Radiol Oncol 2024; 58(2): 186-195. doi: 10.2478/raon-2024-0028 186 review Pathogenesis and potential reversibility of intestinal metaplasia − a milestone in gastric carcinogenesis Jan Drnovsek1,2, Matjaz Homan2,4, Nina Zidar2,3, Lojze M Smid1,2 1 Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 4 Department of Gastroenterology, Hepatology and Nutrition, University Children’s Hospital, Ljubljana, Slovenia Radiol Oncol 2024; 58(2): 186-195. Received 03 November 2023 Accepted 19 March 2024 Correspondence to: Lojze M Šmid, M.D., Ph.D., Department of Gastroenterology, University Medical Centre Ljubljana, SI-1000 Ljubljana, Slovenia. E-mail: alojz.smid@kclj.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Non-cardia gastric cancer remains a major cause of cancer-related mortality worldwide, despite declining incidence rates in many industrialized countries. The development of intestinal-type gastric cancer occurs through a multistep process in which normal mucosa is sequentially transformed into hyperproliferative epithelium, fol- lowed by metaplastic processes leading to carcinogenesis. Chronic infection with Helicobacter pylori is the primary etiological agent that causes chronic inflammation of the gastric mucosa, induces atrophic gastritis, and can lead to intestinal metaplasia and dysplasia. Both intestinal metaplasia and dysplasia are precancerous lesions, in which gas- tric cancer is more likely to occur. Atrophic gastritis often improves after eradication of Helicobacter pylori; however, the occurrence of intestinal metaplasia has been traditionally regarded as “the point of no return” in the carcinogen- esis sequence. Helicobacter pylori eradication heals non-atrophic chronic gastritis, may lead to regression of atrophic gastritis, and reduces the risk of gastric cancer in patients with these conditions. In this article, we discuss the patho- genesis, epigenomics, and reversibility of intestinal metaplasia and briefly touch upon potential treatment strategy. Conclusions. Gastric intestinal metaplasia no longer appears to be an irreversible precancerous lesion. However, there are still many controversies regarding the improvement of intestinal metaplasia after Helicobacter pylori eradi- cation. Key words: Helicobacter pylori; intestinal metaplasia; gastric cancer Introduction The global burden of gastric cancer remains high, ranking fifth for incidence and third for cancer- related mortality worldwide. Early recognition of the disease can lead to potentially successful treat- ment; however, most patients are diagnosed at a late stage.1(1) H. pylori is the main risk factor for non-cardia gastric cancer development. Although most H. pylori-positive individuals remain asymp- tomatic, the infection predisposes them to the development of chronic gastritis2, which can be followed by the inflammation–atrophy–metapla- sia–dysplasia– carcinoma sequence, known as the Correa cascade.3 Both chronic atrophic gastritis and intestinal metaplasia are considered precan- cerous conditions, as they independently confer risk for the development of dysplasia and gastric cancer.4 H. pylori infection is associated with a 3-fold increase in the lifetime risk for developing non- cardia gastric cancer, and H. pylori infection is be- lieved to cause at least 75% of all gastric cancer.5 The eradication reduces the risk of gastric cancer Radiol Oncol 2024; 58(2): 186-195. Drnovsek J et al. / Pathogenesis and potential reversibility of intestinal metaplasia 187 in patients with non-atrophic and atrophic gastri- tis and effectively heals non-atrophic chronic gas- tritis. It may also lead to the regression of atrophic gastritis.6 On the other hand, short-term cancer risk in patients with established intestinal meta- plasia does not seem to change significantly with H. pylori eradication7,8, and intestinal metaplasia has thus been considered irreversible. This con- cept has been challenged in recent years by stud- ies with longer follow up, in which regression of intestinal metaplasia has been observed after H. pylori eradication.9,10 This short review summariz- es the role of H. pylori in intestinal metaplasia and non-cardia gastric cancer, reviews gastric intesti- nal metaplasia pathogenesis, and briefly discusses evidence regarding its reversibility. The following keywords and MeSH terms were used for online searches: [(gastric) AND (metapla- sia) OR (intestinal) AND ((regression) OR (revers- ibility) OR (reversible))]. Reference lists of suitable studies and related previous review articles were reviewed manually to increase search yield and identify other related studies. All searches were restricted to original studies published in the English language. Helicobacter pylori infection and intestinal metaplasia H. pylori, a microaerophilic, spiral-shaped, Gram- negative bacterium, colonizes the gastric epithe- lium in over half of the adult population world- wide. Its prevalence varies widely, ranging from 30% in industrialized regions to 90% in develop- ing countries and Eastern Asia.11,12 H. pylori stands as the most potent single risk factor for non-cardia gastric cancers, including adenocarcinoma and lymphoma13 and was classified as a class I carcino- gen by the International Agency for Research on Cancer (IARC) and the World Health Organization (WHO) in 1994. Gastric adenocarcinoma is gener- ally divided into two main histological subtypes: diffuse and intestinal, and H. pylori contributes to the risk of both.14 Diffuse-type gastric adenocarcinomas, charac- terized by poorly differentiated infiltrating neo- plastic cells without a clear glandular structure, predominantly occur in younger patients. Their development does not require long-standing chronic inflammation, and H. pylori’s exact role in this subtype remains unclear. Diffuse-type cancer is associated with interference in cell adhesion, polarity, and proliferation, all caused by H. pylori infection, leading to the cleavage of E-cadherin, abnormal intracellular accumulation of β-catenin, TP53 mutations, and reduced p27 protein expres- sion.15 On the other hand, intestinal-type gastric adenocarcinoma emerges later in life and consists of irregular glandular structures formed by well- differentiated cancer cells. This type represents the terminal phase of the chronic inflammation-at- rophy-metaplasia-dysplasia-carcinoma sequence, initiated by H. pylori-induced gastritis.16 Atrophic gastritis and gastric intestinal metaplasia, which evolve over decades of chronic infection, are thus established pre-neoplastic lesions for intestinal- type gastric adenocarcinoma.17 This sequence al- lows for the possibility of primary prevention strategies involving either population-based or targeted screening to identify patients with pre- cancerous lesions who may need subsequent sur- veillance.18 H. pylori utilizes urease activity to neutralize the acidic conditions in the host stomach at the in- fection’s onset. The bacterium’s flagella-mediated motility enables movement toward host gastric epithelium cells. This movement, followed by in- teractions between bacterial adhesins and host cell receptors, facilitates successful colonization and persistent infection. Some strains of H. pylori re- lease effector proteins and toxins, such as cytotox- in-associated gene A (CagA) and vacuolating cy- totoxin A (VacA), which can damage host tissue.19 A direct correlation exists between the number of virulence factors in an H. pylori strain and the frequency of associated advanced gastric mucosa pathology.20 However, the characterization of H. pylori virulence genes’ individual roles is complex due to the interaction of methodological21, bacte- rial, and host factors19, often leading to conflicting results and interpretations. Intrabacterial urease activity is required for H. pylori acid resistance, and this activity is regulated by the proton-gated urea channel UreI, which per- mits urea entry only under acidic conditions and thus prevents lethal alkalization during times of relative neutrality. The urease gene cluster is com- posed of seven genes, including catalytic subunits (ureA/B), an acid-gated urea channel (ureI), and ac- cessory assembly proteins (ureE-H).22 Urease can also protect against host innate immune response by modulation of phagosome pH following phago- cytosis and promotion of H. pylori survival inside megasomes.23 Flagella-mediated motility is essential for colo- nization of the gastric mucosa by H. pylori. Loss of any component of the motility and chemo- taxis systems abolishes the ability of H. pylori to Radiol Oncol 2024; 58(2): 186-195. Drnovsek J et al. / Pathogenesis and potential reversibility of intestinal metaplasia188 infect the stomach and establish colonization.24-26 Infection with H. pylori that exhibits higher motil- ity may show enhanced bacterial density, trigger- ing a more pronounced inflammatory response in the upper stomach, and can thus be associated with severe pathological outcomes.27 The flagellar filament consists of two flagellins (FlaA and FlaB) encoded by flaA and flaB.28 FIaA elicits host anti- body response and can be used as a marker of H. pylori infection; host anti-FlaA titer correlates with H. pylori colonization density29 and the presence of gastric intestinal metaplasia.30 The interaction of bacterial adhesins with host cellular receptors protects H. pylori from displace- ment by the forces generated by peristalsis. This bacterial adherence plays an important role in both the initial colonization and long-term persistence of H. pylori in the human gastric mucosa31 and is necessary for the tight adherence of the bacteria to gastric epithelial cells, which facilitates subse- quent delivery of bacterial toxins.32 The H. pylori genome encodes a variety of outer membrane pro- teins (OMPs); several OMPs have been described in detail to date, with most studies focusing on babA2, oipA, homB, and sabA genes.19 BabA is one of the most studied H. pylori adhesins. BabA is capable of binding to Lewis b and related ABO antigens on gastric epithelial cells33, which may play a crucial role in the development of H. pylori related gastric pathology such as severe gastritis, peptic ulcers, and gastric adenocarcinoma.21,34 BabA positive strains appear to be associated with worse clini- cal outcomes in several studies35-37, while another study found no correlation between the presence of babA2 positive strains and atrophy or intestinal metaplasia.21 HomB may be strongly associated with gastric cancer in certain populations38 and display little measurable virulence in others.39 Attachment of cagA-positive H. pylori to host gastric epithelial cells initiates and facilitates the formation of the bacterial type IV secretion sys- tem, involved in the delivery of CagA into host epi- thelial cells.32 The translocated CagA protein local- izes to the inner surface of the plasma membrane via interactions with phosphatidylserine and sub- sequently undergoes tyrosine phosphorylation by the Src family protein tyrosine kinase. However, once injected into the cytoplasm, CagA can alter host cell signaling in both a phosphorylation-de- pendent and phosphorylation-independent man- ner. The phosphorylated CagA binds to the phos- phatase SHP-2, forming CagA-SPH-2 complex, and affects the adhesion, spreading, and migration of the cell.40,41 CagA can also affect the host cell in a phosphorylation-independent manner by stimu- lating the gastric epithelium cells to secrete IL-8, which strongly affects the level of mucosal inflam- mation.42,43 The CagA-SHP-2 complex is predominantly lo- cated in atrophic gastric mucosa and is associated with the transition to atrophic gastritis and pos- sibly intestinal metaplasia.41 Deregulation of the SHP-2 role by CagA is functionally similar to the effect of the gain-of-function mutation of the SHP- 2 gene observed in other human malignancies.44 CagA interference with intracellular signaling may thus lead to deregulation of cellular growth, apop- tosis, and elevated cell motility. This can result in increased cell turnover, which in turn leads to the accumulation of further genetic changes favoring neoplastic cell transformation.45 Unsurprisingly, infection with cagA-positive strains markedly in- FIGURE 1. Gastric intestinal metaplasia, endoscopic (A, B) and histological (C, D) appearance. Gastric intestinal metaplasia is endoscopically characterized by the presence of grey-white velvety or slightly nodular elevated patches, which are clearly demarcated against the surrounding pink gastric mucosa, as illustrated in image A of antral gastric mucosa under white light. Narrow band imaging (NBI, depicted in image B) further enhances the visualization of mucosal and vascular patterns by employing optical filters to narrow the bandwidth of light. This technique offers superior contrast compared to white light endoscopy, thereby improving the detection of metaplastic transformation. Histologically, gastric intestinal metaplasia can be classified into either complete (as seen in image C) or incomplete types (as shown in image D). Image C demonstrates preserved oxyntic mucosa (on the left) adjacent to intestinal metaplasia of the complete type, which features enterocytes with a well-defined brush border, alongside well-formed goblet cells and Paneth cells. In contrast, image D illustrates the intestinal metaplasia of the gastric mucosa of the incomplete type, characterized by goblet cells of variable size and intervening mucin-secreting columnar cells that lack a brush border (both images are hematoxylin and eosin- stained, original magnification 10x). A B C D Radiol Oncol 2024; 58(2): 186-195. Drnovsek J et al. / Pathogenesis and potential reversibility of intestinal metaplasia 189 creases the risk of gastric cancer.46 CagA-positive strains are responsible for 60% of H. pylori infec- tions in individuals worldwide.47-49 Strains isolated in East Asian countries such as Japan, China, and Korea are almost all CagA-positive.50 Furthermore, CagA protein can be divided into the Western-type CagA and East Asian-type CagA. The affinity of the East Asian-type CagA to SHP-2 is significantly higher than that of the Western-type CagA and is more likely to be associated with gastric cancer.40,51 VacA, another key toxin involved in H. pylori pathogenesis, binds to host epithelial cells after secretion from the bacteria. It is then internalized and causes the accumulation of large intracellular vesicles (vacuolation), interferes with mitochon- dria, and causes apoptosis of host cells.52 VacA also appears to disrupt the balance of cell proliferation and death by affecting genes that regulate the cell cycle.53 H. pylori strains producing VacA differ in the potency of cytotoxin, in both its activity (al- lele s1 is more active than s1) and binding (allele m1 is more effective than m2).54 A meta-analysis of 33 studies (1,446 cases and 2,697 controls in to- tal) confirmed the correlation between the vacA s1 genotype and the risk of atrophic gastritis, intes- tinal metaplasia, and gastric cancer. The vacA m1 genotype was associated with intestinal metapla- sia and gastric cancer but did not significantly cor- relate with atrophic gastritis.55 Pathogenesis of gastric intestinal metaplasia Gastric intestinal metaplasia is defined as the re- placement of normal gastric epithelium in the antral or oxyntic mucosa with intestinal epithe- lium, consisting of intestinal cell types including Paneth, goblet, and absorptive cells.56 These meta- plastic glands are characterized by modification of the surrounding stroma and by reorganization of the crypts, with displacement of the prolifera- tive zone from the neck region to the base of the crypts.57 Intestinal metaplasia can be classified as either limited (when confined to one anatomical region) or extensive, if two gastric regions are in- volved (Figure 1). Complete intestinal metaplasia is characterized by small intestinal-type mucosa with mature ab- sorptive cells, and a brush border, with a notable loss of gastric mucin markers (MUC1, MUC5AC, MUC6) and an acquisition of the intestinal mucin TABLE 1. Patients’ related predictive risk factors for gastric intestinal metaplasia Risk Factor Odds ratio (OD) Key findings References Race White Asian Hispanic 1 2.83–3 2.10–5.6 Hispanic and Asian patients have an increased risk for GIM Tan MC et al. (2022)94 Akpoigbe K et al. (2022)95 Age (> 50 years) 1.5–2.03 Risk increases with age, possibly due to accumulated exposure to risk factors. Aumpan N et al. (2021)96 Tan MC et al. (2020)97 Male gender 1.55–2.09 Probably due to genetics and exposure to other risk factors Aumpan N et al. (2020)98 Leung WK et al. (2005)99 Chronic gastritis 3.68–5.76 Chronic inflammation is leads to IM. Yoo YE et al. (2013) 100 Tatsuta M et al. (1993)101 H. pylori infection 2.47–3.65 Strong correlation with IM, especially with CagA positive strains. Aumpan N et al. (2021)96 Nguyen T et al. (2021)102 Family history of gastric cancer 1.5–3.8 Patients with a first-degree relative with gastric cancer have an increased risk of neoplastic progression Nieuwenburg SAV et al. (2021)103 Reddy KM et al. (2006)104 Alcohol consumption 1.27–1.54 Alcohol intake was independently associated with increased risk of developing AG and IM Holmes HM et al. (2021)105 Kim K et al. (2020)106 Tobacco smoking 1.54–2.75 Tobacco smoking is a risk factor for gastric IM. Morais S et al. (2014) 107 Thrift AP et al. (2022)108 Blood group A 1.39–1.42 Blood group A is associated with higher risk of GIM Mao Y et al. (2019) 109 Rizatto C et al. (2013)110 Bile reflux unknown Bile acids not only interefere with gastric mucosa but also regulate multiple carcinogenic pathways Wang M et al. (2023)111 Yu J et al. (2019)112 Salt consumption 0.37–1.53 Salt intake may increase progression to advanced gastric precancerous lesions Dias-Neto M et al. (2010)113 Song JH et al. (2017)114 Industrially processed food unknown Dietary exposure to N-nitroso–containing compounds has been shown to increase the promotion of gastric carcinogenesis Wiseman M (2008)115 Jencks DS et al. (2018)116 Radiol Oncol 2024; 58(2): 186-195. Drnovsek J et al. / Pathogenesis and potential reversibility of intestinal metaplasia190 MUC2. On the other hand, incomplete intestinal metaplasia is characterized by columnar “inter- mediate” cells at various differentiation stages, irregular mucin droplets, and a lack of a brush border, while still maintaining gastric mucin markers alongside the presence of intestinal mucin MUC2.58,59 Earlier gastric metaplasia classifications relied on traditional mucin staining methods (such as periodic acid-Schiff, Alcian blue, and high iron diamine) and cell morphology. This methodology defined three intestinal metaplasia grades: Type I, which encompasses absorptive cells, Paneth cells, and goblet cells that secrete sialomucins; Type II, consisting of goblet and columnar cells secreting sialomucins; and Type III, involving goblet and columnar cells secreting sulfomucins. Presently, Type I aligns with the complete type, while Types II and III correspond to the incomplete type in the contemporary classification.58 The Correa cascade is a widely accepted model of the pathogenesis of gastric cancer (Figure 2).3 This cascade commences with the emergence of chronic mucosal inflammation, mediated by poly- morphonuclear and mononuclear cells. It evolves through a multifactorial process, steered by vari- ous factors including H. pylori, host genetics, envi- ronmental elements, and diet, propelling further alterations in the gastric mucosa towards atrophy, metaplasia, and ultimately, cancer.60-62 Annually, an estimated 0.1%, 0.25%, 0.6%, and 6% of Western patients with atrophic gastritis, intestinal metaplasia, and mild-to-moderate or severe dysplasia, respectively, progress to gastric cancer.62 In contrast, East Asian populations dem- onstrate a higher risk, with about 1.8%, 10%, and 73% of patients with atrophic gastritis, intestinal metaplasia, and dysplasia, respectively, progress- ing to gastric cancer each year.63 Patients with in- complete intestinal metaplasia encounter a 3.3-fold higher relative risk of developing gastric cancer compared to those with complete intestinal meta- plasia. Furthermore, extensive intestinal metapla- sia is linked with a 2.1-fold higher relative risk of progression compared to limited gastric metapla- sia.64,65 Host factors that are associated with higher risk for non-cardia gastric cancer are similar to risk factors for development of intestinal metaplasia (Table 1) and include advanced age, male sex, fam- ily history, and smoking. More than two thirds of all gastric cancers are diagnosed after the age of 55, and roughly two thirds of non-cardia cancers are found in male patients.66 The reason for the latter observation is most likely multifactorial. The dif- ference can be partly attributed to smoking (which is more prevalent in men) and partly to the protec- tive role of estrogen, since increased fertility and late menopause both reduce the risk of gastric can- cer in women.67 Individuals with blood type A have a 20% higher chance of developing gastric cancer when compared to other blood types, according to a prospective blood donor cohort study.68 Ethnicity also plays an important role in gastric cancer risk. The incidence of non-cardia gastric cancer in individuals of African-American, East Asian, or Pacific Islander descent is almost twice that observed in Caucasians.69 A similar pattern was seen in the analysis of intestinal metaplasia H. pylori and its  virulence factors Normal gastric mucosa Superficial chronic gastritis Atrophic gastritis Dysplasia Carcinoma Intestinal metaplasia Reactive oxygen species,  nitric oxide metabolites Loss of gastric acidity,  bacterial overgrowth, N- nitroso compounds Tobacco, high salt diet FIGURE 2. Pathogenesis of intestinal metaplasia and gastric adenocarcinoma – the Corea cascade. This stepwise process starts with chronic gastritis triggered by H. pylori infection. The likelihood of developing gastric cancer is higher in individuals infected with virulent strains of H. pylori, unhealthy diets (rich in salt and smoked foods), low iron levels, and harmful lifestyle choices, including smoking. Persistent inflammation results in the damage and eventual loss of acid-producing parietal cells, causing reduced stomach acidity (hypochlorhydria) and eventually no stomach acid production (achlorhydria). This reduction in acidity allows for the colonization of the stomach by detrimental, pro-inflammatory microbiota. These bacteria can produce genotoxic and pro-inflammatory metabolites and carcinogens, directly contributing to the transformation of stomach epithelial cells into malignant cells. Radiol Oncol 2024; 58(2): 186-195. Drnovsek J et al. / Pathogenesis and potential reversibility of intestinal metaplasia 191 prevalence. A study that reviewed 800,000 gastric biopsies taken in the United States showed 20% prevalence of gastric metaplasia in people of East Asian descent, 12% prevalence in Hispanics, and 8% in all other ethnic backgrounds.62 Tobacco smoking is the second most important environmental factor in gastric cancer pathogen- esis, accounting for 11% of all cases.70 Tobacco use increases the risk of intestinal metaplasia and dou- bles the risk of its progression to dysplasia, accord- ing to a large Chinese population-based study.71 Bile acid reflux into the gastric lumen produces repetitive gastric mucosal injury, which predis- poses patients to intestinal metaplasia and gastric cancer in H. pylori-positive patients.72 Bile acids increase the expression of CDX2, an intestinal- specific transcription factor that directs and main- tains intestinal differentiation in gastric mucosa73, and indirectly damage cellular DNA by induction of oxidative stress and production of reactive oxy- gen species74, which promote intestinal metaplasia and the further accumulation of mutations, lead- ing to increased cancer risk. The role of diet (being an obvious potential factor in gastric disorders) has been extensively studied in gastric cancer pathogenesis. High salt consumption is associated with increased risk of H. pylori infection and upregulation of cagA ex- pression.75,76 Dietary use of processed or preserved meat using smoke or salt is positively and dose-de- pendently associated with non-cardia gastric can- cer.77 Nitrite and nitrate additives form N-nitroso carcinogenic compounds when they combine with amino acids. Similar carcinogens are formed by ingestion of haem (and meat) in the human gastrointesti- nal tract.78 Vegetables and fruits in the diet have a protective role79, and folic acid supplementation has been shown to reduce H. pylori related gastric inflammation and dysplasia in murine models.80 Reversibility of intestinal metaplasia Large prospective trials of H. pylori eradication for non-cardia gastric cancer prevention failed to show a reduction in gastric cancer incidence after eradication in a subpopulation of patients with pre-existing gastric intestinal metaplasia or exten- sive atrophic gastritis.7,81 Intestinal metaplasia has thus been considered irreversible, and its occur- rence is considered to be the histological point of no return in the carcinogenic cascade. These assumptions appeared to be confirmed by prospective studies designed to evaluate the effect of H. pylori eradication on intestinal meta- plasia and atrophic gastritis in eradicated sub- jects. A marked regression of histologic changes associated with acute and chronic gastritis was observed after eradication in one of these studies; however, the level of mucosal atrophy and intesti- nal metaplasia remained unchanged one year af- ter H. pylori eradication.82 Similar results with no regression in intestinal metaplasia were reported in a more recent detailed histological analysis of 88 antral biopsies taken in patients with intestinal metaplasia prior to and several months after H. py- lori eradication.83 Several other smaller studies, all with short intervals of observation, reported simi- lar results.84,85 On the other hand, a number of pro- spective studies with longer observation intervals report the partial regression of intestinal metapla- sia.10,86-87 Hwang et al. postulated that the reason for this apparent discrepancy might stem simply from the slow pace of the process under observation.10 The partial reversibility of intestinal metaplasia after H. pylori eradication is also indirectly sup- ported by a meta-analysis that confirmed reduced gastric cancer incidence in all levels of baseline risk, including patients with gastric metaplasia.88 Another recent meta-analysis directly addressed the natural course of intestinal metaplasia. Its re- gression was observed in 32%, and its persistence in 43%, of 20 relevant studies.89 A recent study of genomic and epigenomic profiling of intestinal metaplasia by Huang et al.90 also addressed the regression of intestinal meta- plasia. Eighty-two eradicated patients with intesti- nal metaplasia were included in an assessment of correlates between molecular features and clini- cal outcome. At the end of surveillance period, 6 patients had developed dysplasia or cancer, 61 showed no change, and regression of intestinal metaplasia was observed in 15 patients. The level of DNA methylation changes correlated with the tendency to progress and was highest among pro- gressors, intermediate in the stable group, and low in patients with intestinal metaplasia regression. Furthermore, H. pylori burden correlated with DNA methylation levels only in the intermedi- ate group, but not in the methylation-high group, which could explain the failure of H. pylori eradi- cation to stabilize or reverse intestinal metaplasia in these patients. Levels of aberrant DNA meth- ylation could thus indicate the point of no return within the scope of intestinal metaplasia. Radiol Oncol 2024; 58(2): 186-195. Drnovsek J et al. / Pathogenesis and potential reversibility of intestinal metaplasia192 Folate is water soluble vitamin that acts a as a methyl group donor in DNA methylation and plays an important role in epigenetic regulation.91 Folic acid (FA) supplementation has been shown to reduce the risk of gastric cancer in 7-year pro- spective randomized trial of 216 patients with chronic atrophic gastritis.92 All 5 observed gastric cancer cases occurred outside the group of FA- treated patients. Furthermore, the use of FA for 12 months was associated with more frequent re- versal of both, atrophy and intestinal metaplasia in comparison to patients receiving placebo. These observations were confirmed by recent meta-anal- ysis of the role of FA supplementation in reversal of gastric precancerous conditions.93 Daily doses of 20–30 mg of FA in the duration of 3-6 months were associated with significant reversal of both, atrophic gastritis and intestinal metaplasia (RR: 1.77, 95% CI: 1.32–2.37).93 Conclusions The long-held belief that intestinal metaplasia of the gastric mucosa represents an irreversible pre- cursor to cancer has increasingly been questioned in recent years. The concept of a ‘point of no re- turn’ in the progression toward gastric cancer is now understood to be more complex than histo- morphological changes alone. Consequently, the histological subtypes of gastric intestinal meta- plasia must be considered during the planning of patient surveillance due to their varying potential for neoplastic transformation. Additionally, epig- enomic alterations and molecular profiling could prove valuable in identifying the pro-carcinogenic transformation of intestinal metaplasia in patients without established risk factors. The eradication of H. pylori remains a critical step towards the poten- tial reversibility of intestinal metaplasia; however, identifying patients at high risk of progression to cancer continues to be essential. The question of intestinal metaplasia progression despite H. py- lori eradication could be addressed by examining changes in DNA methylation levels. Furthermore, non-H. pylori related host risk factors in the patho- genesis of gastric cancer are under thorough in- vestigation. Significant challenges remain, such as accurately quantifying these factors and determin- ing their exposure duration to assess their actual impact on intestinal metaplasia progression accu- rately. Recent studies highlighting the role of bile acids, N-nitroso–containing compounds, and defi- ciencies in vitamin C and folate have shown prom- ise, yet their clinical relevance remains to be fully elucidated. An enduring unresolved issue is the long-term monitoring of these individuals, where the patchy nature of intestinal metaplasia could lead to sampling errors and potentially incorrect assessments of intestinal metaplasia reversibility. References 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424. doi: 10.3322/caac.21492 2. de Brito BB, da Silva FAF, Soares AS, Pereira VA, Santos MLC, Sampaio MM, et al. 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