Note：All the information in this draft can be edited by authors. And the entry will be online only after authors edit and submit it.

1. Introduction

Micronutrient deficiencies are relatively common worldwide and are recognized as a global public health issue [1,2]. In particular, deficiencies of the erythropoietic micronutrients, iron, and cobalamin may potentially lead to life-threatening clinical consequences when not promptly recognized and treated, especially in elderly patients [3]. The stomach plays an important role in the homeostasis of several important hematopoietic micronutrients such as cobalamin and iron, and probably in others equally important like ascorbic acid, calcium, and magnesium [4–6].

Micronutrient deficiencies are relatively common worldwide and are recognized as a global public health issue ^[1][2]. In particular, deficiencies of the erythropoietic micronutrients, iron, and cobalamin may potentially lead to life-threatening clinical consequences when not promptly recognized and treated, especially in elderly patients ^[3]. The stomach plays an important role in the homeostasis of several important hematopoietic micronutrients such as cobalamin and iron, and probably in others equally important like ascorbic acid, calcium, and magnesium ^[4][5][6].

A key role is played by the gastric oxyntic mucosa composed of parietal cells whose main function is gastric acid secretion and production of intrinsic factor. Gastric acid secretion is necessary for the digestion and absorption of cobalamin and the absorption of iron, calcium, and probably magnesium, and is also essential for the secretion, activation, and absorption of ascorbic acid.

Cobalamin absorption from food requires the presence of gastric acid for at least two steps of this complex process: to release into the stomach the strictly protein-bound dietary cobalamin and to enhance the affinity of unbound cobalamin for salivary R proteins instead of intrinsic factor; besides, for the ileal absorption of cobalamin, intrinsic factor is necessary, which is also secreted by gastric parietal cells [5,7,8]. For the absorption of the non-haemic ferric iron, the most frequent form of iron in the Western diet, gastric acid is necessary to maintain solubilization, to avoid precipitation, and to make possible reduction and chelation by ascorbic acid, an important promoter of iron absorption [9]. Gastric acidity seems to play a role also in the homeostasis of ascorbic acid, the reduced form of vitamin C, as in a non-acidic environment, it is converted to dehydroascorbic acid, a less active form [5,10]. Ascorbic acid further promotes iron absorption, thus decreased bioavailability of this micronutrient may imply negative effects on iron absorption [11].

Cobalamin absorption from food requires the presence of gastric acid for at least two steps of this complex process: to release into the stomach the strictly protein-bound dietary cobalamin and to enhance the affinity of unbound cobalamin for salivary R proteins instead of intrinsic factor; besides, for the ileal absorption of cobalamin, intrinsic factor is necessary, which is also secreted by gastric parietal cells ^[5][7][8]. For the absorption of the non-haemic ferric iron, the most frequent form of iron in the Western diet, gastric acid is necessary to maintain solubilization, to avoid precipitation, and to make possible reduction and chelation by ascorbic acid, an important promoter of iron absorption ^[9]. Gastric acidity seems to play a role also in the homeostasis of ascorbic acid, the reduced form of vitamin C, as in a non-acidic environment, it is converted to dehydroascorbic acid, a less active form ^[5][10]. Ascorbic acid further promotes iron absorption, thus decreased bioavailability of this micronutrient may imply negative effects on iron absorption ^[11].

Several pathological conditions such as Helicobacter pylori-related gastritis and corpus atrophic gastritis [5,6,12], as well as antisecretory drugs, especially proton pump inhibitors [13], and also gastric surgery [14–16], may interfere with the normal functioning of the gastric oxyntic mucosa and micronutrients homeostasis. The hypochlorhydric stomach in patients with autoimmune and non-autoimmune corpus atrophic gastritis has been shown to allow the survival and colonization of bacterial strains other than Helicobacter pylori, and it is suggested that gastric dysbiosis is related to the increased risk of gastric cancer in this condition [17]. The specific role of gastric dysbiosis in the impairment of micronutrient bioavailability or absorption has not been reported so far.

Several pathological conditions such as Helicobacter pylori-related gastritis and corpus atrophic gastritis ^[5][6][12], as well as antisecretory drugs, especially proton pump inhibitors ^[13], and also gastric surgery ^[14][15][16], may interfere with the normal functioning of the gastric oxyntic mucosa and micronutrients homeostasis. The hypochlorhydric stomach in patients with autoimmune and non-autoimmune corpus atrophic gastritis has been shown to allow the survival and colonization of bacterial strains other than Helicobacter pylori, and it is suggested that gastric dysbiosis is related to the increased risk of gastric cancer in this condition ^[17]. The specific role of gastric dysbiosis in the impairment of micronutrient bioavailability or absorption has not been reported so far.

This often forgotten link between the stomach and micronutrients may have a relevant impact on a huge amount of people. Taking into consideration the high prevalence of Helicobacter pylori infection all over the world, its role in micronutrient malnutrition may have paramount clinical implications: albeit a decreasing trend has been shown globally in the last years, yet more than 50% of people in the world are infected by Helicobacter pylori¸ and in Africa, Central and South America, a large part of the population is infected by Helicobacter pylori [18]. This is even more true when taking into account that in poorly industrialized, developing regions, a high prevalence of Helicobacter pylori infection and micronutrient malnutrition are concomitant [19,20]. The estimated prevalence of corpus atrophic gastritis ranges up to 24% based on serology and 34% based on histology [12]. Moreover, antisecretory agents, in particular, proton pump inhibitors are one of the most widely used drugs in the Western world [21], and are the mainstay of treatment of gastroesophageal reflux disease and its complications, including short- and long-term therapy of Helicobacter pylori-negative peptic ulcers; healing and prevention of drug-associated gastric ulcers; co-therapy with endoscopic procedures to control upper digestive bleeding; medical treatment of Zollinger Ellison syndrome, and; eradication of Helicobacter pylori infection together with two or more antibiotics [22]. In the last years, gastric surgical procedures are increasingly performed to treat obesity. According to a 2013 worldwide survey, the total number of bariatric procedures performed worldwide in 2013 was 468,609, with the vast majority (95.7%) carried out laparoscopically, and the highest number (n = 154,276) performed in the USA/Canada. Worldwide, the most common procedure was Roux-en-Y gastric bypass (45%) followed by sleeve gastrectomy (37%) [23].

This often forgotten link between the stomach and micronutrients may have a relevant impact on a huge amount of people. Taking into consideration the high prevalence of Helicobacter pylori infection all over the world, its role in micronutrient malnutrition may have paramount clinical implications: albeit a decreasing trend has been shown globally in the last years, yet more than 50% of people in the world are infected by Helicobacter pylori¸ and in Africa, Central and South America, a large part of the population is infected by Helicobacter pylori ^[18]. This is even more true when taking into account that in poorly industrialized, developing regions, a high prevalence of Helicobacter pylori infection and micronutrient malnutrition are concomitant ^[19][20]. The estimated prevalence of corpus atrophic gastritis ranges up to 24% based on serology and 34% based on histology ^[12]. Moreover, antisecretory agents, in particular, proton pump inhibitors are one of the most widely used drugs in the Western world ^[21], and are the mainstay of treatment of gastroesophageal reflux disease and its complications, including short- and long-term therapy of Helicobacter pylori-negative peptic ulcers; healing and prevention of drug-associated gastric ulcers; co-therapy with endoscopic procedures to control upper digestive bleeding; medical treatment of Zollinger Ellison syndrome, and; eradication of Helicobacter pylori infection together with two or more antibiotics ^[22]. In the last years, gastric surgical procedures are increasingly performed to treat obesity. According to a 2013 worldwide survey, the total number of bariatric procedures performed worldwide in 2013 was 468,609, with the vast majority (95.7%) carried out laparoscopically, and the highest number (n = 154,276) performed in the USA/Canada. Worldwide, the most common procedure was Roux-en-Y gastric bypass (45%) followed by sleeve gastrectomy (37%) ^[23].

2. Physiology of Gastric Oxyntic Mucosa: Secretion of Gastric Acid and Intrinsic Factor

The human stomach has both exocrine and endocrine secretory activities. The proximal part of the stomach (fundus and corpus) is characterized by oxyntic glands (composed of: mucous cell [mucus]; parietal cell [hydrochloric acid and intrinsic factor]; D cell [somatostatin]; chief cell [pepsinogen and leptin]; enterochromaffin-like cell [histamine]; A-like or Gr Cell [ghrelin]), and the distal part (antrum) presented pyloric glands (composed of: mucous cell [mucus]; G cell [gastrin]; D cell [somatostatin]; enterochromaffin cell [atrial natriuretic peptide]) [24,25]. Among these substances, hydrochloric acid (HCl) and intrinsic factor (IF) is essential for the proper absorption of some micronutrients.

The human stomach has both exocrine and endocrine secretory activities. The proximal part of the stomach (fundus and corpus) is characterized by oxyntic glands (composed of: mucous cell [mucus]; parietal cell [hydrochloric acid and intrinsic factor]; D cell [somatostatin]; chief cell [pepsinogen and leptin]; enterochromaffin-like cell [histamine]; A-like or Gr Cell [ghrelin]), and the distal part (antrum) presented pyloric glands (composed of: mucous cell [mucus]; G cell [gastrin]; D cell [somatostatin]; enterochromaffin cell [atrial natriuretic peptide]) ^[24][25]. Among these substances, hydrochloric acid (HCl) and intrinsic factor (IF) is essential for the proper absorption of some micronutrients.

HCl is produced by proton pumps, membrane proteins with ATPase activity (H+, K + ATPase) located on the parietal cells. The secretion of HCl is finely regulated by the coordination of several signals (endocrine, paracrine, and neurocrine) acting directly and/or indirectly on its release [26,27]. Table 1 provides a summary of the principal stimulants and inhibitors of HCl secretion and their relative mechanisms of action [25–28].

HCl is produced by proton pumps, membrane proteins with ATPase activity (H+, K + ATPase) located on the parietal cells. The secretion of HCl is finely regulated by the coordination of several signals (endocrine, paracrine, and neurocrine) acting directly and/or indirectly on its release ^[26][27]. Table 1 provides a summary of the principal stimulants and inhibitors of HCl secretion and their relative mechanisms of action ^{[25][26][27][28]}.

Table 1.

Principals stimulants and inhibitors of human gastric acid secretion and their mechanisms of action.

ECL = enterochromaffin-like

Similarly, IF secretion is stimulated via all pathways known to stimulate gastric acid secretion: histamine, gastrin, and acetylcholine ^[29].

Thus, an inflammatory injury eventually leading to apoptosis of gastric glands or pharmacological inhibition of gastric stimulants such as H₂ blockers, or of specific functions like proton pump inhibitors, give arise to impairment of the functioning of these highly specialized cells. When gastric parietal cells are involved in this process, this may give rise to reduced production of gastric acid and/or intrinsic factor. Gastric secretion may be reduced also by another mechanism: when important stimulants of gastric acid secretion are lacking, for example, antral G cells after partial gastric resection, gastric acid secretion is heavily impaired and intragastric pH will increase.

3. The Role of the Stomach in Non-Bleeding-Related Iron Deficiency

Dietary iron is available in two different forms, such as heme and non-heme iron [11]. The heme iron (ferrous form) contained in the hemoglobin and myoglobin of meat, includes 5–10% of the total dietary iron in the Western diet. It is easily absorbed by the small intestine mucosal cells through a surface receptor. Non-heme iron (ferric iron) contained in cereals, vegetables, legumes, and fruits represents 80% of the dietary iron [30]. Non-heme iron is transported across the apical membrane of the enterocyte by divalent metal-ion transporter 1 (DMT1) and is exported into the circulation via ferroportin 1 (FPN1) [31]. This latter form is less-absorbable, not soluble, and precipitates at pH 3, being absorbable only when reduced to the ferrous or chelated form [11]. In physiological conditions, HCl and ascorbic acid play a crucial role in iron absorption promoting the reduction of non-heme iron from its ferric form to the ferrous form. Moreover, at acid pH (<3), ascorbic acid constitutes soluble chelates with ferric iron-reducing its polymerization and precipitation [32]. Keeping in mind these mechanisms, it is understandable how some pathological gastric conditions might affect iron absorption leading to iron deficiency and eventually iron deficiency anemia.

Dietary iron is available in two different forms, such as heme and non-heme iron ^[11]. The heme iron (ferrous form) contained in the hemoglobin and myoglobin of meat, includes 5–10% of the total dietary iron in the Western diet. It is easily absorbed by the small intestine mucosal cells through a surface receptor. Non-heme iron (ferric iron) contained in cereals, vegetables, legumes, and fruits represents 80% of the dietary iron ^[30]. Non-heme iron is transported across the apical membrane of the enterocyte by divalent metal-ion transporter 1 (DMT1) and is exported into the circulation via ferroportin 1 (FPN1) ^[31]. This latter form is less-absorbable, not soluble, and precipitates at pH 3, being absorbable only when reduced to the ferrous or chelated form ^[11]. In physiological conditions, HCl and ascorbic acid play a crucial role in iron absorption promoting the reduction of non-heme iron from its ferric form to the ferrous form. Moreover, at acid pH (<3), ascorbic acid constitutes soluble chelates with ferric iron-reducing its polymerization and precipitation ^[9]. Keeping in mind these mechanisms, it is understandable how some pathological gastric conditions might affect iron absorption leading to iron deficiency and eventually iron deficiency anemia.

Helicobacter pylori infection is the main etiologic factor of chronic gastritis [33–35]. This infection is one of the most common in humans worldwide and it is estimated that more than half of the world population is infected [36]. It is highly prevalent in developed countries and in Europe, it has been estimated that a variable proportion of subjects ranging from 11% to 84.2% are infected [37]. Sero-epidemiological studies published several years ago supported the association between Helicobacter pylori infection and low ferritin values [5,38–43].

Helicobacter pylori infection is the main etiologic factor of chronic gastritis ^[32][33][34]. This infection is one of the most common in humans worldwide and it is estimated that more than half of the world population is infected ^[35]. It is highly prevalent in developed countries and in Europe, it has been estimated that a variable proportion of subjects ranging from 11% to 84.2% are infected ^[36]. Sero-epidemiological studies published several years ago supported the association between Helicobacter pylori infection and low ferritin values ^{[5][37][38][39][40][41][42]}.

More recently, other authors worldwide reported the association between Helicobacter pylori infection and iron deficiency anemia. A recent study conducted in Mexico found a 7.8% prevalence of Helicobacter pylori infection in iron deficiency anemia patients referred to an academic hematology center [44], while an Egyptian study showed a higher prevalence of Helicobacter pylori infection in refractory iron deficiency anemia (61.5%) and a significant correlation between administration of anti-Helicobacter pylori treatment plus iron and improvement in terms of hemoglobin, mean corpuscular volume, iron, and ferritin levels [45]. A recent systematic review and meta-analysis showed that compared to uninfected subjects, Helicobacter pylori-infected individuals showed an increased likelihood of iron deficiency anemia (OR 1.72; 95%CI 1.23–2.42); and iron deficiency (OR 1.33; 95%CI 1.15–1.54), reporting increased ferritin levels following anti-Helicobacter pylori eradication therapy plus iron therapy as compared with iron therapy alone [46].

More recently, other authors worldwide reported the association between Helicobacter pylori infection and iron deficiency anemia. A recent study conducted in Mexico found a 7.8% prevalence of Helicobacter pylori infection in iron deficiency anemia patients referred to an academic hematology center ^[43], while an Egyptian study showed a higher prevalence of Helicobacter pylori infection in refractory iron deficiency anemia (61.5%) and a significant correlation between administration of anti-Helicobacter pylori treatment plus iron and improvement in terms of hemoglobin, mean corpuscular volume, iron, and ferritin levels ^[44]. A recent systematic review and meta-analysis showed that compared to uninfected subjects, Helicobacter pylori-infected individuals showed an increased likelihood of iron deficiency anemia (OR 1.72; 95% CI 1.23–2.42); and iron deficiency (OR 1.33; 95% CI 1.15–1.54), reporting increased ferritin levels following anti-Helicobacter pylori eradication therapy plus iron therapy as compared with iron therapy alone ^[45].

Among the hypothesized mechanisms determining the association between Helicobacter pylori and iron deficiency and/or iron deficiency anemia (i.e., virulence factors, competition with the host for the acquisition of alimentary iron), the most accredited hypothesis is that particular gastritis patterns with a more extensive degree of mucosal inflammation (pangastritis or corpus predominant gastritis) compared to a more limited, antrum-restricted gastritis may lead to iron malabsorption [11]. The corpus gastric inflammation causes an increase in intragastric pH, which was significantly higher in anemic patients than in controls (median value of 5.7 vs. 2) [47]. Thus, it is plausible that the gastric corpus involvement leads to reduced availability of alimentary iron due to decreased acidity.

Among the hypothesized mechanisms determining the association between Helicobacter pylori and iron deficiency and/or iron deficiency anemia (i.e., virulence factors, competition with the host for the acquisition of alimentary iron), the most accredited hypothesis is that particular gastritis patterns with a more extensive degree of mucosal inflammation (pangastritis or corpus predominant gastritis) compared to a more limited, antrum-restricted gastritis may lead to iron malabsorption ^[11]. The corpus gastric inflammation causes an increase in intragastric pH, which was significantly higher in anemic patients than in controls (median value of 5.7 vs. 2) ^[46]. Thus, it is plausible that the gastric corpus involvement leads to reduced availability of alimentary iron due to decreased acidity.

Similarly, corpus atrophic gastritis, a condition characterized by atrophy of oxyntic glands due to a long-standing Helicobacter pylori infection or autoimmunity, determines reduced gastric acid production with consequent iron malabsorption and eventually iron deficiency anemia ^[12]. Even if corpus atrophic gastritis has been traditionally considered as synonymous with pernicious anemia, and thus of cobalamin (vitamin B

₁₂) malabsorption, already in the 1960s the correction of iron absorption by adding gastric juice in patients with pernicious anemia was observed [48,49], suggesting the role of HCl in the absorption process. Firstly, Dickey et al. showed that about 20% of iron deficiency anemia patients had corpus atrophic gastritis, diagnosed by both gastric histology and high serum levels of gastrin [50]. Later, other authors reported that 19.5% to 26% of iron deficiency anemia patients without gastrointestinal symptoms have corpus atrophic gastritis [51,52]. Similar results were obtained by Hershko et al., who found that 27% of iron deficiency anemia patients in absence of evident gastrointestinal diseases, presented autoimmune atrophic gastritis [53]. In a more recent observational single-center study by Zilli et al., iron deficiency and iron-deficiency anemia were present in 34% and 13.1% of atrophic autoimmune gastritis patients respectively [6].

) malabsorption, already in the 1960s the correction of iron absorption by adding gastric juice in patients with pernicious anemia was observed ^[47][48], suggesting the role of HCl in the absorption process. Firstly, Dickey et al. showed that about 20% of iron deficiency anemia patients had corpus atrophic gastritis, diagnosed by both gastric histology and high serum levels of gastrin ^[49]. Later, other authors reported that 19.5% to 26% of iron deficiency anemia patients without gastrointestinal symptoms have corpus atrophic gastritis ^[50][51]. Similar results were obtained by Hershko et al., who found that 27% of iron deficiency anemia patients in absence of evident gastrointestinal diseases, presented autoimmune atrophic gastritis ^[52]. In a more recent observational single-center study by Zilli et al., iron deficiency and iron-deficiency anemia were present in 34% and 13.1% of atrophic autoimmune gastritis patients respectively ^[6].

Thus, in patients with iron deficiency or iron-deficiency anemia without manifest or occult bleeding, an accurate diagnosis of Helicobacter pylori infection and related gastritis is mandatory and the presence of corpus atrophic gastritis needs to be ruled out [36,54]. Therefore, gastroscopy with standard bioptic sampling is necessary. Superficial Helicobacter-pylori gastritis requires eradication treatment based on antibiotics and cure of infection generally leads to regression of iron deficiency or iron-deficiency anemia. Once corpus atrophic gastritis is present, the cure of Helicobacter pylori infection, when present, uncommonly gives rise to regression of anemia, and oral or intravenous iron supplementation is necessary depending on the severity of anemia.

References

1. Biebinger, R.; Hurrell, R.F. 3—Vitamin and mineral fortification of foods. In Food Fortification and Supplementation; Ottaway, P.B., Ed.; Woodhead Publishing: Cambridge, UK, 2008; pp. 27–40.
2. Maggini, S.; Pierre, A.; Calder, P.C. Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients 2018, 10, 1531, doi:10.3390/nu10101531.
3. Halawi, R.; Moukhadder, H.; Taher, A. Anemia in the elderly: A consequence of aging? Expert Rev. Hematol. 2017, 10, 327–335, doi:10.1080/17474086.2017.1285695.
4. Lahner, E.; Persechino, S.; Annibale, B. Micronutrients (Other than iron) and Helicobacter pylori Infection: A Systematic Review. Helicobacter 2012, 17, 1–15, doi:10.1111/j.1523-5378.2011.00892.x.
5. Annibale, B.; Capurso, G.; Fave, G.D. Consequences of Helicobacter pylori infection on the absorption of micronutrients. Liver Dis. 2002, 34, S72–S77, doi:10.1016/s1590-8658(02)80170-0.
6. Zilli, A.; Cavalcoli, F.; Ciafardini, C.; Massironi, S. Deficiency of micronutrients in patients affected by chronic atrophic autoimmune gastritis: A single-institution observational study. Liver Dis. 2019, 51, 505–509, doi:10.1016/j.dld.2018.08.028.
7. Carmel, R. 10 Malabsorption of food cobalamin. Baillieres Clin. Haematol. 1995, 8, 639–655.
8. Andrès, E.; Loukili, N.H.; Noel, E.; Kaltenbach, G.; Ben Abdelgheni, M.; Perrin, A.E.; Noblet-Dick, M.; Maloisel, F.; Schlienger, J.-L.; Blicklé, J.-F. Vitamin B12 (cobalamin) deficiency in elderly patients. Med Assoc. J. 2004, 171, 251–259.
9. Condrad, M.E.; Schade, S.G. Ascorbic acid chelates in iron absorption: Non-steroidal anti-inflammatory drugs; PA, perni cious anaemia—A role for hydrochloridric acid and bile. Gastroenterology 1968, 55, 35–45.
10. Salgueiro, J.; Zubillaga, M.; Goldman, C.; Barrado, A.; Sarrasague, M.M.; Leonardi, N.; Boccio, J. Review article: Is there a link between micronutrient malnutrition and Helicobacter pylori infection? Pharmacol. Ther. 2004, 20, 1029–1034.
11. Annibale, B.; Capurso, G.; Fave, G.D. The stomach and iron deficiency anaemia: A forgotten link. Liver Dis. 2003, 35, 288–295.
12. Lahner, E.; Zagari, R.M.; Zullo, A.; Di Sabatino, A.; Meggio, A.; Cesaro, P.; Lenti, M.V.; Annibale, B.; Corazza, G.R. Chronic atrophic gastritis: Natural history, diagnosis and therapeutic management. A position paper by the Italian Society of Hospital Gastroenterologists and Digestive Endoscopists [AIGO], the Italian Society of Digestive Endoscopy [SIED], the Italian Society of Gastroenterology [SIGE], and the Italian Society of Internal Medicine [SIMI]. Liver Dis. 2019, 51, 1621–1632, doi:10.1016/j.dld.2019.09.016.
13. Ito, T.; Jensen, R.T. Association of Long-Term Proton Pump Inhibitor Therapy with Bone Fractures and Effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium. Gastroenterol. Rep. 2010, 12, 448–457.
14. Lupoli, R.; Lembo, E.; Saldalamacchia, G.; Avola, C.K.; Angrisani, L.; Capaldo, B. Bariatric surgery and long-term nutritional issues. World J. Diabetes 2017, 8, 464–474, doi:10.4239/wjd.v8.i11.464.
15. Lange, J.; Königsrainer, A. Malnutrition as a Complication of Bariatric Surgery—A Clear and Present Danger? Med. 2019, 35, 305–311, doi:10.1159/000503040.
16. Shankar, P.; Boylan, M.; Sriram, K. Micronutrient deficiencies after bariatric surgery. Nutrition 2010, 26, 1031–1037, doi:10.1016/j.nut.2009.12.003.
17. Conti, L.; Annibale, B.; Lahner, E. Autoimmune Gastritis and Gastric Microbiota. Microorganisms 2020, 8, 1827, doi:10.3390/microorganisms8111827.
18. Burucoa, C.; Axon, A. Epidemiology of Helicobacter pylori infection. Helicobacter 2017, 22, e12403, doi:10.1111/hel.12403.
19. Black, R.E.; Victora, C.G.; Walker, S.; Bhutta, A.Z.; Christian, P.; De Onis, M.; Ezzati, M.; Grantham-McGregor, S.; Katz, J.; Martorell, R.; et al. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 2013, 382, 427–451, doi:10.1016/s0140-6736(13)60937-x.
20. Bailey, R.L.; West, K.P., Jr.; Black, R.E. The Epidemiology of Global Micronutrient Deficiencies. Nutr. Metab. 2015, 66, 22–33, doi:10.1159/000371618.
21. DeVault, K.R.; Talley, N.J. Insights into the future of gastric acid suppression. Rev. Gastroenterol. Hepatol. 2009, 6, 524–532.
22. Savarino, V.; Marabotto, E.; Zentilin, P.; Furnari, M.; Bodini, G.; De Maria, C.; Pellegatta, G.; Coppo, C.; Savarino, E. Proton pump inhibitors: Use and misuse in the clinical setting. Expert Rev. Clin. Pharmacol. 2018, 11, 1123–1134, doi:10.1080/17512433.2018.1531703.
23. Angrisani, L.; Santonicola, A.; Iovino, P.; Formisano, G.; Buchwald, H.; Scopinaro, N. Bariatric Surgery Worldwide 2013. Surg. 2015, 25, 1822–1832, doi:10.1007/s11695-015-1657-z.
24. Sáenz, J.B.; Mills, J.C. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Rev. Gastroenterol. Hepatol. 2018, 15, 257–273, doi:10.1038/nrgastro.2018.5.
25. Schubert, M.L.; Kaunitz, J.D. Gastric secretion. In Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/ Management, 9th ed.; Feldman, M., Friedman, L.S., Brandt, L.J., Eds.; Elsevier: Philadelphia, PA, USA, 2010; p. 817–32.
26. Kopic, S.; Geibel, J.P. Gastric Acid, Calcium Absorption, and Their Impact on Bone Health. Rev. 2013, 93, 189–268, doi:10.1152/physrev.00015.2012.
27. Engevik, A.C.; Kaji, I.; Goldenring, J.R. The Physiology of the Gastric Parietal Cell. Rev. 2020, 100, 573–602, doi:10.1152/physrev.00016.2019.
28. Schubert, M.L. Physiologic, pathophysiologic, and pharmacologic regulation of gastric acid secretion. Opin. Gastroenterol. 2017, 33, 430–438, doi:10.1097/mog.0000000000000392.
29. Festen, H.P.M. Intrinsic Factor Secretion and Cobalamin Absorption: Physiology and Pathophysiology in the Gastrointestinal Tract. J. Gastroenterol. 1991, 26, 1–7, doi:10.3109/00365529109111222.
30. Conrad, M.E.; Umbreit, J.N.; Moore, E.G. Iron Absorption and Transport. J. Med Sci. 1999, 318, 213–29, doi:10.1097/00000441-199910000-00002.
31. Anderson, G.J.; Frazer, D.M. Current understanding of iron homeostasis. J. Clin. Nutr. 2017, 106, 1559S–1566S, doi:10.3945/ajcn.117.155804.
32. Conrad, M.E.; Schade, S.G. Ascorbic Acid Chelates in Iron Absorption: A Role for Hydrochloric Acid and Bile. 1968, 55, 35–45.
33. Sipponen, P.; Marshall, B.J. Gastritis and Gastric Cancer. Clin. North Am. 2000, 29, 579–592, doi:10.1016/s0889-8553(05)70131-x.
34. Kuipers, E.J.; Klinkenberg-Knol, E.C.; Vandenbroucke-Grauls, C.M.; Appelmelk, B.J.; Schenk, B.E.; Meuwissen, S.G. Role of Helicobacter pylori in the pathogenesis of atrophic gastritis. J. Gastroenterol. 1997, 223, 28–34.
35. Sugano, K.; Tack, J.; Kuipers, E.J.; Graham, D.Y.; El-Omar, E.M.; Miura, S.; Haruma, K.; Asaka, M.; Uemura, N.; Malfertheiner, P. Kyoto global consensus report onHelicobacter pylorigastritis. Gut 2015, 64, 1353–1367, doi:10.1136/gutjnl-2015-309252.
36. Zagari, R.M.; Romano, M.; Ojetti, V.; Stockbrugger, R.; Gullini, S.; Annibale, B.; Farinati, F.; Ierardi, E.; Maconi, G.; Rugge, M.; et al. Guidelines for the management of Helicobacter pylori infection in Italy: The III Working Group Consensus Report 2015. Liver Dis. 2015, 47, 903–912, doi:10.1016/j.dld.2015.06.010.
37. Carabotti, M. Helicobacter pyloriinfection in obesity and its clinical outcome after bariatric surgery. World J. Gastroenterol. 2014, 20, 647–653, doi:10.3748/wjg.v20.i3.647.
38. Peach, H.G.; Bath, E.N.; Farish, S.J. Helicobacter pylori infection: An added stressor on iron status of women in the community. J. Aust. 1998, 169, 188–190.
39. Milman, N.; Rosenstock, S.; Andersen, L.; Jørgensen, T.; Bonnevie, Serum ferritin, hemoglobin, and Helicobacter pylori infection: A seroepidemiologic survey comprising 2794 Danish adults. Gastroenterology 1998, 115, 268–274.
40. Parkinson, A.; Gold, B.D.; Bulkow, L.; Wainwright, R.B.; Swaminathan, B.; Khanna, B.; Petersen, K.M.; Fitzgerald, M.A. High Prevalence of Helicobacter pylori in the Alaska Native Population and Association with Low Serum Ferritin Levels in Young Adults. Diagn. Lab. Immunol. 2000, 7, 885–888.
41. BergBeckhoff, G.; Bode, G.; Blettner, M.; Boeing, H.; Brenner, H. Helicobacter Pylori Infection and Serum Ferritin: A Population-Based Study Among 1806 Adults in Germany. J. Gastroenterol. 2001, 96, 1014–1018, doi:10.1111/j.1572-0241.2001.03686.x.
42. Qu, X.-H.; Huang, X.-L.; Xiong, P.; Zhu, C.-Y.; Huang, Y.-L.; Lu, L.-G.; Sun, X.; Rong, L.; Zhong, L.; Sun, D.-Y.; et al. Does Helicobacter pylori infection play a role in iron deficiency anemia? A meta-analysis. World J. Gastroenterol. 2010, 16, 886–896, doi:10.3748/wjg.v16.i7.886.
43. Muhsen, K.; Cohen, D. Helicobacter pyloriInfection and Iron Stores: A Systematic Review and Meta-analysis. Helicobacter 2008, 13, 323–340, doi:10.1111/j.1523-5378.2008.00617.x.
44. López-García, Y.K.; Colunga-Pedraza, P.R.; Tarín-Arzaga, L.; Garza, M.I.L.; Jaime‐Pérez, J.C.; Gómez-Almaguer, D. Iron deficiency anemia referral to the hematologist. Real-world data from Mexico: The need for targeted teaching in primary care. Hematology 2018, 23, 658–663.
45. El Demerdash, D.M.; Ibrahim, H.; Hassan, D.M.; Moustafa, H.; Tawfik, N.M. Helicobacter pylori associated to unexplained or refractory iron deficiency anemia: An Egyptian single-center experience. Transfus. Cell Ther. 2018, 40, 219–225, doi:10.1016/j.htct.2018.02.001.
46. Hudak, L.; Jaraisy, A.; Haj, S.; Muhsen, K. An updated systematic review and meta-analysis on the association between Helicobacter pylori infection and iron deficiency anemia. Helicobacter 2016, 22, e12330, doi:10.1111/hel.12330.
47. Capurso, G.; Lahner, E.; Marcheggiano, A.; Caruana, P.; Carnuccio, A.; Bordi, C.; Fave, G.D.; Annibale, B. Involvement of the corporal mucosa and related changes in gastric acid secretion characterize patients with iron deficiency anaemia associated with Helicobacter pylori infection. Pharmacol. Ther. 2001, 15, 1753–1761, doi:10.1046/j.1365-2036.2001.01101.x.
48. Cook, J.D.; Brown, G.M.; Valberg, L.S. The Effect of Achylia Gastrica on Iron Absorption*. Clin. Investig. 1964, 43, 1185–1191, doi:10.1172/jci105002.
49. Dickey, W. Iron deficiency, gastric atrophy and Helicobacter pylori. Liver Dis. 2002, 34, 313–315, doi:10.1016/s1590-8658(02)80121-9.
50. Dickey, W.; Kenny, B.D.; McMillan, S.A.; Porter, K.G.; McConnell, J.B. Gastric as well as Duodenal Biopsies May Be Useful in the Investigation of Iron Deficiency Anaemia. J. Gastroenterol. 1997, 32, 469–472, doi:10.3109/00365529709025083.
51. Marignani, M.; Fave, D.G.; Mecarocci, S.; Bordi, C.; Angeletti, S.; D’Ambra, G.; Aprile, M.; Corleto, V.; Monarca, B.; Annibale, B.; et al. High Prevalence of Atrophic Body Gastritis in Patients With Unexplained Microcytic and Macrocytic Anemia. J. Gastroenterol. 1999, 94, 766–772, doi:10.1111/j.1572-0241.1999.00949.x.
52. Annibale, B.; Capurso, G.; Chistolini, A.; D’Ambra, G.; DiGiulio, E.; Monarca, B.; Dellefave, G. Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms. J. Med. 2001, 111, 439–445, doi:10.1016/s0002-9343(01)00883-x.
53. Hershko, C.; Ronson, A.; Souroujon, M.; Maschler, I.; Heyd, J.; Patz, J. Variable hematologic presentation of autoimmune gastritis: Age-related progression from iron deficiency to cobalamin depletion. Blood 2006, 107, 1673–1679, doi:10.1182/blood-2005-09-3534.
54. Malfertheiner, P.; Megraud, F.; O’Morain, C.; Gisbert, J.P.; Kuipers, E.; Axon, A.; Bazzoli, F.; Gasbarrini, A.; Atherton, J.; Graham, D.; et al. Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report. Gut 2016, 66, 6–30, doi:10.1136/gutjnl-2016-312288.

Thus, in patients with iron deficiency or iron-deficiency anemia without manifest or occult bleeding, an accurate diagnosis of Helicobacter pylori infection and related gastritis is mandatory and the presence of corpus atrophic gastritis needs to be ruled out ^[35][53]. Therefore, gastroscopy with standard bioptic sampling is necessary. Superficial Helicobacter-pylori gastritis requires eradication treatment based on antibiotics and cure of infection generally leads to regression of iron deficiency or iron-deficiency anemia. Once corpus atrophic gastritis is present, the cure of Helicobacter pylori infection, when present, uncommonly gives rise to regression of anemia, and oral or intravenous iron supplementation is necessary depending on the severity of anemia.