Review Open Access
Copyright ©The Author(s) 2003. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 15, 2003; 9(10): 2137-2139
Published online Oct 15, 2003. doi: 10.3748/wjg.v9.i10.2137
Helicobacter pylori infection and micronutrient deficiencies
Javed Yakoob, Wasim Jafri, Shahab Abid, Section of Gastroenterology, Department of Medicine, Aga Khan University Hospital, Stadium Road, Karachi, Pakistan
Author contributions: All authors contributed equally to the work.
Correspondence to: Javed Yakoob, MBBS, PhD. Section of Gastroe-nterology, Department of Medicine, Agha Khan University Hospital, Stadium Road, Karachi-74800, Pakistan. yakoobjaved@hotmail.com
Telephone: +92-21-48594661 Fax: +92-21-4934294
Received: June 5, 2003
Revised: August 12, 2003
Accepted: August 19, 2003
Published online: October 15, 2003

Abstract

It is known that deficiencies of micronutrients due to infections increase morbidity and mortality. This phenomenon depicts itself conspicuously in developing countries. Deficiencies of iron, vitamins A, E, C, B12, etc are widely prevalent among populations living in the third world countries. Helicobacter pylori (H pylori) infection has a high prevalence throughout the world. Deficiencies of several micronutrients due to H pylori infection may be concomitantly present and vary from subtle sub-clinical states to severe clinical disorders. These essential trace elements/micronutrients are involved in host defense mechanisms, maintaining epithelial cell integrity, glycoprotein synthesis, transport mechanisms, myocardial contractility, brain development, cholesterol and glucose metabolism. In this paper H pylori infection in associaed with various micronutrients deficiencies is briefly reviewed.




INTRODUCTION

Helicobacter pylori (H pylori) is a gram negative, microaerophilic human pathogen which colonizes the gastric mucosa. Infection with H pylori leads to gastritis and is associated with the development of peptic ulcer disease, gastric carcinoma and lymphoma[1]. H pylori may be acquired at any age, and the infection persists for years once acquired. The age specific prevalence of H pylori infection is higher in developing countries and particularly in lower socioeconomic group[2]. In developing countries H pylori infection occurs early in life, and hypochlorhydria commonly seen in the malnourished predisposes them to repeated gastrointestinal infection, persistent diarrhea and malnutrition[3]. H pylori infection usually causes both acute and chronic inflammatory cell infiltration, leading to an increase in reactive oxygen species (ROS) which have been shown to accumulate in H pylori gastritis[4]. Excessive production of reactive oxygen metabolites (ROMs) by phagocytic cells is thought to contribute to mucosal lesions produced by H pylori infection. These are highly reactive compounds capable of combining with DNA in a number of potentially genotoxic ways[5]. Reactive oxygen species can react with the lipid-bilayers releasing peroxidation products such as malondialdehyde. These processes could lead to alterations in the structure of DNA facilitating mutations and carcinogenesis.

Nutrition is a critical determinant of the outcome of host microbe interactions through a modulation of the immune response. “Micronutrient” or “trace elements” are generally defined as constituting less than 0.01% of body mass and are needed in much smaller amounts. Trace minerals and vitamins are essential for life and include iron (Fe), zinc (Zn), copper (Cu), nickel (Ni), etc. They act as essential cofactors of enzymes and as organizers of the molecular structures of the cell, e.g. mitochondria and its membrane. Deficiencies of micronutrients influence immune homeostasis and thus affect infection-related morbidity and mortality. Micronutrients like β carotene, vitamin C, selenium, copper and others are powerful antioxidants and have a significant impact on infection related morbidity in humans. Subclinical deficiencies are known to impair biological and immune functions in the host. Antioxidants play a part in gastric mucosal defense by protecting against damage caused by excessive oxygen derived free radicals. β-carotene and α-tocopherol are lipophilic and have been shown to suppress the oxidation induced by either lipophilic or hydrophilic radical species[6]. In addition, they could act as anti-carcinogens through their ability to prevent the formation of N-nitrosamines which are important in the development of gastric carcinoma[7]. These vitamins are the major oxidant scavengers in biomembranes in contrast to vitamin C, which is mainly responsible for scavenging free radicals in the aqueous phase. However, compensatory mechanisms may become defective while gastric inflammation develops from normal to chronic gastritis and finally to gastric atrophy/intestinal metaplasia, perhaps due to reduced infiltration of inflammatory cells, loss of gastric gland cells and increased ROM production.

IRON

Iron deficiency anemia affects all groups of the under privileged population in most developing countries. Iron is an essential growth factor for H pylori, which contains Fe in their outer membrane protein and a system for intracellular storage of iron, consisting of ferritin like molecules pfr and napA[8]. Patients with H pylori associated iron deficiency anemia (IDA) would have involvement of both antral and corporal mucosa when compared with controls (90% vs 42.7%; P = 0.0001)[9]. Iron deficiency anemia associated with H pylori gastritis is characterized by a concomitant increase in median intragastric pH value > 3 and lowering of intragastric concentrations of ascorbic acid. A significant percentage (43%) of H pylori positive IDA patients presented atrophic changes in the gastric body, and the remaining had a superficial gastritis extended to the fundic mucosa, in contrast with H pylori positive controls[10]. H pylori eradication has also been shown to improve the absorption of other nutrients besides iron, and produce more rapid and complete clinical responses in patients with iron deficiency anemia[11].

COPPER

Copper is involved in the function of several enzymes. It is required for infant growth, host defense mechanisms, bone strength, red and white cell maturation, iron transport, etc. Acquired deficiency is mainly seen in infants. However, it has been diagnosed also in malnourished children and adults[12]. A gene, copA, associated with copper transport, has been isolated from H pylori UA802. The adenosine triphosphatase-derived copper-transporting mechanism is employed by various H pylori strains[13]. As a cofactor in various redox enzymes and an essential trace metal required for the synthesis of metalloproteins, copper plays a role in the pathogenesis of H pylori. H pylori has a differential effect on some gastric mucosal scavenger enzymes of ROMs, namely mitochondrial and cytoplasmic superoxide dismutases reflected by a large increase in the cytokine inducible manganese superoxide dismutase and a decrease in the constitutive copper/zinc superoxide dismutase[14].

VITAMIN B12

The mechanisms of vitamin B12 malabsorption caused by H pylori infection are unclear but following are the possibilities: a) The diminished acid secretion in H pylori induced gastritis may lead to a failure of critical splitting of vitamin B12 from food binders and its subsequent transfer to R binder in the stomach. b) A secretory dysfunction of the intrinsic factor. c) Decreased secretion of ascorbic acid from the gastric mucosa and increased gastric pH[15,16]. Annibale et al[17] studied the prevalence of H pylori infection in pernicious anemia patients and have demonstrated that almost two thirds of pernicious anemia patients had evidence of H pylori but only those with an active H pylori infection had distinctively functional and histological features. These findings support the hypothesis that H pylori infection could play a triggering role in a subgroup of pernicious anemia patients, and suggest the possibility that H pylori is involved in the early stages of PA that lead to severe corpus atrophy. The later progress of gastritis seems to be dependent on factors other than H pylori, most likely “autoimmune” mechanisms[18]. H pylori may also be involved in the pathogenesis of pernicious anemia via antigenic mimicry as antibodies directed against the H+, K+- adenosine-triphosphate protein that has been found in high numbers of patients with H pylori infection[19]. Food cobalamin malabsorption may occur without gastric atrophy or achlorhydria. Malabsorption can respond to antibiotics, but only in some patients[20].

VITAMIN A

Vitamin A has effects on important determinants of immune function and epithelial cell integrity such as gene expression, cellular proliferation and differentiation and also glycoprotein synthesis. Loss of integrity of the epithelial lining of mucus membranes in a vitamin A deficient state could explain its close association with increased susceptibility to infections particularly of gastrointestinal, respiratory and genitourinary tracts especially in children and pregnant women[21]. Even mild or subclinical vitamin A deficiency could induce keratinizing metaplasia of the epithelium and depletes goblet cells from mucosal linings thus causing xerosis of the membrane[22]. The xerotic surfaces form potential sites for increased bacterial adherence thus leading to bacterial colonization. The antimicrobial enzyme lysozyme depends on vitamin A for its synthesis. A decrease in T cell number with no change in proliferative activity has been demonstrated in children suffering from mild xerophthalmia due to vitamin A deficiency. H pylori infection and low β-carotene in plasma contribute to the increased risk of gastric atrophy, indicating that H pylori infection might be associated with low plasma β-carotene[23].

VITAMIN E

Vitamin E is composed of a group of compounds termed tocopherols and tocotrienols. α-tocopherol is the major active form in the human body, accounting for 95% of vitamin E and is the most effective lipid soluble anti-oxidant in biomembranes. It acts as the major chain breaking antioxidant and is able to interfere with the propagation of lipid peroxidation. It plays an immune modulatory part and is capable of increasing natural killer cell activity. Concentrations of α-tocopherol in H pylori negative subjects were higher in the corpus than in the antrum or duodenum[6]. This distribution of α-tocopherol is reversed in the presence of antral H pylori infection. These findings may reflect a mobilization of antioxidant defenses to the sites of maximal inflammation in the stomach.

VITAMIN C

Vitamin C exists as ascorbic acid (AA) or dehydroascorbic acid. The stomach secretes ascorbic acid across the gastric mucosa into the gastric juice against a concentration gradient. Ascorbic acid is the reduced form of the vitamin and can act as a potent antioxidant, and is able to scavenge ROS in gastric mucosa. This has been proposed as one means by which it exerts an anti-carcinogenic effect. Ascorbic acid may also prevent formation of N-nitroso compounds in gastric juice by scavenging nitrite. It has been observed that diets poor in foods containing AA were associated with an increased risk of gastric cancer[24]. Wei-cheng et al[25] showed that presence of H pylori infection at the baseline and smoking were strongly associated with progression to dysplasia or gastric cancer, whereas the risk of progression was decreased by 80% among subjects with baseline ascorbic acid levels in the highest tertile compared with those in the lowest tertile. A number of studies have demonstrated that gastric juice but not gastric mucosal AA levels were reduced in the presence of H pylori gastritis and that successful eradication restored the juice/plasma AA ratio[23,26]. The lower plasma AA concentration in H pylori positive subjects could be due to reduced bioavailability, active secretion from plasma to gastric juice in attempts to restore the positive gastric juice/plasma ratio or both[27]. In some studies no difference was found in the gastric juice AA concentration between patients with antral-limited gastritis and H pylori negative healthy controls, while lower AA levels were observed in patients with gastric body involvement and increased pH[28]. These observations suggest that AA, which is very unstable in the presence of increased pH, is converted to the less active form of dehydroascorbic acid, in the presence of gastric damage extending to the corporal mucosa with consequent hypochlorhydria[29,30]. It has been demonstrated that eradication of H pylori could lead to a reduction in ROS activity in gastric mucosa[31]. Ascorbic acid has also been shown to inhibit H pylori urease activity and growth in vitro[32]. H pylori infection associated low gastric juice-ascorbic acid levels return to normal after successful eradication of the infection[33]. A study of antibiotic treatment failure showed that compliant patients in whom H pylori infection did not clear had lower baseline plasma and gastric juice vitamin C concentrations than patients whose infection was cleared[26].

In developing countries micronutrient deficiencies facilitated by H pylori infection are a clinical and public health problem. It is essential to define the precise extent of the problem. Several micro and macronutrient deficiencies could be concomitantly present in the population with several other deficits. They will require correction to achieve significant effects on the over all health of the population.

Footnotes

Edited by Wang XL

References
1.  Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology. 1998;114:1169-1179.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 625]  [Cited by in F6Publishing: 595]  [Article Influence: 22.9]  [Reference Citation Analysis (0)]
2.  Graham DY. Helicobacter pylori: its epidemiology and its role in duodenal ulcer disease. J Gastroenterol Hepatol. 1991;6:105-113.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 254]  [Cited by in F6Publishing: 254]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
3.  Gilman RH, Partanen R, Brown KH, Spira WM, Khanam S, Greenberg B, Bloom SR, Ali A. Decreased gastric acid secretion and bacterial colonization of the stomach in severely malnourished Bangladeshi children. Gastroenterology. 1988;94:1308-1314.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Farinati F, Della Libera G, Cardin R, Molari A, Plebani M, Rugge M, Di Mario F, Naccarato R. Gastric antioxidant, nitrites, and mucosal lipoperoxidation in chronic gastritis and Helicobacter pylori infection. J Clin Gastroenterol. 1996;22:275-281.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 62]  [Article Influence: 2.2]  [Reference Citation Analysis (1)]
5.  Guyton KZ, Kensler TW. Oxidative mechanisms in carcinogenesis. Br Med Bull. 1993;49:523-544.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Sies H, Stahl W. Vitamins E and C, beta-carotene, and other carotenoids as antioxidants. Am J Clin Nutr. 1995;62:1315S-1321S.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Hwang H, Dwyer J, Russell RM. Diet, Helicobacter pylori infection, food preservation and gastric cancer risk: are there new roles for preventative factors? Nutr Rev. 1994;52:75-83.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 47]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
8.  Dundon WG, Polenghi A, Del Guidice G, Rappuoli R, Montecucco C. Neutrophil-activating protein (HP-NAP) versus ferritin (Pfr): comparison of synthesis in Helicobacter pylori. FEMS Microbiol Lett. 2001;199:143-149.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 34]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
9.  Annibale B, Capurso G, Delle Fave G. Consequences of Helicobacter pylori infection on the absorption of micronutrients. Dig Liver Dis. 2002;34 Suppl 2:S72-S77.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 46]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
10.  Annibale B, Capurso G, Lahner E, Passi S, Ricci R, Maggio F, Delle Fave G. Concomitant alterations in intragastric pH and ascorbic acid concentration in patients with Helicobacter pylori gastritis and associated iron deficiency anaemia. Gut. 2003;52:496-501.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 117]  [Cited by in F6Publishing: 113]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
11.  Annibale B, Marignani M, Monarca B, Antonelli G, Marcheggiano A, Martino G, Mandelli F, Caprilli R, Delle Fave G. Reversal of iron deficiency anemia after Helicobacter pylori eradication in patients with asymptomatic gastritis. Ann Intern Med. 1999;131:668-672.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 133]  [Cited by in F6Publishing: 134]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
12.  Olivares M, Uauy R. Copper as an essential nutrient. Am J Clin Nutr. 1996;63:791S-796S.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Ge Z, Jiang Q, Taylor DE. Conservation and diversity of the Helicobacter pylori copper-transporting ATPase gene (copA) sequence among Helicobacter species and Campylobacter species detected by PCR and RFLP. Helicobacter. 1996;1:112-117.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
14.  Götz JM, Thio JL, Verspaget HW, Offerhaus GJ, Biemond I, Lamers CB, Veenendaal RA. Treatment of Helicobacter pylori infection favourably affects gastric mucosal superoxide dismutases. Gut. 1997;40:591-596.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 22]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
15.  Del Corral A, Carmel R. Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice. Gastroenterology. 1990;98:1460-1466.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Appelmelk BJ, Simoons-Smit I, Negrini R, Moran AP, Aspinall GO, Forte JG, De Vries T, Quan H, Verboom T, Maaskant JJ. Potential role of molecular mimicry between Helicobacter pylori lipopolysaccharide and host Lewis blood group antigens in autoimmunity. Infect Immun. 1996;64:2031-2040.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Annibale B, Lahner E, Bordi C, Martino G, Caruana P, Grossi C, Negrini R, Delle Fave G. Role of Helicobacter pylori infection in pernicious anaemia. Dig Liver Dis. 2000;32:756-762.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 46]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
18.  Varis O, Valle J, Siurala M. Is Helicobacter pylori involved in the pathogenesis of the gastritis characteristic of pernicious anemia? Comparison between pernicious anemia relatives and duodenal ulcer relatives. Scand J Gastroenterol. 1993;28:705-708.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 30]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
19.  Claeys D, Faller G, Appelmelk BJ, Negrini R, Kirchner T. The gastric H+,K+-ATPase is a major autoantigen in chronic Helicobacter pylori gastritis with body mucosa atrophy. Gastroenterology. 1998;115:340-347.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 168]  [Cited by in F6Publishing: 171]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
20.  Cohen H, Weinstein WM, Carmel R. Heterogeneity of gastric histology and function in food cobalamin malabsorption: absence of atrophic gastritis and achlorhydria in some patients with severe malabsorption. Gut. 2000;47:638-645.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 34]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
21.  Christian P, Schulze K, Stoltzfus RJ, West KP. Hyporetinolemia, illness symptoms, and acute phase protein response in pregnant women with and without night blindness. Am J Clin Nutr. 1998;67:1237-1243.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Reddy V, Rao V, Arunjyothi M. Conjunctival impression cytology for assessment of vitamin A status. Am J Clin Nutr. 1989;50:814-817.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Tsugane S, Kabuto M, Imai H, Goy F, Tai Y, Hanaoka T, Sugano K, Watanabe S. Helicobacter pylori, dietary factors and atrophic gastritis in five Japanese populations with different gastric can-cer mortality. Cancer Causes Control. 1993;4:297-305.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 92]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
24.  Block G. Epidemiologic evidence regarding vitamin C and cancer. Am J Clin Nutr. 1991;54:1310S-1314S.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  You WC, Zhang L, Gail MH, Chang YS, Liu WD, Ma JL, Li JY, Jin ML, Hu YR, Yang CS. Gastric dysplasia and gastric cancer: Helicobacter pylori, serum vitamin C, and other risk factors. J Natl Cancer Inst. 2000;92:1607-1612.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 190]  [Cited by in F6Publishing: 174]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
26.  Ruiz B, Rood JC, Fontham ET, Malcom GT, Hunter FM, Sobhan M, Johnson WD, Correa P. Vitamin C concentration in gastric juice before and after anti-Helicobacter pylori treatment. Am J Gastroenterol. 1994;89:533-539.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Woodward M, Tunstall-Pedoe H, McColl K. Helicobacter pylori infection reduces systemic availability of dietary vitamin C. Eur J Gastroenterol Hepatol. 2001;13:233-237.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 49]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
28.  Zhang ZW, Patchett SE, Perrett D, Katelaris PH, Domizio P, Farthing MJ. The relation between gastric vitamin C concentrations, mucosal histology, and CagA seropositivity in the human stomach. Gut. 1998;43:322-326.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 101]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
29.  Sobala GM, Schorah CJ, Shires S, Lynch DA, Gallacher B, Dixon MF, Axon AT. Effect of eradication of Helicobacter pylori on gastric juice ascorbic acid concentrations. Gut. 1993;34:1038-1041.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 106]  [Cited by in F6Publishing: 115]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
30.  Waring AJ, Drake IM, Schorah CJ, White KL, Lynch DA, Axon AT, Dixon MF. Ascorbic acid and total vitamin C concentrations in plasma, gastric juice, and gastrointestinal mucosa: effects of gastritis and oral supplementation. Gut. 1996;38:171-176.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 89]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
31.  Goodman KJ, Correa P, Tenganá Aux HJ, DeLany JP, Collazos T. Nutritional factors and Helicobacter pylori infection in Colombian children. J Pediatr Gastroenterol Nutr. 1997;25:507-515.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 70]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
32.  Nilius M, Bode G, Lehnhardt G, Malfertheiner P. In vitro inhibition of Helicobacter pylori urease: biochemical and ultrastructural analysis. Eur J Clin Invest. 1991;21:551-557.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 21]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
33.  Phull PS, Green CJ, Jacyna MR. A radical view of the stomach: the role of oxygen-derived free radicals and anti-oxidants in gastroduodenal disease. Eur J Gastroenterol Hepatol. 1995;7:265-274.  [PubMed]  [DOI]  [Cited in This Article: ]