Improvement in Chronic Atrophic Gastritis After Treatment with Zinc L-Carnosine

Introduction

Persistent inflammation of the gastric mucosa results in a clinical condition known as chronic gastritis [1–3]. This prolonged inflammatory state can lead to the loss of glandular cells, progressing to chronic atrophic gastritis (CAG) [4–6], which requires active monitoring because of its precancerous potential [7–9].

In Western populations, the estimated annual progression rates to gastric cancer (GC) are 0.1% for atrophic gastritis, 0.25% for intestinal metaplasia (IM), 0.6% for mild-to-moderate dysplasia, and 6% for severe dysplasia [10]. The risk appears substantially higher in East Asian populations, where annual progression rates reach 1.8% for atrophic gastritis, 10% for IM, and 73% for dysplasia [11]. Patients with incomplete IM have a 3.3-fold higher relative risk of developing GC compared with those exhibiting complete IM; those with extensive IM have a 2.1-fold higher risk than those with limited IM [12,13]. To facilitate clinical risk assessment for the progression of CAG and IM to GC, the Operative Link on Gastritis Assessment (OLGA) histologic classification was developed, which stratifies GC risk into 4 stages [14–16].

Currently, 3 forms of CAG are recognized: autoimmune, characterized by the presence of anti–parietal cell antibodies; Helicobacter pylori-related; and mixed. Autoimmune CAG is primarily distinguished by atrophy of the gastric body and fundus, severe impairment of gastric secretion, and reduced vitamin B12 absorption [17,18]. Clinical examinations indicate that dyspepsia is the most common symptom in patients with CAG; it is associated with delayed gastric emptying in approximately 80% of cases [19,20].

The management of CAG generally involves 4 key components: (1) testing for and eradicating H. pylori infection; (2) performing endoscopic and histologic surveillance every 3 to 5 years; (3) treating coexisting conditions, such as iron and/or vitamin B12 deficiency; and (4) monitoring gastric function via serum pepsinogen assessment [21].

With the exception of H. pylori eradication, which has been clearly established as the primary means of halting the Correa cascade and alleviating dyspeptic symptoms in affected patients [22], there remains no definitive evidence regarding other therapeutic options [23]. Recently, various compounds have been proposed as effective and safe in these patients because of their detoxifying, antioxidant, anti-inflammatory, and reparative properties against gastric mucosal injury [22].

Among the proposed compounds, L-carnosine appears to be a promising candidate. Zinc L-carnosine, a chelate compound of zinc and L-carnosine, is insoluble in saline but dissolves in acidic environments and exhibits a polymeric structure with strong affinity for inflamed tissue [24]. This property results from its pronounced local adhesiveness at lesion sites, where zinc binds to exposed carrier proteins while L-carnosine is released locally. Both components are rapidly metabolized, with minimal influence on their systemic concentrations at therapeutic doses [24]. Zinc L-carnosine has been shown to reduce gastric acetaldehyde levels, alleviating symptoms and stabilizing mucosal atrophy [25,26]. It also exerts direct cytoprotective and anti-inflammatory effects through antioxidant activity and cytokine modulation [27–29], with similar benefits observed in organs other than the stomach [30]. Furthermore, it is able to restore gastric function and improve dyspeptic symptoms, which frequently affect patients with CAG [31,32]. Given these properties, zinc L-carnosine may play a therapeutic role in CAG by attenuating inflammation and potentially reducing the risk of GC according to the Correa cascade [33], while concurrently improving dyspeptic symptoms. Here, we report 2 cases in which long-term zinc L-carnosine treatment led to improvement in dyspeptic symptoms, gastric function, and histologic features of CAG.

Case Reports

CASE 1:

A 51-year-old woman underwent esophagogastroduodenoscopy in March 2023 for a 2-year history of dyspeptic symptoms, including slow digestion, early satiety, and epigastric heaviness. She had previously (February 2022) undergone H. pylori eradication at the onset of dyspeptic symptoms, with success confirmed by 13C urea breath test in April 2022. She was not taking any medications when she presented for esophagogastroduodenoscopy. Endoscopic examination revealed visible submucosal vessels throughout the stomach without additional lesions (Figure 1). Multiple biopsies (5 in total) were obtained from all gastric regions. Histologic analysis demonstrated mild-to-moderate atrophy in the antrum and angulus with IM, consistent with OLGA stage 2 [14–16]. H. pylori infection, evaluated by Warthin-Starry staining and urea breath test, was absent. Symptom severity was evaluated using the mean global symptom index (8-MGSI) for dyspepsia [34], and the baseline score was 26. Gastric function parameters, including pepsinogen I (PGI), pepsinogen II (PGII), and gastrin 17 (G17), were assessed by chemiluminescent immunoassay (Maglumi, Shenzhen New Industries Biomedical Engineering Co., SNIBE, Shenzhen, China); results were consistent with atrophic gastritis (PGI 14 ng/mL, PGI/PGII ratio 1.8, G17 229 pmol/L).

Because zinc L-carnosine has demonstrated efficacy in relieving dyspeptic symptoms among patients with CAG [35], treatment with zinc L-carnosine (Hepilor® Capsules, Azienda Farmaceutica Italiana srl, Sant’Egidio alla Vibrata, Teramo, Italy; approved by the Italian Ministry of Health in July 2016) was initiated at a dose of 39.5 mg orally twice daily (10 a.m. and 10 p.m.), with 1 h of fasting maintained after each dose as part of long-term therapy.

The patient reported rapid symptom improvement, such that the 8-MGSI score decreased to 22 after 6 months of therapy. After 1 year of continuous zinc L-carnosine treatment (August 2024), repeat endoscopy showed decreased prominence of submucosal vessels throughout the stomach. Histologic examination revealed very mild atrophy in the antrum and angulus with mild IM (OLGA stage 1), again without evidence of H. pylori infection. At that time, the 8-MGSI score had further decreased to 20, and gastric function parameters demonstrated additional recovery (PGI 18 ng/mL, PGI/PGII ratio 2.2, G17 103 pmol/L). The patient remains on daily zinc L-carnosine therapy. Follow-up clinical, endoscopic, histologic, and laboratory evaluations are scheduled in the coming months.

CASE 2:

An 87-year-old man underwent esophagogastroduodenoscopy in February 2022 for a 1-year history of dyspeptic symptoms, including slow digestion, early satiety, and epigastric heaviness, accompanied by unintentional weight loss. He was not taking any medications when he presented for esophagogastroduodenoscopy. Fecal H. pylori antigen testing performed prior to esophagogastroduodenoscopy showed negative results. The baseline 8-MGSI score was 28, and gastric function parameters were consistent with severe CAG (PGI 4.7 ng/mL, PGI/PGII ratio 0.41, G17 301.6 pmol/L). Anti-parietal cell antibody test results were positive, with a titer of 1: 160. No significant evidence of malabsorption was observed except for vitamin B12 deficiency (177 pg/mL; reference range: 197–771 pg/mL); no supplementation was performed at this time. Abdominal ultrasonography and fecal occult blood testing results were unremarkable. Endoscopic examination revealed diffuse mucosal atrophy with visible submucosal vessels throughout the stomach; no additional lesions were noted. Multiple biopsies (5 in total) were obtained from all gastric regions. Histologic analysis demonstrated severe atrophy of both the antrum (Figure 2A) and corpus (Figure 2B) with focal IM, corresponding to OLGA stage 3. H. pylori infection was not detected by Warthin-Starry staining.

The patient was subsequently treated with zinc L-carnosine (Hepilor^® Capsules) 39.5 mg orally twice daily (10 a.m. and 10 p.m.), and 1 h of fasting was maintained after each dose as part of long-term therapy.

The patient reported rapid symptom improvement and underwent repeat endoscopic and histologic assessment in November 2024. At that time, all clinical parameters had improved: body weight increased by 5 kg, dyspeptic symptoms substantially decreased (8-MGSI score 22), and gastric function parameters showed partial recovery (PGI 3.8 ng/mL, PGI/PGII ratio 0.56, G17 257 pmol/L). Although endoscopic findings remained largely unchanged, with persistent evidence of submucosal vessels throughout the stomach, histologic evaluation demonstrated very mild atrophy in the antrum and angulus (Figure 2C) and in the fundus (Figure 2D), as well as focal IM consistent with OLGA stage 1. The patient continues daily zinc L-carnosine therapy; follow-up clinical and laboratory evaluations (excluding endoscopy and histology) are scheduled in the coming months.

Discussion

Historically, the development of CAG and IM has been regarded as the “point of no return” in the gastric carcinogenesis sequence. It is well established that atrophic gastritis may improve after H. pylori eradication; however, the potential of IM to regress following eradication remains unclear [36–39].

The question of how and where to perform biopsy sampling to assist pathologic recognition of CAG and IM has been addressed by introduction of the OLGA classification. Acquisition of biopsies from the antrum, angulus, and fundus, along with application of the OLGA scoring system, has clarified that the risk of GC is substantially higher in patients with OLGA stage III or IV disease [40].

Nonetheless, as Marjorie Walker noted in 2003, a central question persists: is gastric IM reversible [39]? More specifically, can IM be reversed even in patients without H. pylori infection? According to the Correa cascade, chronic gastric mucosal inflammation progresses through a multifactorial process involving H. pylori infection, host genetics, and environmental factors such as diet and tobacco use, ultimately leading to atrophy, metaplasia, and GC [33]. Other conditions warrant consideration in the absence of H. pylori infection, particularly autoimmune gastritis. Although autoimmune gastritis itself is not generally recognized as a risk factor for GC [40], rare cases involving incomplete IM may pose such a risk [41]. The persistence of chronic inflammation throughout the long course of the disease may also contribute to carcinogenesis according to the Correa cascade. Therefore, inflammation control remains fundamental to GC prevention. Although H. pylori eradication continues to serve as the cornerstone for reversing IM, nutraceutical interventions are increasingly under investigation as potential adjunctive strategies in this context [22].

Among these nutraceutical agents, folate has been extensively studied. It is a water-soluble vitamin that functions as a methyl group donor in DNA methylation and plays an essential role in epigenetic regulation [42]. Folate has been shown to promote a higher rate of reversal of both atrophy and IM compared with placebo [43], a finding confirmed by a recent meta-analysis [44]. Ascorbic acid may also have a therapeutic role in this context. When administered as an adjunct to H. pylori eradication therapy, it significantly improved IM [45]. Berberine likewise appears to be beneficial. This plant-derived compound exerts broad metabolic effects that influence host health [46]. In the context of IM and GC, berberine has been shown to suppress H. pylori infection, reduce mucosal inflammation via cytokine regulation, reverse gastric precancerous lesions by promoting apoptosis, and modulate macrophage polarization and autophagy [47]. Certain pharmacologic agents have also demonstrated potential in reversing IM. A recent randomized clinical trial revealed that metformin, a widely used antidiabetic medication, was effective and safe in promoting regression of IM in non-diabetic patients without H. pylori infection [48]. Finally, moluodan, a traditional Chinese patent medicine with mechanisms similar to those described for berberine, has recently demonstrated efficacy and safety in reversing gastric precancerous lesions, particularly IM and dysplasia [49].

The present cases exemplify observations encountered in clinical practice. We described 2 patients with CAG of different etiologies – 1 following H. pylori infection and the other associated with autoimmune gastritis. In both cases, zinc L-carnosine (Hepilor® Capsules) was administered to alleviate dyspeptic symptoms because this formulation has demonstrated efficacy in controlling such symptoms among patients with CAG [35]. These cases are noteworthy for 2 main reasons. First, they confirm that zinc L-carnosine can effectively relieve dyspeptic symptoms and improve gastric function in patients with CAG. Second, and more importantly, the treatment appeared to promote histologic improvement of CAG according to the OLGA classification. This potential effect of zinc L-carnosine has not been thoroughly investigated and may be related to the compound’s biological properties. Zinc L-carnosine is known to reduce levels of several proinflammatory cytokines, including interferon-γ, tumor necrosis factor-α, interleukin (IL)-21, IL-6, and IL-15 [50]. It has also been hypothesized that G17 participate in the mechanism underlying CAG improvement. G17 levels increase in CAG as a compensatory response to reduced gastric acidity through a negative feedback mechanism [5]. However, elevated G17 levels can stimulate cell proliferation, particularly at higher concentrations, and may act as an important risk factor for GC by promoting cellular proliferation, invasion, and migration in a dose-dependent manner [51]. Because zinc L-carnosine has been shown to lower G17 concentrations [35], as observed in our cases, we hypothesize that improvements in CAG can result from the combined effects of G17 reduction, mucosal protection through anti-inflammatory and antioxidant mechanisms, suppression of excessive cellular proliferation, and enhancement of mucus production.

Conclusions

Reduction of G17 levels, increased anti-inflammatory and antioxidant activity in the gastric mucosa, decreased cellular proliferation, and enhanced mucus production may represent the mechanisms underlying symptom control and histologic improvement of CAG among patients treated with zinc L-carnosine. However, definitive conclusions cannot yet be drawn; further studies are required to confirm these preliminary but encouraging findings.