H Pylori Vitamin C

Abstract

Several clinical studies have shown that higher prevalence of Helicobacter pylori infection is associated with low vitamin C (Vit C) level in serum. The aim of this study was to assess the effect of supplementation of Vit C on the eradication rates of clarithromycin-based triple therapy for H. pylori infection. This study included 100 patients diagnosed with H. pylori gastritis using magnifying narrow-band imaging endoscopy supported by stool antigen test. Patients were divided into two groups: Patients in group A (n = 50) received amoxicillin, clarithromycin, and esomeprazole for 2 weeks while patients in group B (n = 50) received Vit C for 4 weeks, in addition to amoxicillin, clarithromycin, and esomeprazole for 2 weeks. The eradication rates were assessed using per-protocol (PP) and intention-to-treat (ITT) analysis. Our results revealed that, eradication was achieved in 31 (70.45%) of 44 patients by PP and 31 (62.%) of 50 by ITT analysis in group A, while in group B, eradication was achieved in 34 (73.91%) of 46 patients by PP and 34 (68%) of 50 by ITT analysis. However, when Vit C supplementation was added to the clarithromycin-based triple therapy it was observed that there were no statistically significant differences between groups A and B (P = .663 in ITT analysis and P = .727 in PP analysis).Our results demonstrated that supplementing Vit C to clarithromycin-based triple therapy did not provide an additional advantage for achieving significantly higher eradication rates for H. pylori-related chronic gastritis and most likely to be preventive rather than curative.

1 INTRODUCTION

Chronic infection with Helicobacter pylori is widespread, occurring in approximately half of the world's population, and infection is typically acquired early in life, especially among those in lower socioeconomic groups.1 Chronic gastric infection due to H. pylori initially causes chronic active gastritis, which can then lead to the development of peptic ulcers, atrophic gastritis, gastric cancer, and mucosa-associated lymphoid tissue lymphoma.2 The World Gastroenterology Organization reported that the H. pylori prevalence in Egypt was 90% in adults.3 H. pylori is not an acidophile, but the main reason for its ability to overcome the acidic gastric environment is due to its ability to synthesize a large amount of urease enzyme that catalyzes the hydrolysis of urea to yield ammonia and carbonic acid. The activation of the urease is a key factor in the successful colonization of bacteria into the gastric mucosa because it can allow the bacteria to survive at a very low acidic pH of 2.5. However, in the absence of the enzyme urease, the bacteria can only survive at a pH of 4.0-8.0.4 The effect of this reaction is an increase in pH and formation of a basic ammonium cloud around the bacteria allowing H. pylori to survive and to colonize on the gastric epithelium.5 The most important factor affecting H. pylori cure rates is the antibiotic resistance of H. pylori strains. The number of H. pylori strains that are resistant to antibiotics is increasing.6 Egyptian patients are frequently exposed to metronidazole for treatment of intestinal parasitic infections; therefore, use of metronidazole for the treatment of H. pylori in Egypt should be avoided due to high resistance. In one of the Egyptian study, the metronidazole resistance was high (60%-80%); however, the resistance to other tested antimicrobial agents was rare (4% for clarithromycin, erythromycin, and azithromycin resistance vs 2% for ciprofloxacin and ampicillin resistance).3 The vitamin C (Vit C) content in gastric juice has recently pulled in numerous researchers, suggesting that Vit C might be a protective agent against the H. pylori infection especially against the development of gastric cancer.7 There have been several clinical studies which demonstrated that high H. pylori infection rate is related to low Vit C (ascorbic acid [AA]) level in the gastric juice as well as in the serum.8 Additionally, many studies demonstrated that a high dose of Vit C would inhibit the growth and colonization of H. pylori and even eradicate them.9 Vit C can be used as a preventative agent against H. pylori infection as Vit C acts as a biological antioxidant, an oxidative stress reducer, a factor in immune function, and in enzyme activation.10 Vit C exists in two major forms: reduced form as AA, as well as its oxidized form as dehydroascorbic acid, which may be interconvertible,11 by a dehydroascorbic acid reductase, glutaredoxins, or other thiols acting as an electron donor. The reduced form as AA has scavenger properties and may be beneficial to eliminate free radicals under the formation of semi-dehydroascorbic acid, which is a nonreactive radical.12 The dehydroascorbic acid may spontaneously hydrolyze and dehydrate; however, the AA is more stable and does not show the same tendency to irreversibly hydrolyze particularly at pH >4. This mechanism is essential for the inhibition of the growth of H. pylori.13

2 PATIENTS AND METHODS

This study was conducted at Gastro-Intestinal Endoscopy Unit, Internal Medicine Department of El Hussein University Hospital, AL-Azhar University, Cairo, Egypt, between May 2018 and November 2018. In this study, 100 sequential Egyptian patients with dyspeptic symptoms (epigastric pain, epigastric fullness, nausea, vomiting) for at least 1 month were consecutively enrolled. All patients underwent baseline evaluation including blood laboratory tests, detailed medical history assessment, and physical examination. Informed consent was obtained from all patients. Diagnostic esophago-gastro-duodenoscopy using magnifying narrow band imaging was performed for all patients afterward; if the patient had endoscopic findings suggesting H. pylori chronic gastritis, stool antigen test for detection of H. pylori infection was conducted to support endoscopic diagnosis. Patients in group A (n = 50) received amoxicillin, clarithromycin, and esomeprazole for 2 weeks. Patients in group B (n = 50) received Vit C for a month, in addition to amoxicillin, clarithromycin, and esomeprazole for 2 weeks. Compliance and adverse events (ie, nausea, vomiting, and diarrhea) of the treatment were determined. H. pylori eradication was determined via stool antigen test performed 4 weeks after the end of therapy.

2.1 Inclusion criteria

100 sequential patients diagnosed with H. pylori chronic gastritis by magnifying endoscopy and narrow band imaging (ME-NBI) along with positive stool antigen test for H. pylori infection.
Age 18-70 years.
Provision of written consent.

2.2 Exclusion criteria

Current use of proton pump inhibitors (PPIs) or Vit C supplement.
Known hypersensitivity to PPI or antibiotics.
Pregnant or lactating women.
Patients who had previously received H. pylori eradication treatment, corticosteroids/immuno- suppressive treatment, antibiotics, anti-inflammatory, and acid suppressive treatment in the prior 2 months.
A history of systemic inflammatory or autoimmune disorders, gastric surgery, renal failure, liver cirrhosis, and malignancies.

2.3 Treatment protocol

Patients in group A (n = 50) received amoxicillin (1 g bid), clarithromycin (500 mg bid), and esomeprazole (20 mg bid) for 2 weeks. Patients in group B (n = 50) received Vit C (500 mg bid) for 4 weeks, in addition to amoxicillin (1 g bid), clarithromycin (500 mg bid), and esomeprazole (20 mg bid) for 2 weeks. For patient who fails to eradicate H. pylori infection at the end of study will be given levofloxacin-based triple therapy as rescue regimen (esomeprazole 20 mg bid, levofloxacin 500 mg daily, and amoxicillin 1000 mg bid) for 10 days.

2.4 Endoscopic evaluation

The instruments used in this study were a videoendoscope and an electronic endoscopic system (Olympus EVIS Lucera Ellit CV-290; Olympus Medical Systems, Tokyo, Japan) and equipped with three imaging modes: high-resolution white light endoscopy (WLE), autofluorescence imaging (AFI), and NBI. Mode switch from WLE to NBI or AFI was controlled by buttons on the control head. Combining ME and the NBI system can lead to visualizing microscopic mucosal structures and its capillary patterns more clearly. All patients were offered conscious sedation with intravenous midazolam (2.5-5 mg) and/or propofol (40-200 mg) and then underwent endoscopic assessment for presence or absence of regular arrangement of collecting venules (RAC) as well mucosal and vascular patterns of the gastric body. All of the endoscopic examinations were performed by one senior endoscopist with more than 10 years experiences in diagnostic and therapeutic endoscopy. The entire endoscopic procedure was recorded on a DVD. NBI endoscopic diagnosis was performed in two occasions, in the first occasion diagnosis was done during real-time endoscopy, while the second occasion was done on the basis of the pictures and videos obtained then was confirmed. Using ME-NBI, the normal gastric body mucosal pattern was determined by small, round pits surrounded by subepithelial capillary networks, making honeycombing pit pattern with presence of spider-like regular arrangement of collecting venules (RAC-positive) (Figure 1), while diagnosis of H. pylori chronic gastritis was done according to presence of obviously enlarged, oval, or prolonged pit with increased density of irregular vessels as well as presence of well-demarcated, oval, or tubulovillous pit with clearly visible coiled or wavy subepithelial capillary networks along with absence of regular arrangement of collecting venules (RAC-negative) (Figure 2).

Narrow band imaging of normal gastric corpus mucosal and vascular pattern (A) regular arrangement of collecting venules (spiderlike pattern) (Red arrows). (B) Normal: small, round pits surrounded by subepithelial capillary networks (honeycombing like pit pattern) being regularly interspersed with collecting venules

Narrow band imaging of *H. pylori* chronic gastritis. (A) Obviously enlarged, oval or prolonged pit. (B) well-demarcated, oval or tubulovillous pit with clearly visible coiled or wavy subepithelial capillary networks

2.5 Laboratory measurements

2.5.1 Stool antigen test for H. pylori infection

Small piece of stool samples (~5 mm in diameter; ~150 mg) added and diluted into 1 mL of sample treatment solution in a test tube and mixed thoroughly. H. pylori infection was detected by specific antigens in stool sample (fecal antigen test) and by ELISA (commercially available). Purified H. pylori antibody was coated on surface of microcells. An aliquot of diluted stool sample was added to wells, and the H. pylori antigens, if present, bind to the antibody. Unbound materials were washed. After adding enzyme conjugate, it binds to antibody-antigen complex. Excess enzyme conjugate was washed and tetramethylbenzidine chromogenic substrate was added. The enzyme conjugate catalytic reaction stopped at a specific time, and the color-generated intensity was proportional to antigen amount, and read by a micro well reader compared in a parallel manner with calibrator and controls (interpretation: negative <15 ng/mL, positive >20 ng/mL, borderline: 15-20 ng/mL).

2.6 Statistical analysis

The overall eradication rates were assessed by intention-to-treat (ITT) and per-protocol (PP) analyses. All of the participants were included in the ITT analysis. Participants who did not follow the study protocol or dropped out of the study were excluded from the PP analysis. The data obtained from the history, clinical examination, and investigations were tabulated and statistically analyzed using the GraphPad Prism program version 6. Mean SDs were used to identify the data related to the continuous variables, and categorical variables were provided as percentages. The comparison of the variables with normal distribution was tested with an unpaired t test, and the comparison of the variables without normal distribution was tested with a Mann-Whitney U test. The categorical variables were compared with Pearson's chi-square test. A P value of less than .05 was considered to be statistically significant for the tests.

3 RESULTS

The present study was carried out on 100 patients diagnosed with H. pylori chronic gastritis by ME-NBI plus stool antigen test and divided into two groups: Patients in group A (n = 50) received amoxicillin, clarithromycin, and esomeprazole for 2 weeks. Patients in group B (n = 50) received Vit C for a month, in addition to amoxicillin, clarithromycin, and esomeprazole for 2 weeks. A total of 90 patients finished the study. Ten patients were excluded from the study (six from group A and four from group B) because of four patients did not visit our clinic after treatment, and six patients left the study due to side effect (four patients reported diarrhea and two reported nausea and vomiting) (Figure 3). Clinical laboratory and demographic features of our patients are shown in (Table 1), with no statistically significant differences between the two groups. The total prevalence of peptic ulcer disease among our patients was 16% in which 7% had gastric ulcer and 9% had duodenal ulcer. Our results revealed that, eradication was achieved in 31 (70.45%) of 44 patients by PP and 31 (62%) of 50 by ITT analysis in group A, while in group B, eradication was achieved in 34 (73.91%) of 46 patients by PP and 34 (68%) of 50 by ITT analysis (Table 2). Although Vit C supplementation was added to the clarithromycin-based triple therapy, it was observed that there were no statistically significant differences between groups A and B (P = .663 in ITT analysis and P = .727 in PP analysis).

Table 1. Demographic and laboratory data of group A (clarithromycin-based triple therapy) and group B (clarithromycin-based triple therapy plus vitamin C)

Variable	Group A (n = 50)	Group B (n = 50)	P value
Gender
Male	30 (60%)	32 (64%)	.807
Female	25 (50%)	18 (36%)
Age (years)	36.64 ± 15.51	38.21 ± 13.59	.647
BMI (kg/m²)	23.90 ± 2.56	25.97 ± 2.40	.942
Hb (g/dL)	13.20 ± 0.92	12.77 ± 1.19	.402
WBC (10³/mm³)	6.10 ± 1.85	4.85 ± 1.54	.875
DM	15 (30%)	12 (24%)	.164
Smoking	20 (40%)	18 (36%)	.362
Alcohol	5 (10%)	3 (6%)	.675
Gastric ulcer	4 (8%)	3 (6%)	.786
Duodenal ulcer	5 (10%)	4 (8%)	.578
ALT (U/L)	23.0 ± 7.80	22 ± 5.70	.432
AST (U/L)	25.0 ± 7.10	27 ± 6.87	.610
GGT (IU/L)	42.00 ± 1.51	35.93 ± 16.71	.162
ALP (IU/L)	114.90 ± 54.30	120.07 ± 60.04	.581
Cholesterol (mg/dL)	170.29 ± 36.97	200.0 ± 55.71	.197
Creatinine (mg/dL)	0.9 ± 0.27	0.72 ± 0.16	.757

Note: No significant difference between the two groups regarding laboratory data and demographic characteristics.
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DM, diabetes mellitus; GGT, gamma-glutamyl transferase; Hb, hemoglobin; WBC, white blood cells.

Table 2. Eradication rates of Helicobacter pylori treatment

Eradication rates	Group A (n = 50)	Group B (n = 50)	P value
Per-protocol, %	31 of 44 (70.45%)	34 of 46 (73.91%)	.727
Intention-to-treat, %	31 of 50 (62%)	34 of 50 (68%)	.663

Note: There was no significant higher eradication rates in group B as compared to group A in both per-protocol and intention-to-treat analyses.

4 DISCUSSION

The differences of the success rates of the treatment protocols to cure H. pylori infection mostly depend on antibiotic resistance and poor compliance. For improving the eradication rate of H. pylori, alternative therapy options combined with plant extracts, probiotics, bovine lactoferrin, curcumin, honey, and antioxidants have been investigated.14 Increasing rates of antimicrobial resistance to clarithromycin present challenges in maintaining optimal eradication rates. Various methods of enhancing the eradication rates of H. pylori have been investigated, including changing combinations or durations of established drugs, adding adjuvant drugs. In the present study, we have evaluated the possible supplementation of Vit C to clarithromycin-based triple therapy and if it could provide an additional advantage for achieving significantly higher eradication rates for H. pylori infection. Our results revealed that eradication rate was higher in Vit C treated group (group B) than in non-Vit C treated group (group A) (73.91% and 70.45%, respectively). Although Vit C supplementation was added to the clarithromycin-based triple therapy, there were no statistically significant differences between group A and B (P = .663 in ITT analysis and P = .727 in PP analysis) (Table 2). Several clinical studies have shown that high H. pylori infection rate is related to low AA/Vit C level in serum as well as in gastric juice.8 On the other hand high dose of Vit C have been shown to inhibit H. pylori growth, colonization, or even eradication of H. pylori infection in few studies, while others gave nonconclusive results. But still it is not clear how Vit C level can affect the course of H. pylori infection in stomach and how the infection affects the level of Vit C in serum and gastric juice.9 Urease is an important enzyme that constitutes approximately 5% to 6% of the total protein of H. pylori and it is linked to its pathogenicity,15 due to its ability to colonize on the gastric mucosa at a low pH.16 The ability of Vit C to inhibit urease action plays an important role in understanding the mechanism of H. pylori infection and bacterial eradication. Studies show that the high concentration of Vit C favors reduction of the nickel center in the urease enzyme,17 which in turn inhibits the activity of the enzyme and may reduce the H. pylori manifestations. Vit C, a reducing agent of urease, when added to the gastric lumen results in urease becoming structurally unstable, therefore, irreversibly losing its enzyme activity. Therefore, Vit C can be beneficial in inhibiting the growth, colonization, and endurance of H. pylori at an earlier period of the infection and may be helpful in the eradication of the bacteria.16 In low gastric pH, once urease is inactive it becomes difficult for H. pylori to survive and colonize in stomach. But once it successfully colonizes into stomach wall, H. pylori stays within the gastric mucosa, where the pH is suitable for the survival of the bacteria, due to the bicarbonate buffer from gastric epithelium secreted into the luminal surface.18 Moreover, after chronic infection, a proportion of patients develop relative achlorhydria, leading to higher pH of gastric juice.19 So at this stage of infection, role of urease for its survival is relatively less. This might explain the fact that even a high-dose AA supplementation is not able to eradicate H. pylori infection in a significant percentage of cases.9 Thus it is possible that AA can have an anti-H. pylori effect during initiation, spreading, and perpetuation of the infection although major effect could be during initiation of colonization. Despite we did not found sufficient studies assessing the effect of supplementation of Vit C to the eradication therapy for H. pylori infection, nevertheless there have been a few recent studies report an increased eradication of H. pylori when triple therapy was supplemented with Vit C.13 Zojaji et al conducted a study in which two groups were given amoxicillin 1 g with metronidazole 500 mg bid and bismuth 240 mg bid, with omeprazole 40 mg qid in two divided doses. The second group was given an additional 500 mg of Vit C. Experimental results showed that 78% of individuals of group B with the additional Vit C were able to eradicate H. pylori as compared to 48.8% of individuals from group A.20 Additionally, similar results were shown by Jarosz et al in which two groups of patients with H. pylori infection were treated without the administration of any antibiotics. The control group was treated with antacids for 4 weeks, whereas the second group was treated with the same antacids for 4 weeks with an additional dose of 5 g of Vit C daily for a span of 4 weeks. Plasma and gastric juice total Vit C levels were measured at baseline, at the end of 4 weeks' treatment, and again 4 weeks after treatment cessation. In the control group, H. pylori infection remained unchanged in all the patients; however, the patients with Vit C treatment were able to eradicate the H. pylori (P = .01).21 Interestingly, in one study Vit C was supplemented two more weeks following completion of triple therapy showing better eradication rate than achievable by triple therapy alone.22 These studies do show promising results; however, more research must be conducted to determine the best treatment options accompanied by Vit C dosages for the treatment of H. pylori. In the opposite direction, another few clinical studies have been carried out where different conventional anti-H. pylori regimens supplemented with Vit C were used. The results of these studies range from no benefit on Vit C supplementation with conventional anti-H. pylori regimens to studies which reported that Vit C decreased effectiveness of conventional anti-H. pylori.23 Yet there is no convincing evidence if supplementation of Vit C along with triple therapy could be beneficial in eradicating resistant H. pylori infection. On the other hand, there is considerable interest in diagnostic methods for H. pylori infection both before and after treatment. Generally, H. pylori infection can be diagnosed by invasive (endoscopy and biopsy) and noninvasive techniques (eg, serology, urea breath test [UBT], stool test). In recent years, various new endoscopic techniques have been developed that allow a clear visualization of minute mucosal structures. The new detailed images have enabled endoscopists to observe microscopic structures, such as gastric pit patterns, microvessels, cell morphology, and even microbes. NBI is a novel endoscopic technique that may enhance the accuracy of diagnosis by using narrow-bandwidth filters in a red-green-blue sequential illumination system.24 In the present study, we use the ME-NBI for diagnosis of H. pylori infection because it was studied by several researchers in both Asian and Western populations with high sensitivity and specificity. Furthermore, some Japanese studies demonstrated up to 100% specificity. Actually this NBI modality for diagnosis of H. pylori was established in many gastrointestinal endoscopy units, including our unit, without the need to do biopsy or rapid urease test. In addition, we add stool antigen test just to increase our already high sensitivity and specificity by ME-NBI for diagnosis of H. pylori infection, which reaches to 93% and 95%, respectively. According to Yagi's classification, the normal body mucosa shows collecting venules and true capillaries that form a network surrounding gastric pits with a pinhole-like appearance (Z0 pattern), while other three types (Z1, Z2, and Z3) corresponded to the H. pylori-positive mucosa. Z0 pattern had a 93.8% sensitivity and a 96.2% specificity for predicting normal gastric mucosa without H. pylori infection.25 Similarly, Nakagawa's classification divided the morphology of collecting venules into three patterns: regular (R), irregular (I), and obscured (O). The sensitivity and specificity of R pattern gastric mucosa as an indicator of the absence of H. pylori infection were 63.9% and 100%, respectively.26 Anagnostopoulos et al27 tested the feasibility of magnifying endoscopy in a Western population, and the gastric body was categorized into four types: type 1, regular arrangement of the majority of the studies to evaluate gastric mucosal patterns have been conducted by Japanese investigators collecting venules and regular, round pits; type 2, regular, round pits, but loss of collecting venules; type 3, loss of normal collecting venules, with enlarged white pits surrounded by erythema; and type 4, loss of normal round pits, with irregular arrangement of collecting venules. The sensitivity and specificity of types 2 and 3 patterns for predicting H. pylori infection were 100% and 92.7%, respectively. The type 4 pattern corresponded to atrophic gastritis with a sensitivity of 90% and a specificity of 96%. In the present study we combined both ME-NBI to diagnose H. pylori chronic gastritis supported with stool antigen test as a gold standard to increase sensitivity and specificity for detection of H. pylori infection. In this study we conducted stool antigen test for H. pylori infection to support our endoscopic diagnosis as stool antigen test is a sensitive and specific noninvasive test in the diagnosis of H. pylori infection. It is inexpensive28 and easy to perform and is highly accurate in patients untreated for H. pylori infection. Although some authors have reported a high number of false-positive results in post eradication assessment using H. pylori stool antigen test, the majority of studies suggest that the test is very accurate, and in a recent post-therapy follow-up study involving 10 dedicated European centers, the sensitivity and specificity of H. pylori stool antigen test (93.8% and 96.9%) and UBT (90.6% and 99.2%) were very similar.29 In the present study, there were several limitations including small sample size; therefore, more prospectively designed clinical trials considering Vit C in combination with clarithromycin-based triple therapy are needed. Non-randomized controlled trials can detect associations between an intervention and an outcome, they cannot rule out the possibility that the association was caused by a third factor linked to both intervention and outcome.

Our results demonstrated that supplementing Vit C to clarithromycin-based triple therapy did not provide an additional advantage for achieving significantly higher eradication rates for H. pylori-related chronic gastritis and most likely to be preventive rather than curative. Moreover, a further randomized trial to evaluate the effect of Vit C supplementation in H. pylori eradication is mandatory.

ACKNOWLEDGMENTS

Thanks to Dr Mohamed Nabil Rafat, the head of our Internal Medicine Department and Dr Fathy El Ghamry, the head of Gastroenterology Unit. Special thanks to gastroenterology units of El Hussein University Hospital.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

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H Pylori Vitamin C

Source: https://onlinelibrary.wiley.com/doi/full/10.1002/aid2.13148

H Pylori Vitamin C