-S671. doi:10.14309/01.ajg.0000707376.86601.3a
  6. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastricht IV/ Florence Consensus Report. Gut. 2012;61(5):646-664. doi:10.1136/gutjnl-2012-302084
  7. Shiotani A, Roy P, Lu H, Graham DY. Helicobacter pylori diagnosis and therapy in the era of antimicrobial stewardship. Ther Adv Gastroenterol. 2021;14:1-19. doi:10.1177/17562848211064080
  8. Argueta EA, Moss SF. How we approach difficult to eradicate Helicobacter pylori. Gastroenterology. 2022;162(1):32-37. doi:10.1053/j.gastro.2021.10.048
  9. Chen Y, Yuan H, Ye H, et al. Application of a semi-automatic, intensive follow-up for improving efficacy and adherence of Helicobacter pylori eradication therapy: A randomized controlled trial. MicrobiologyOpen. 2021;10(1):e1172. doi:10.1002/mbo3.1172