1Departments of Medication, Washington College College of Medication in St. Louis
2Michael E. DeBakey Veterans Affairs Medical Middle and Baylor Faculty of Medication, Houston, Texas
Summary
Introduction
Vitamin C is a micronutrient important for human well being. Vitamin C deficiency ends in scurvy which for hundreds of years was a serious well being drawback for armies and for blue water sailors. It was lengthy identified that ingestion of assorted vegetation (e.g., citrus fruits and scurvy grass) would end in medical enchancment of the illness. As well as, early human experimentation confirmed that scurvy might be prevented by ingestion of citrus fruits and juice, however regardless of this proof the trigger remained unknown and the information controversial [1]. Within the late nineteenth and early twentieth centuries, animal and human experimentation explored the etiology of pellagra, Beri Beri, and scurvy all of which subsequently proved to be vitamin deficiency ailments [1–3]. Throughout that interval, investigators have been drastically influenced by the work of Pasteur and the germ concept and though the experimental outcomes usually pointed to a relation between a meals and a illness, the likelihood that these ailments have been microbial in origin (e.g., a results of contaminated corn or rice) usually appeared to the investigators to be a extra possible clarification than a easy deficiency of a selected nutrient [1–3].
The invention and synthesis of what we now know as nutritional vitamins and proof that particular ailments might be quickly reversed or prevented by administration of the particular dietary components introduced that section of discovery to an finish and prompted the nonetheless ongoing investigations into the position of nutritional vitamins in well being and illness. Right here, we discover the associations of vitamin C (ascorbic acid) in gastritis with an emphasis on Helicobacter pylori-associated gastritis and the H. pylori-associated ailments, peptic ulcer illness and gastric most cancers.
Vitamin C in well being and illness
People are unable to synthesize ascorbic acid de novo and should depend on dietary sources for vitamin C and its oxidation product, dehydroascorbic acid [4]. Ascorbic acid is an anti-oxidant that additionally performs a essential position within the manufacturing of key proteins similar to collagen, norepinephrine and serotonin [4]. The each day suggestion of ascorbic acid is 90 mg for males and 75 mg for girls. All kinds of meals, similar to oranges, lemons, cabbage, broccoli, tomatoes and potatoes are excessive in ascorbic acid and lots of ready meals are actually fortified with artificial vitamin C.
Ascorbic acid and dehydroascorbic acid have equal bioavailability. Each are absorbed from the abdomen and alongside your complete size of the small gut by way of particular uptake mechanisms involving a lot of trans-membrane proteins that facilitate the transport of ascorbic acid on the intestinal brush border. Ascorbic acid is absorbed throughout mobile membranes by way of two saturable transporters: the Sodium dependent Vitamin C Transporters 1 (SVCT1) and Sodium dependent Vitamin C Transporter 2 (SVCT2) [5]. Each transporters exhibit considerably greater affinities for L-ascorbic acid in comparison with D-ascorbic acid or dehydroascorbic acid and rely on the co-transport of two Na+ ions; nonetheless, the transporters differ of their protein kinetics and tissue distribution. SVCT1 has persistently been discovered to have the next capability to move ascorbate (i.e., greater Vm), whereas SVCT2 has a barely greater affinity for ascorbate, with a K0.5 of 10–70 μM versus 20–100 μM for SVCT1. Per its enzyme kinetics, SVCT1 is discovered largely within the bulk transporting epithelium of the small gut, renal proximal tubule, and the liver whereas SVCT2 is extra broadly expressed. SVCT2 is positioned within the gastric mucosa from the bottom of the abdomen to the isthmus and is suspected to mediate basolateral uptake of L-ascorbic acid by gastric glands in opposition to a focus gradient [6]. Research of ascorbate absorption have proven that each SVCT1 and SVCT2 mRNA are expressed in human intestinal epithelium. Ascorbate transport measurement and imaging evaluation utilizing the human intestinal epithelial cell line, Caco-2, revealed that SVCT1 has a predilection for localization in apical membranes [7]. Additional examine revealed {that a} area within the carboxyl-terminal portion of SVCT1 targets the protein to the apical membrane of polarized intestinal epithelial cells [7]. As within the abdomen, SVCT2 is localized to the basolateral membrane of intestinal cells.
Dehydroascorbic acid absorption happens alongside your complete small gut by way of facilitated diffusion by means of sodium-independent carriers; dehydroascorbic acid competes with glucose for uptake by means of the mammalian glucose transporters GLUT1, GLUT3, and GLUT4 [8]. Human enterocytes include reductases that convert dehydroascorbic acid to ascorbate, which maintains a low intracellular focus of dehydroascorbic acid and kinds a gradient for continued dehydroascorbic acid uptake [4].
In plasma, ascorbic acid exists primarily within the type of ascorbate ion and reaches a focus of 30–60 μM, with a maximal focus of 90 μM, the renal threshold for full ascorbate reabsorption [4]. Gastric gland ascorbate concentrations are three to 10 instances greater than plasma ranges suggesting energetic transport of ascorbic acid into gastric tissue and kinetic evaluation of ascorbic acid accumulation in KATO III and AGS gastric epithelial cells revealed the presence of a excessive affinity saturable transport system with a Km of three–11 μmol/L [6].
Regular ascorbic acid ranges
Utilizing fashionable strategies, the traditional focus of ascorbic acid within the serum ranges between 30 to 90 μmol/L (0.5 and 1.6 mg/dL). Plasma values between 11 and 23 μmol/L point out marginal deficiency and values beneath 11 μmol/L (~0.18 mg/dL) point out deficiency [9]. These fashionable values are strikingly just like these revealed by Theodore H. Ingalls in 1937 (Desk 1) [10].
Measurement of ascorbic acid – “vitamin c ulcer”
The early 1900’s was a time of nice curiosity in ascorbic acid which culminated in 1928 when Albert Szent-Gyorgyi remoted hexuronic acid from the bovine adrenal cortex [11]. By 1933, analysis from the College of Pittsburgh confirmed that hexuronic acid, which had been renamed ascorbic acid, had anti-scorbutic properties [8;12;13]. In 1933, Szent-Gyorgyi remoted massive quantities of ascorbic acid from Hungarian paprika and in 1937 was awarded the Nobel Prize in physiology and drugs.
In 1930, Tillmans took benefit of the decreasing property of vitamin C to measure plasma and tissue ascorbic acid focus by titration of examine samples with the redox-dye 2,6 dichlorophenol indophenols [14]. Van Eekelen and Harris subsequently confirmed it was doable to estimate physique shops of ascorbic acid measuring the urinary excretion of ascorbic acid by administration of ample vitamin C to saturate physique shops through the saturation course of [15]. They confirmed that it was doable to provide repeated doses of ascorbic acid to topics with depleted physique shops with out a concomitant improve in urinary excretion. Nevertheless, when the deficiency was corrected, urinary ascorbic acid excretion would improve. The purpose the place this occurred was outlined because the saturation level. They discovered that the dose mandatory to provide saturation was related to a plasma degree of 1.4 mg/dL and was inversely proportional to the extent of depletion of vitamin C shops within the physique [15]. This method offered a easy, sensible check to evaluate the diploma of hypovitaminosis and was subsequently utilized by many investigators as a medical check to look at the position of ascorbic acid deficiency in illness [16].
Ascorbic acid deficiency in peptic ulcer and gastritis
Utilizing the ascorbic acid saturation check in management sufferers who ingested the “minimal optimal” each day dose of ascorbic acid of 25 mg/day, Harris et al. recognized the each day urinary excretion of the minimal optimum shops to be 13 mg/day [16]. In 1936, Harris et al. measured vitamin C shops in 74 hospitalized sufferers together with 19 with gastric ulceration or dyspepsia [16]. They discovered that the typical each day excretion of ascorbic acid amongst hospitalized sufferers was decrease than the minimal optimum shops (8.9 mg/day vs. 13 mg/day). Moreover, the 19 gastric ulceration and dyspepsia sufferers had a mean excretion of solely 5.6 mg/day. That very same 12 months Archer and Graham studied the physique saturation of ascorbic acid in 9 sufferers with gastric or duodenal ulcer and located 6 (66.6%) to have urinary excretion much less then 13 mg/day (Determine 1) [17].
In 1937, Ingalls studied the urinary excretion of ascorbic acid in kids and concurrently measured plasma ranges to ascertain the plasma values for ascorbic acid deficiency (Desk 1) [18]. Later that 12 months, Ingalls and Warren in contrast ascorbic acid ranges in 20 peptic ulcer sufferers with 2 wholesome hospital employees. The ulcer sufferers had a mean plasma ascorbic acid roughly 15% of controls (0.19 mg/dL in comparison with 1.25 mg/dL) [10]. In 1940, Area et al. reported that 39 of 58 ulcer sufferers had blood ascorbic acid ranges beneath 0.5 mg/dL, which is taken into account a borderline scorbutic degree [19]. Twelve (31%) of those sufferers suffered gastrointestinal bleeding through the examine and 10 of those had plasma ascorbic acid ranges of lower than 0.4 mg/dL [19]. In 1941, Riggs et al. reported that the typical plasma ascorbic acid degree amongst 53 ulcer sufferers was 0.24 mg/dl in comparison with 0.52 mg/dL for 15 controls [20].
In 1938, Portnoy and Wilkinson evaluated the impact of oral and intravenous administration of 1,000 mg of ascorbic acid on complete physique ascorbic acid shops [21]. They studied 107 topics together with 26 regular controls, 25 hospitalized affected person controls, 25 ulcer sufferers with out a GI bleed, and 31 ulcer sufferers with a GI bleed. The plasma ascorbic acid ranges of the management teams ranged from 0.60 to 1.85 mg/dL in comparison with 0.14 to 0.59 mg/dL in these with peptic ulcer. Oral administration of 1,000 mg of ascorbic acid to the controls resulted in a speedy improve in plasma ascorbic acid within the first two hours with peaks between 1.80 and three.5 mg/dL and the urinary focus of ascorbic acid confirmed “a maximal increase”. In distinction, ulcer sufferers with preliminary low ascorbic acid values confirmed will increase to plasma ranges of solely 0.48 to 0.60 mg/dL with little or no will increase in urinary ranges. Utilizing the urinary excretion ascorbic acid saturation check (the excretion fee for sufferers with “minimal optimal” shops being 13 mg/day) they reported that the urinary ascorbic acid excretion was regular for non-hospitalized controls (29 mg/day) and for hospitalized controls (17 mg/day). In distinction, ulcer sufferers had each day ascorbic acid urinary excretion of solely 7 mg/day. The quantity of ascorbic acid wanted to saturate physique shops was between 500 and 1,000 mg for non-hospitalized controls, 1,252 mg for hospitalized controls, 3,691 mg for ulcer sufferers with out bleeding and 4,543 mg for ulcer sufferers who had bled (Desk 2) [21].
In 1947, Crescenzo and Cayer studied ascorbic acid loading in ulcer sufferers and controls [22]. They obtained fasting plasma ascorbic acid ranges and subsequently offered a 1,000 mg loading dose of ascorbic acid. The plasma ascorbic acid focus was assessed hourly for 3 hours after ascorbic acid loading; the outcomes confirmed the prior observations that sufferers with peptic ulcer, particularly these with ulcer hemorrhage, usually had ascorbic acid deficiency (Desk 3) [22].
In 1957, Freeman and Hafkesbring in contrast the plasma and gastric fluid ascorbic acid concentrations (which have been identified to reliably signify the entire physique shops of ascorbic acid) of 108 sufferers with gastric illness and 113 controls [23]. They confirmed that imply plasma and imply gastric ascorbic acid degree have been 50% and 42% respectively decrease in these with gastritis, peptic ulcer illness, pernicious anemia and gastric most cancers in comparison with controls (Determine 2) [23]. Importantly, as shall be emphasised beneath, low ascorbic acid ranges have been proven to be current in pernicious anemia, a non-H. pylori type of gastritis.
Mechanisms of ascorbic acid deficiency in gastric ailments
Rising proof of a excessive prevalence of ascorbic acid deficiency amongst peptic ulcer sufferers led to investigations into the position of vitamin C within the pathogenesis and the course of peptic ulcer illness. Researchers studied whether or not ascorbic acid deficiency performed a job within the pathogenesis of the ulcer or its issues in addition to whether or not ascorbic acid remedy would deal with the ulcer or forestall ulcer issues. Ludden et al. proposed 4 elements that is likely to be chargeable for ascorbic acid deficiency in gastrointestinal illness together with: 1) decreased absorption, 2) inadequate consumption, 3) elevated metabolic requirement, and 4) speedy destruction within the GI tract [24].
“vitamin c ulcer”