Complete blood count-derived inflammatory indices: A noninvasive aid for risk stratification in gastric ulcer

Abstract

Gastric ulcer (GU) remains a significant global health concern, often leading to severe complications such as bleeding and perforation. While Helicobacter pylori infection and nonsteroidal anti-inflammatory drug use are well-recognized etiological factors, systemic inflammation plays a pivotal but underexplored role in GU pathogenesis. Shen et al provide compelling evidence linking complete blood count-derived inflammatory biomarkers with GU prevalence, identifying the systemic inflammatory response index as the most discriminative marker. Their cross-sectional analysis underscores the potential of routine hematological parameters as cost-effective, accessible tools for early identification of high-risk individuals. Importantly, this study adds to the growing body of literature suggesting that simple indices - neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and systemic inflammatory response index - may serve not only as diagnostic aids but also as windows into disease mechanisms involving immune dysregulation and oxidative stress. Future prospective and mechanistic studies are warranted to determine whether these markers can predict ulcer recurrence, guide therapeutic interventions, or integrate into precision gastroenterology. By leveraging widely available blood tests, we may move closer to a paradigm where inexpensive inflammatory indices refine GU risk stratification and management strategies.

Key Words: Gastric ulcer; Systemic inflammation; Complete blood count; Inflammatory biomarkers; Systemic inflammatory response index; Risk stratification

Core Tip: Gastric ulcer is a prevalent gastrointestinal disorder with multifactorial causes including Helicobacter pylori infection, non-steroidal anti-inflammatory drugs use, and systemic inflammation. Recent evidence highlights the role of complete blood count-derived inflammatory biomarkers - such as neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and particularly the systemic inflammatory response index - as promising noninvasive indicators for risk stratification. These inexpensive and accessible markers may provide valuable insights into immune dysregulation, predict disease severity, and guide individualized management, representing an important step toward precision gastroenterology.

TO THE EDITOR

Gastric ulcer (GU) is a chronic form of peptic ulceration defined by the presence of focal lesions in the mucosal lining of the stomach, which may extend through the submucosa and, in severe cases, the muscularis propria. These ulcers are mostly located in the gastric antrum along the lesser curvature, although they may occasionally affect other stomach regions or the proximal duodenum. During endoscopy, GUs appear as well-circumscribed, round or oval defects with varying depths and surrounding inflammatory changes[1,2]. During clinical examinations, patients frequently experience episodic epigastric discomfort, often relieved by the ingestion of food or alkaline substances, accompanied by dyspepsia, nausea, vomiting, heartburn, and black, tarry stools in some cases[3,4].

GU affects approximately 5%-10% of the global population, with approximately four million new cases occurring each year. Helicobacter pylori (H. pylori) infection is implicated in approximately 75% of GUs, with this bacterium colonizing over half of the world’s population[5,6]. Additional risk factors include chronic non-steroidal anti-inflammatory drug (NSAID) use, excessive alcohol consumption, smoking, stress, and genetic predisposition. Even certain blood groups, such as O-positive, may increase parietal cell volume and acid secretion, enhancing mucosal vulnerability[7].

The pathogenesis of GU involves an imbalance between aggressive factors - such as gastric acid, pepsin, H. pylori infection, NSAIDs, ethanol, and oxidative stress - and protective mechanisms, including mucus secretion, epithelial regeneration, and mucosal blood flow. H. pylori disrupt the protective mucus layer, modulates cytokine expression, and impairs parietal cell function, leading to mucosal injury[8]. NSAIDs inhibit cyclooxygenase enzymes, decreasing prostaglandin synthesis and weakening mucosal defense[9]. Ethanol and oxidative stress induce mucosal injury through reactive oxygen species generation, lipid peroxidation, and apoptosis[10,11]. Gastric acid hypersecretion, stimulated by histamine, acetylcholine, and gastrin, further contributes to tissue damage, particularly in susceptible individuals[12,13]. The pathogenesis of GUs is also profoundly influenced by the autonomic nervous system, which acts as a key mediator between central nervous system activity (including stress) and local gastric physiology[14].

The parasympathetic limb, primarily mediated by the vagus nerve, is a major aggressor in ulcer pathogenesis through its control of gastric acid secretion. Vagal stimulation releases acetylcholine, which directly binds to M3 receptors on parietal cells to stimulate acid production. Vagal input also indirectly promotes acid secretion by stimulating gastrin release from G-cells and histamine release from enterochromaffin-like cells. An imbalance favoring excessive parasympathetic tone can therefore significantly contribute to mucosal damage by driving acid hypersecretion[15].

Conversely, the sympathetic nervous system plays a critical role, especially in stress-induced ulcers (such as physical exercise-induced or critically ill-related ulcers)[16]. Sympathetic activation leads to the release of catecholamines, resulting in vasoconstriction of the splanchnic circulation (the blood supply to the stomach). This shunting of blood flow causes gastric mucosal ischemia, severely impairing mucosal defense mechanisms (like mucus production and bicarbonate secretion) and delaying the healing process[17]. This reduction in local blood flow, coupled with systemic increases in inflammatory mediators captured by complete blood count (CBC) indices, exacerbates the vulnerability of the gastric lining to injury[3].

Central to the neuro-hormonal regulation and ultimate treatment of GU is the potent inhibitory peptide, somatostatin[18]. It is released by D-cells primarily in the gastric antrum and duodenum, acts through paracrine and endocrine pathways to suppress the release of key aggressive factors[19]. Its central mechanism involves powerfully inhibiting the release of gastrin from G-cells and histamine from enterochromaffin-like cells[20]. By curtailing these primary acid secretagogues, somatostatin effectively reduces overall gastric acid output, thereby playing a critical role in mucosal protection and ulcer healing, which is why synthetic analogs are used therapeutically in certain upper gastrointestinal bleeding conditions[21]. Furthermore, somatostatin is implicated in a complex interaction with H. pylori. While its primary function is hormonal, some studies suggest that somatostatin or its analogs can directly inhibit the growth or virulence factors of H. pylori[21]. More commonly, its role is viewed through the inflammatory lens: H. pylori infection can modulate D-cell function, leading to impaired somatostatin release in the infected gastric mucosa[22]. This local deficiency in a key protective and inhibitory hormone further tips the balance in favor of ulceration. Addressing this hormonal dysregulation alongside infection eradication is therefore a crucial aspect of managing gastric and duodenal ulcers[23]. Beyond primary chemical and biological aggressors, stress-induced ulcers represent an important category in GU pathogenesis. This includes both psychological and physical stressors, with intense physical exercise being a notable, yet often under-discussed, clinical example[24]. During periods of strenuous or prolonged physical activity, the body prioritizes blood flow to the skeletal muscles, resulting in the sympathetic nervous system activation and the subsequent vasoconstriction of the splanchnic circulation (the blood supply to the stomach and intestines). This diversion of blood flow induces transient gastric mucosal ischemia[25]. This state of localized ischemia rapidly compromises the mucosal defense barriers, which rely heavily on adequate blood supply for oxygenation, nutrient delivery, and rapid removal of toxins. Simultaneously, intense physical activity is associated with a systemic increase in circulating catecholamines and oxidative stress. The combined effect of ischemia, barrier disruption, and heightened systemic inflammation - which may be captured by the very CBC indices [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic inflammatory response index (SIRI)] discussed in this manuscript - creates a highly ulcerogenic environment, accelerating mucosal damage and contributing to the overall burden of GU disease[25].

Untreated GU can result in complications such as hemorrhage, perforation, obstruction, and over time, gastric carcinoma, underscoring the need for timely diagnosis and management[3]. Diagnostic methods include upper endoscopy, non-invasive urea breath tests, and serological H. pylori markers[26]. Therapeutic strategies are etiology-specific: H. pylori-positive ulcers require antibiotic eradication combined with proton pump inhibitors, whereas NSAID-induced ulcers necessitate cessation of the offending drug alongside mucosal protection using proton pump inhibitors or H2 receptor antagonists. Despite treatment advances, adverse effects and high relapse rates remain challenging[4,26]. Experimental models in animals, including ethanol, NSAID, and H. pylori-induced ulceration, support mechanistic studies and therapeutic testing[27]. Bibliometric analyses provide insights into research trends and emerging hotspots, guiding future investigations in GU pathophysiology and management[5].

CBC is a fundamental laboratory test providing a comprehensive overview of hematologic health. CBC quantifies red blood cells, white blood cells, platelets, hemoglobin, hematocrit, and derived indices. Advanced indices such as NLR, PLR, monocyte-to-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII) have emerged as sensitive markers of systemic inflammation and immune regulation[28]. These markers reflect the balance between innate and adaptive immune responses and correlate with disease severity, prognosis, and treatment response across inflammatory and chronic disorders. A recent cross-sectional study by Shen et al[3] evaluated the associations between complete-blood-count-derived inflammatory markers and GU prevalence, focusing particularly on the SIRI[2]. Using logistic regression, receiver operating characteristic curve analysis, and rigorous variable selection methods, including least absolute shrinkage and selection operator and stepwise regression, the study found that SIRI was significantly associated with GU and demonstrated high discriminatory power. These findings underscore the relevance of CBC-derived indices, particularly composite markers like SIRI, as practical indicators of systemic inflammation linked to gastric mucosal injury. Incorporating such markers alongside traditional diagnostic approaches could enhance risk stratification, early detection, and individualized management of GU.

In the context of GU, CBC-derived inflammatory markers offer insights into systemic immune responses associated with mucosal injury. Elevated NLR and PLR indicate heightened neutrophil activity alongside relative lymphocyte suppression, representing systemic inflammatory burden[28]. Studies in pediatric pneumonia and adult coronavirus disease 2019 support the relevance of these indices, demonstrating strong correlations between WBC counts, neutrophil and lymphocyte percentages, and disease severity[29,30]. These findings suggest that CBC-derived markers can serve as proxies not only for local mucosal inflammation but also for overall systemic immune activation.

Although CBC-derived inflammatory indices such as NLR, PLR, MLR, and SII have gained increasing attention due to their accessibility, low cost, and ability to reflect systemic inflammatory burden, their primary limitation lies in their low disease specificity[31]. These biomarkers represent generalized patterns of immune activation - namely neutrophilia, lymphocyte suppression, platelet activation, and monocyte-driven inflammatory responses - that are not unique to GU pathology[32]. As a result, elevations in these indices may occur across a wide spectrum of unrelated clinical conditions. For example, increased NLR and PLR values can be observed in chronic and acute infections[33], autoimmune diseases[34], various malignancies[35], metabolic syndrome and obesity-related low-grade inflammation[36], type 2 diabetes mellitus[37], cardiovascular disease[38], chronic kidney disease[39], psychological stress, and physical exertion[40]. Similarly, MLR and SII can rise in response to systemic oxidative stress, aging-related immune remodeling, or subclinical inflammatory states. This broad overlap significantly limits the diagnostic precision of these biomarkers when used in isolation[41].

Given these limitations, the interpretation of CBC-derived inflammatory markers must always be contextualized within a comprehensive clinical framework[42]. Their clinical significance becomes meaningful only when integrated with essential diagnostic elements, including endoscopic visualization of mucosal lesions, laboratory testing for H. pylori infection, patient symptomatology, medication history - particularly NSAID use - existing comorbidities, and complementary inflammatory indicators such as C-reactive protein (CRP)[43]. An isolated elevation in NLR, PLR, MLR, or SII cannot reliably distinguish GU-related inflammation from other systemic or local inflammatory processes[42,44]. Instead, these indices should be understood as supportive adjuncts that reflect the magnitude of systemic inflammation rather than as stand-alone diagnostic tools for GU[45].

Demographic factors modulate CBC-derived inflammatory responses. Males often exhibit higher WBC counts and CRP levels than females, reflecting sex-specific immune patterns[46]. Age also influences these markers: Older adults display stronger associations between elevated inflammatory indices and adverse outcomes such as frailty and delayed tissue repair[29,30]. Ethnicity, comorbidities, and environmental factors, including high-altitude exposure, further affect systemic inflammation, highlighting the need for contextual interpretation when assessing CBC-derived indices in GU patients[47].

Differentiating the elevation of CBC-derived inflammatory indices in GU from their rise in other inflammatory or pathological conditions requires careful clinical integration, as these markers reflect systemic rather than disease-specific immune activation[48]. Elevated NLR, PLR, MLR, and SII may occur in numerous conditions such as respiratory and gastrointestinal infections, autoimmune disorders, malignancies, metabolic diseases, chronic kidney disease, cardiovascular pathology, and acute stress responses[31]. Therefore, to attribute such elevations specifically to GU-related mucosal injury, clinicians must rely on a combination of diagnostic elements, including characteristic endoscopic findings, a positive H. pylori test, symptom patterns consistent with ulcer disease, and the exclusion of alternative sources of systemic inflammation[49]. In particular, the presence of localized mucosal defects on gastroscopy, accompanied by compatible clinical symptoms and absence of competing inflammatory processes, strengthens the interpretation that CBC-derived abnormalities reflect GU-associated inflammation rather than unrelated systemic pathology.

CRP serves as an additional immune-inflammatory biomarker that can assist in this differentiation. CRP levels often correlate with shifts in CBC-derived ratios, particularly NLR and SII, as increases in neutrophil count and decreases in lymphocyte count frequently accompany elevations in CRP during acute inflammatory responses[50]. However, CRP also lacks disease specificity and may rise in many non-ulcer conditions. Within the context of GU, CRP provides supportive evidence of an underlying inflammatory state but does not independently diagnose the disease. Instead, its primary value lies in helping distinguish acute inflammatory activation, for example, in complicated or bleeding ulcers - from baseline inflammatory conditions[51]. When CBC-derived indices and CRP are interpreted together, especially in conjunction with endoscopic findings and H. pylori testing, they can improve diagnostic confidence by confirming systemic inflammatory involvement while ensuring that elevations are not misattributed to non-ulcer etiologies[52].

Comorbid conditions, including type 2 diabetes mellitus, atherosclerotic cardiovascular disease, and chronic kidney disease, alter CBC-derived inflammatory markers. Patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease often exhibit distinct CBC and lipid ratio profiles indicative of systemic inflammation, which may exacerbate gastric mucosal injury and delay ulcer healing[47]. In pediatric populations, timely monitoring of these markers facilitates early identification of at-risk individuals, improving outcomes in infection-associated ulcer complications[28]. Comorbidities also influence treatment planning, emphasizing the integration of CBC-derived markers into comprehensive clinical assessment.

Genetic predispositions affect inflammatory responses and ulcer susceptibility. Certain genotypes are associated with elevated NLR, PLR, and SII levels, which correlate with increased risks of frailty, mortality, and disease progression[53]. Oxidative stress, a key mediator of tissue injury, further alters CBC parameters through lipid peroxidation, protein oxidation, and nucleic acid damage. Elevated oxidative stress markers, such as malondialdehyde and hydrogen peroxide, are observed in cancer, obesity, and postmenopausal populations, illustrating the interplay between systemic oxidative stress, immune activation, and mucosal injury[54]. Dietary antioxidants, such as quercetin, mitigate oxidative stress, stabilize hematologic indices, and support mucosal repair[55].

The gut microbiome also modulates systemic inflammation reflected in CBC indices. Diet, body mass index, age, and geographic factors influence microbial diversity, affecting inflammatory profiles[56]. Dysbiosis can exacerbate GU-associated inflammation, whereas probiotic supplementation reduces systemic inflammatory markers, improves oxidative stress balance, and enhances mucosal healing[57]. Machine learning and meta-analytic studies identify microbial signatures associated with inflammatory states, supporting personalized interventions to modulate systemic and local inflammation.

Immune cell subtypes are central to GU-associated inflammation. Neutrophils, monocytes, fibroblasts, and lymphocyte subsets orchestrate both tissue injury and repair, with their dynamics mirrored in CBC-derived indices[58]. High-throughput single-cell transcriptomics reveal neutrophil and fibroblast subsets driving pathological inflammation, highlighting potential therapeutic targets. CBC-derived markers thus provide practical surrogates for monitoring these complex interactions, guiding prognosis and individualized therapy.

FUTURE DIRECTIONS AND RESEARCH SUGGESTIONS

Recent advances in CBC-derived inflammatory markers and GU research highlight multiple promising avenues for future investigation. Longitudinal studies that integrate CBC indices with endoscopic, histopathological, and molecular data could clarify temporal relationships between systemic inflammation and mucosal injury, enabling clinicians to predict ulcer progression, identify high-risk patients, and optimize individualized therapeutic regimens[28]. The integration of multi-omics approaches, including transcriptomics, proteomics, and metabolomics, may further uncover mechanistic pathways linking neutrophil, lymphocyte, and platelet dynamics with gastric mucosal repair and systemic inflammatory states, while high-throughput single-cell sequencing and spatial transcriptomics could elucidate the roles of immune cell subsets, fibroblasts, and microbiome interactions in ulcer pathophysiology[36,37]. Personalized medicine strategies should account for demographic, genetic, and environmental factors that modulate systemic inflammation, as sex-specific, age-dependent, and ethnicity-related differences in CBC-derived indices may necessitate tailored diagnostic thresholds and treatment approaches[45]. Additionally, emerging research on gut microbiome modulation and probiotic therapy suggests potential for adjunctive interventions that reduce systemic inflammatory burden while enhancing mucosal repair, with machine learning algorithms offering the ability to identify microbial signatures predictive of ulcer complications[57,58]. Finally, novel therapeutic strategies targeting oxidative stress, neuroinflammatory pathways, and specific immune cell subsets could complement standard treatments, as antioxidants, immune modulators, and targeted biologics may mitigate systemic and local inflammation, reduce recurrence, and improve healing rates; clinical trials incorporating CBC-derived markers as surrogate endpoints could accelerate the translation of these interventions into clinical practice[54,58]. Addressing these research priorities promises to deepen our understanding of the interplay between systemic inflammation, immune regulation, and gastric mucosal injury, ultimately enhancing prognostic assessment and personalized management of GU.

Finally, to facilitate the integration of these cost-effective and accessible biomarkers into routine clinical practice, we recommend that clinical laboratories explore the feasibility of automatically calculating and reporting the key inflammatory indices - NLR, PLR, MLR, and the SIRI - as part of the standard, routine CBC report. This simple, automated enhancement would immediately improve the noninvasive risk stratification capacity for GU and other inflammation-associated gastrointestinal diseases, allowing clinicians to utilize these prognostic tools without manual calculation.

CONCLUSION

CBC-derived inflammatory markers integrate multiple aspects of GU pathophysiology, including systemic inflammation, immune cell dynamics, comorbidities, oxidative stress, genetic predispositions, and microbiome interactions. These markers offer accessible, cost-effective tools for risk stratification, disease monitoring, and personalized management. By linking systemic immune activation with local mucosal pathology, CBC-derived indices enhance prognostic precision and therapeutic decision-making, ultimately improving clinical outcomes in GU care.