Introduction
It is commonly assumed that the decline in gastric acid production observed through later adult life (approximately 30% of the population over 65 years are hypochlorhydric) is a "normal" and very common consequence of the ageing process. Recent evidence, however, shows that these assumptions are incorrect and that the frequently observed reduction or loss of gastric acid production is generally the result of often-undiagnosed asymptomatic atrophic gastritis. The atrophic gastritis often has underlying infections as its root cause.

This mini review describes the prevalence and causes of atrophic gastritis and its linkage with achlorhydria, and then outlines protocols for how the disease can be resolved and prevented from recurring. As the most common observed symptom of atrophic gastritis is probably hypochlorhydria, it is important to review the basic physiology of gastric acid production.

Physiology of Gastric Acid Production
The physiological role of gastric (hydrochloric) acid may be summarized as:
1) Initiation of protein breakdown through activation of pepsinogen
2) Augmentation of nutrient absorption, notably dietary calcium and iron
3) Provides a barrier effect of entry of microorganisms to the GI tract.
Approximately 2 liters of gastric juice are produced per day, stimulated by a combination of vagus nerve excitation and production of gastrin, acting to stimulate the release of histamine. This in turn causes parietal or oxyntic cells to produce hydrochloric acid. Parietal cells are located in the fundus and body sections of the stomach (Figure 1).

Figure 1. The Main Anatomical Features of the Stomach (adapted from Smith & Moreton, 2001)

The diagonal line (\) shows the approximate division of the stomach into the two secretory regions: the oxyntic secretory area consisting of the fundus and the body, and the pyloric secretory area consisting of the pyloric antrum.

Gastric Acid Release in Response to Food
HCl is secreted at approximately 10% of maximal rate into the resting stomach and, with nothing to neutralize the acid, maintains the pH in the range of 1.8-2.8. In the empty stomach the hydrogen ion concentration provides a feedback loop that stops production of acid once a pH of 1.8-2.0 is reached, so preventing over-acidification.

The sensory stimuli, which are activated just prior to eating, provoke strong release of gastric juice depending on the quantity and type of food eaten. However, this is balanced upon ingestion, because the food itself has a buffering or neutralizing effect on the pH value. This typically results in the pH of the full stomach being between 3.5-4.5. Following a meal the pH decreases once more back to empty stomach level of 1.8-2.8.

Figure 2. Hourly intragastric acidity in nine subjects eating six normal meals during a 24-hour period (Redrawn from Pounder & Frazer, 1993)

Key: D=Dinner; N=Nightcap; B=Breakfast; C=Coffee; L=Lunch; T=Tea

Effects of Age on Gastric Acid Secretion
It has long been the belief that the production of gastric acid decreases steadily with age — especially after the age of 45. Indeed, virtually all studies up to 1970 showed a decline in basal and stimulated acid production with increasing age (Blackman et al., 1970). Contrary to this, recent studies have indicated that in the normal stomach, the secretion of gastric acid does not decrease with age, and the trend is actually to increase, especially in men. However, this is masked by the astonishingly high prevalence of atrophic gastritis, and Helicobacter pylori infections, both of which have been found to be associated with secondary hypochlorhydria in older individuals (Goldschmiedt et al., 1991; Greenwald & Brandt, 2003).

Atrophic Gastritis
Atrophic gastritis is typically a non-erosive gastritis where inflammation is associated with a loss of function of the secretary cells of the fundus and antrum sections of the stomach. The level of inflammation tends to be variable, with infiltration of macrophages and lymphocytes into the mucosa being either very low and patchy or uniformly high.

The prevalence of atrophic gastritis is remarkably high. Siurala et al. (1960) reported a 28% prevalence rate in 142 randomly selected subjects between 16 and 65 years of age. Similarly, incidence rates of 20% and 28% have been found on similar studies in healthy adults (Villako et al., 1997; Kreuning et al., 1978). All of these studies noted a marked increase with age, which was confirmed by Krasinsky et al. (1986) who found an incidence of 31.5% in a free living, largely asymptomatic population between 60-99 years of age.

A summary of the data strongly suggests an incidence of atrophic gastritis of greater than 15% in adults above 25 years and greater than 30% in people older than 60.

Symptoms and Causes of Atrophic Gastritis
The progression of atrophic gastritis can occur over a period of years and can be co-presented with erosive gastritis especially if there is regular use of non-steroidal, anti-inflammatory drugs (NSAIDs). Often the disease is largely asymptomatic but nonetheless, sufferers will often complain of intermittent dyspepsia, abdominal pain, distention or bloating, and nausea or vomiting. In addition, there are related sequelae resulting from the atrophy of the functional components of the stomach. Thus, loss of parietal cells causes reduction in acid production and intrinsic factor, the latter making vitamin B12 deficiency common.

The most common cause of atrophic gastritis and hence of lowered stomach acidity is chronic infection by Helicobacter pylori. This organism is the most common chronic bacterial pathogen in humans and is also a common focus of chronic inflammation, which is increasingly implicated in progressive, often intractable, diseases such as atherosclerosis and age related mental disorders such as Alzheimer's disease, depression and bipolar disorder. In addition, the symptoms synonymous with the chronic elevation of the pro-inflammatory cytokines TNF, IL-1 and IL-6 resulting from prolonged H. pylori infection are precisely the same symptom manifestations as seen with chronic fatigue and chronic pain syndromes such as chronic fatigue syndrome and fibromyalgia. Hence, chronic infections such as H. pylori may cause, or be a strong contributor, to these diseases.

In general, the prevalence of H. pylori infection increases 1% for every year of life, and so 50% of 50 year olds are typically infected. This picture is similar for most industrialized countries, with populations of developing countries showing even greater frequency (Figure 3) resulting from high infection rates in children and young adults.

Interestingly, as well as H. pylori being responsible for reduction in gastric acidity via atrophic gastritis, it is also now recognized that the initial infection with the bacterium probably takes place only when the acidity level in the stomach is decreased, albeit even on a temporary basis. Thus in two human inoculation experiments, infection could not be established unless the pH of the stomach was raised by use of histamine antagonists (Marshall et al., 1985; Morris & Nicholson, 1987). Indeed, it is now known that H. pylori, like most microorganisms, is sensitive to gastric acid, but avoids the strongly acidic environment of the lumen by infecting when acid output is temporarily lowered (a common occurrence) and then migrating below the mucous layer in contact with the epithelium. In this way, it protects itself from acid output once it becomes normalized.
The increasing incidence of H. pylori infection with age indicates that once infection is established, it is persistent, perhaps lifelong in many cases, and that it clearly survives normal antibiotic therapy. The clinical outcomes of chronic infection with H. pylori are diverse but it is now estimated that in individuals with unresolved chronic infection:

• 80% will demonstrate atrophic gastritis
• 20% will develop duodenal ulcers
• 10% will develop gastric ulcers
• 1% will develop gastric/duodenal cancer

Moreover, of all cases of duodenal and gastric ulcers, an estimated 90% and 65% respectively are caused by H. pylori (Parsonnet, 1998). Interestingly, the majority of the other gastric ulcers are caused by long-term use of NSAIDs. The reason for the development of disease in some individuals and not others is unclear but smoking and excessive alcohol consumption are known risk factors.

Figure 3. Prevalence of Helicobacter pylori infection by age in industrialized countries (from Taylor & Blaser, 1991)

Once diagnosed, usually by biopsy and urease-positive testing, or by ELISA identification of IgG specific antigens, Helicobacter infections are treated by antibiotics. One of the most common combinations is metronidazole, tetracycline and bismuth for 2 weeks. This provides eradication in 70-90% of cases but the symptoms of gastric disturbance can continue for a minimum of 12 months thereafter.

Similarly, in terms of atrophied gastric mucosa, there is no confirming evidence that eradication of Helicobacter pylori results in resumption of normal gastric acid secretion and so there is a strong likelihood of permanent reduction in acid production following many cases of chronic infection.

Hypochlorhydria and Achlorhydria
A significant consequence of atrophic gastritis is hypochlorhydria and achlorhyria, which in turn may have the following effects on physiology (Howden & Hunt, 1987; Modlin et al., 1994):
1) Increased microbial enteric infections and small intestinal bacterial overgrowth
2) Increase in intestinal permeability resulting from malabsorption and/or bacterial overgrowth or alteration of gastric mucosa architecture as a result of low acidity levels
3) Nutrient malabsorption.

Intestinal Infection
It is well recognized that reduction in stomach acidity increases risk of infection by Salmonella, Shigella, E. coli, Vibrio cholerae and the protozoan Giardia (Howden & Hunt, 1987). In developed nations where hygiene standards and microbial water quality is high, this may be a relatively insignificant problem. However, in developing nations, this is often not the case and increasing levels of achlorhydria is seen as being a major contributor to the levels of enteric infection and diarrhea (Howden & Hunt, 1987).

Similarly, it is known from animal experiments that low acid production increases susceptibility to nematode and helminthes infections. This is unlikely to be different for humans and may be one of the contributing factors to the enormous prevalence of parasitic infections in both developed and developing countries.

Small Intestine Bacterial Overgrowth
Overgrowth of bacteria in the stomach, duodenum and jejunum is commonly associated with hypochlorhydria, especially if chronically associated with atrophic gastritis. The overgrowth organisms are typically Staphylococci, Streptococci, Enterococci, and Candida and they probably originate from oral source rather than "growback" from the ileum and large intestine. The normal fragile flora of Lactobacilli typically found in the healthy small intestine appears to be overwhelmed (Husebye et al., 1992). Because these organisms are considered commensals, acute adverse effects from their overgrowth are rare. However, the overgrowth of potentially antibiotic resistant Staphylococci and Enterococci is never desirable, and may have marked adverse effects in the immunocompromised or those intending to have intestinal surgery.

In addition to this, there is a growing body of opinion and data that suggests that dysbiosis in the intestine can be responsible for, or be a significant contributor to, irritable bowel syndrome, chronic fatigue syndrome, arthralgias and depression (Madden & Hunter, 2002).

Long-term chronic sequelae to bacterial overgrowth are likely to become more recognized as studies accumulate, and indeed our own research group found in open human invasive trials that mucosal colonization by Candida albicans and other yeasts is very common whenever intestinal overgrowth with these fungi occurs (Madden et al. — in press). The importance of the mucosal colonization by the yeast was that it triggered a change in morphology from the single cell to hyphal form of the yeast. This in turn elicits an inflammatory response in the mucosa, which if not resolved could give rise to a chronic inflammatory condition.

Nutrient Malabsorption

Macronutrients
Possibly as a result of the overall over-consumption of food by the population, the lack of gastric acidity seems to have little effect on absorption of fat and carbohydrates (Saltzman et al., 1994).

However, the reduction in acid production has a direct effect on reducing the production of pepsin, which is converted from the precursor pepsinogen by hydrochloric acid (Modlin et al., 1996). Although gastric pepsin is responsible for between 20-25% of protein digestion, it is likely that in most but not all circumstances, the production of proteases by the pancreas in younger adults compensates for the gastric pepsin deficiency (Smith & Morton, 2001). However, the age-related decrease in production of pancreatic enzyme output together with the lack of gastric pepsin is certain to be a major contributory factor in the increasing levels of protein and amino acid inadequacy seen in people as they age past 50 years (Greenwald & Brandt, 2003).

Achlorhydria is known to have profound effects on the absorption of some micronutrients, the most important of which are described below.

Vitamin B12 and Folic Acid
Perhaps the most obvious nutritional consequence of achlorhydria associated with atrophic gastritis is the resultant malabsorption of vitamin B12. The major mechanism of this effect is that the acid-producing parietal cells also produce intrinsic factor and once atrophied, this capacity is lost (Glass, 1963). In addition, however, lack of acid may inhibit the liberation of B12 from other nutrient components in food and bacterial overgrowth microorganisms may compete for the B12 that is available (Schade & Shilling, 1967; Simon & Gorbach, 1984). The metabolism of vitamin B12 and folic acid is related, in that vitamin B12 is necessary for the incorporation of folic acid into human tissue. This level is reflected in red blood cell level of folate, and not serum levels, which simply indicates the recent dietary intake of folic acid. This relationship between these two nutrients means that vitamin B12 deficiency is a very strong predictor of simultaneous deficiency in folic acid.

While the extreme deficiency associated with pernicious anemia is relatively rare, the common epidemiological finding of sub-clinical deficiency of folic acid vitamin-B12 in 15-40% of the population, especially in the elderly, is undoubtedly due to the under-recognized and under-diagnosed level of atrophic gastritis (National Diet & Nutrition Survey, 1994/5).

Other Nutrients
Insufficient acid production leads to an increase in small intestinal pH (Krasinski et al., 1986) and this has been shown to cause reduction in absorption of calcium, inorganic iron, and vitamins A and E (Recker, 1985; Mackenzie & Russell, 1976; Hollander, 1980; Muralidhara & Hollander, 1977).

Alteration of Intestinal Permeability
It would be expected that atrophy of the gastric mucosa and consequent bacterial overgrowth in the small intestine would have a combination effect on intestinal permeability. This is indeed the case, with both transcellular and paracellular permeability, as measured by mannitol and lactulose uptake respectively, being substantially increased in atrophic gastritis sufferers compared to control patients (Salzman et al., 1994).

In addition, the clearance test for the acute phase protein alpha-antitrypsin was also numerically higher in the atrophic gastritis group indicating the presence of systemic reaction to inflammation. By implication, this means that the mucosal barrier has been breached in these people with the probability of significant translocation of microorganisms and dietary antigens into the systemic environment.

Atrophic Gastritis — Prevention and Treatment
Fortunately the prognosis of both prevention and treatment for atrophic gastritis is very good, which is comforting given the frequency of the disease. All treatment programs both for clinical and sub-clinical cases require the same basic approach:
1) Eradicate the underlying cause of the atrophic gastritis
2) Manage the symptoms resulting from the gastritis while the long term healing process takes place.

Eradicating the Cause of Atrophic Gastritis — Helicobacter pylori
The two most common causes of atrophic gastritis are infection with Helicobacter pylori — approximately 65%, and chronic use of NSAID's — approximately 30% (Parsonnet, 1998). Helicobacter pylori infection is not successfully resolved with normal antibiotic therapy, but combination use of antimicrobials and other drugs are successful in eradication. Thus the most widely used therapies currently are:
1) 2 weeks metronidazole, tetracycline and bismuth (>70% eradication)
2) 2 weeks of omeprazole with clarithromycin or amoxicillin (>50% eradication)
3) 1 week of omeprazole with clarithromycin and either metronidazole or amoxicillin (>90% eradication).

The Effect of Plant Antimicrobials
A different approach to the use of antibiotics has been investigated by researchers at the University of Wolverhampton in Great Britain, who have assessed the potential for use of plant antimicrobials in treatment of Helicobacter infections. They found that three different strains of H. pylori were highly sensitive to some mixtures of essential oils, particularly oregano. The most effective was a mixture of oregano, clove, wormwood and ginger oils. A summary of their results is shown below (Table 1). It can be seen that the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) lies between 17-47mcg/ml and 35-110mcg/ml respectively for all strains tested.

N.B. MIC is the minimum concentration of antimicrobial agent necessary to inhibit the growth of 1.0 million/ml of the target microorganism. MBC is the minimum concentration of antimicrobial agent required to kill the target organism, to a viable count of less than 100 cfu/ml.

Table 1. Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of a mixture of oregano, clove, wormwood and ginger oils against three strains of Helicobacter pylori — compared to E. coli

These results confirmed that H. pylori is particularly sensitive to essential oils, especially when compared to E. coli, which is far less susceptible to this particular mixture and requires a different approach for effective in-vivo control.

Following the release of this data, Pharmax developed a product, Pyloricin, containing the same mixture of oils. In addition, in this product, the oil mixture is emulsified so that once in the stomach it produces a milky emulsion, enabling the antimicrobials to effectively disperse and penetrate the mucous layer and attack the surface and crypt-bound H. pylori cells.

Feedback from practitioners throughout the USA and UK indicates that eradication rates with Pyloricin is >70% and this is now being confirmed in independent human clinical trials using the radioactive labeled urea/urease breath test, which is rapidly becoming the gold standard for diagnosis.

Management of Residual Gastritis
In most cases, the residual cellular atrophy and gastritis affecting the stomach mucosa, repairs itself following eradication of H. pylori, but this process can take many months or even years. Thus, it is important to manage the deficiencies in intestinal function during this period of repair, and this can be achieved best by targeted supplementation.

Supplementing HCl and Pepsin
Probably the most common consequence of atrophic gastritis, even if it is slowly resolving, is the state of hypochlorhydria. The repercussions of the hypochlorhydric state are outlined above, and if you add the likelihood of re-infection by H. pylori onto this list, then the need for re-acidification of the stomach by supplemental means is very persuasive.

How Much HCl and Pepsin Should be Provided?
HCl is usually supplied by providing betaine hydrochloride, which dissociates in water to release betaine and free HCl. A 0.5% or 500mg/100mls aqueous solution of betaine hydrochloride has a pH of 2.0. This means that to acidify 400mls of gastric juice to a level of pH 2.0 prior to eating, 2,000mg of betaine hydrochloride is required.

Pepsin is also supplied alongside the HCl to ensure that sufficient proteolytic activity is present in the stomach. The level of pepsin contained in a combined product should be matched so as to provide sufficient activity to break down approximately 3 grams of protein per 600mg of added betaine hydrochloride.

In all cases, it is prudent to begin supplementation to an individual in steadily increasing levels. So, if a capsule of a product contains say 600mg of betaine HCl, then an individual should start with one per meal and then build up to 3 capsules per meal, which will be the level required in the typical chronically hypochlorhydric patient.

Combined HCl and pepsin supplements should be given prior to a meal to provide both acid and pepsin augmentation. However, it is important to maintain basal acidity in the empty stomach to provide the bacteriostatic barrier. In this case, it is better to take the supplement without pepsin, as excessive pepsin in the empty stomach can cause irritation of the mucosa.

Nutritional Consequences
The lack of intrinsic factor production resulting from atrophic gastritis will substantially reduce the level of vitamin B12 absorption. The route of absorption via intrinsic factor begins with the release of vitamin B12 from food protein complexes by pepsin. The B12 then binds to glycoproteins called R-proteins, which transport the B12 into the duodenum. Here, the complex is degraded by pancreatic protease, releasing free B12 once more, which this time binds to intrinsic factor produced in the stomach. In this conjugated form, the B12 travels to the terminal ileum where it is absorbed by active transport.

However, approximately 1-2% of vitamin B12 is passively absorbed in the intestine without the need for intrinsic factor (Smith & Morton, 2001) and as such, if doses of 1mg or more per day are delivered, then between 10-20mcg will be absorbed.

Hence a good quality multivitamin, providing 1mg or more of B12 per dose, should be sourced and will be sufficient in most cases. If severe B12 deficiency is suspected, then initial intravenous dosing to build up tissue levels could be considered.

Resolution of Bacterial Overgrowth and Mucosal Conditioning
The bacterial overgrowth in the stomach and duodenum will begin to resolve naturally with the re-establishment of acid production and/or supplementation with betaine HCl. However, it is appropriate to accelerate this process by use of plant antimicrobials to eliminate existing overgrowth and replace with the normal lactic acid bacteria-dominated flora in the small intestine. To achieve this, the antimicrobials allicin from garlic, cinnamaldehydes from cinnamon, and also berberine from goldenseal have been found to profoundly inhibit overgrowth organisms such as Staphylococci, Coliforms, and yeasts without affecting Lactobacilli and Bifidobacteria (Rees et al., 1993). The inhibitory effects of allicin against Salmonella, Staphylococcus aureus and E. coli are visually depicted in Figure 4.

Figure 4. The anti-bacterial activity of allicin

Table 1. MIC of allicin against various microorganisms

The antimicrobial nature of berberine against microorganisms such as E. coli and Candida albicans is shown in Table 2, as well as the lack of similar effect against the lactic acid bacteria, Lactobacillus plantarum and Lactobacillus acidophilus.

Table 2. MIC of berberine against various microrganisms

Products containing these antimicrobials should be taken with a high potency probiotic for a minimum of 60 days alongside the administration of HCl.
Finally, glutamine and arginine should be taken to help recondition the mucosal architecture and underlying immune system.

Conclusion and Summary

• Atrophic gastritis affects 20-30% of the adult population
• Incidence increases with age
• Atrophic gastritis is highly associated with Helicobacter pylori infection
• Hypochlorhydria is probably the most common symptom of atrophic gastritis
• Gastric acid secretion does not decrease with increasing age in healthy (non atrophic gastritis) individuals
• Hypochlorhydria can result in increased risk of enteric infections, nutrient malabsorption, bacterial overgrowth and dysbiosis, and increased permeability of the intestine
• Atrophic gastritis is a strong risk factor for gastric and duodenal ulcers and gastric cancer
• Effects of atrophied gastric mucosa remain for months or years after eradication of H. pylori
• Resolution of atrophic gastritis and symptoms depends upon:
  a. elimination of H. pylori
  b. treatment of residual atrophic gastritis.

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