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GERD part 3

GERD and HYPOCHLORHYDRIA
By Renata Trister DO
The stomach is meant to produce acid. It is an important component of the digestive process. Acid is found in the digestive processes of all vertebrates. We will discuss the roles of stomach acid and the effects of having low acidity – hypochlorhydria.

The vital role stomach acid play in our bodies is often underestimated. The common view is that stomach acid is not needed and is actually the cause of illness is a misconception. Somewhat proliferated by drug companies. Subsequently, millions of people use antacids on a chronic, everyday basis. Although painful symptoms are managed, the underlying condition is not.

The primary consequences of hypochlorhydria are:

Impaired ability to resist infection
Increased bacterial overgrowth
Impaired nutrient absorption
Increased risk of illnesses including cancer

Bacterial Overgrowth
Low gastric acidity causes bacterial overgrowth in the stomach and other parts of the intestine. This is a result of impaired carbohydrate digestion and decreased ability to fight off ingested bacteria – both consequences of hypochlorhydria. Bacterial digestion of carbohydrates through fermentation produces gas. This gas increases the intra-abdominal pressure, which overpowers the lower esophageal sphincter (LES). The dysfunctional opening of the LES allows acidic stomach contents to enter the esophagus, producing the painful symptoms GERD. Although the stomach contents are deficient in acid to function properly, they are still acidic enough to damage the delicate lining of the esophagus.

Bacterial overgrowth has several cascading effects as well. Mainly – reduced nutrient absorption leads to increasing and chronic inflammation, which increases the risk of developing stomach cancer. Studies have confirmed that proton-pump inhibitors (PPIs) significantly change the bacterial population of the GI tract by suppressing stomach acid. One study found that 50% of patients using PPIs had small bowel bacterial overgrowth (SIBO), in comparison only 6% of control subjects not taking PPIs.

Impaired Nutrient Absorption

Gastric acidity plays an important role in digestion. Proper breakdown of nutrients occurs within a narrow range of acidity. Hypochloridia impairs the normal reactions required to properly assimilate nutrients. This can eventually lead to osteoporosis, anemia, depression, cardio-vascular disease and other issues.

Breakdown of Macronutrients

The proper digestion of macronutrients (fats, carbohydrates and proteins) needs acidity. The secretion of acid (HCL) in the stomach induces the production of pepsin. Pepsin is the enzyme required to digest protein. If not enough HCL is present pepsin levels will also be low. Proteins will not be broken down properly into their component amino acids and peptides. A deficiency of essential amino acids can subsequently develop and may lead to depression and anxiety.

Proteins that escape digestion by pepsin may end up in the bloodstream. Since this is not supposed to happen, the body treats these proteins as foreign pathogens, causing allergic and autoimmune responses.

Micronutrients

Years of research confirm that low stomach acid reduces absorption of several key nutrients. These include iron, B12, folate, calcium, magnesium and zinc.

Iron
Iron deficiency causes chronic anemia. In one study of 40 patients with chronic anemia 35 were found to also have acid secretion. Iron-deficiency anemia is an established side effect of surgeries that remove portions of the stomach where acid is made. Inhibition of acid production by Tagamet, in another study, resulted in a significant reduction of iron. Furthermore, giving acid to patients with achlorhydria, improved iron absorption.

Vitamin B12
Taking proton pump inhibitors (PPIs – such as Prilosec, Nexium and Prevacid) for more than two years was linked to a 65 percent increase in the risk of vitamin B-12 deficiency.
Researchers also found that using acid-suppressing drugs called histamine-2 receptor antagonists (H2 blockers – such as Tagamet, Pepcid and Zantac) for two years was associated with a 25 percent increase in the risk of B-12 deficiency. Vitamin B12 is critical to proper nerve and brain function. Sufficient HCl (and pepsin) is essential, independent of intrinsic factor secretion, for separating B12 from carrier proteins in food. This is thought to be a major cause of deficiency in the elderly, who generally suffer from low stomach acid. If B12 is not separated from its carrier proteins it will not be absorbed. In patients with atrophic gastritis (chronic inflammation of the stomach mucosa causing mucosal atrophy), more than 50 percent have low vitamin B12 levels. This is of course a consequence of the damage to the parietal cells. Parietal cells produce HCL and intrinsic factor. Intrinsic factor is a glycoprotein that binds B12 & facilitates B12 absorption in the small intestine. lack of intrinsic factor as well as low acidity subsequent to
Various approaches have examined the negative effect of PPI therapy on B12 absorption. Even in healthy subjects treated with daily doses of Prilosec for two weeks, B12 absorption was reduced by as much as 50%. The consequences of B12 deficiency are vast and will be discussed in a future article.

Folate
Folate (folic acid) is essential for a healthy cardiovascular system and for proper fetal development. Hypochloridia impairs folate absorption by raising the pH in the small intestine. Folate given to achlorydric patients together with an HCL supplement, absorption of the vitamin can be increased by roughly 50 percent.

In a study, Tagamet reduced folate absorption. The overall reduction of folate absorption was a modest 15 percent. Although this reduction is probably not severe enough to cause harm a healthy person who gets enough folate through diet, it may cause further issues in those with a folate deficiency.

Calcium
Calcium has a vast number of important functions functions in our body. The absorption of dietary calcium is thought to be mediated by gastric acid release of ionized calcium from insoluble calcium salts. Hence, there have been concerns that hypochlorhydric states, in particular those induced by PPIs, may impair calcium absorption. The effect low acidity has on calcium absorption was first discovered in the 1960s, one group of researchers found that some ulcer patients were barely absorbing any calcium at all (> 2 percent). It was found that these patients had a high gastric pH (6.5) and very little stomach acid. However, when these patients were given HCL supplements, lowering the pH to 1, calcium absorption increased five-fold. In 2010 the FDA even issued a product label warning for all PPIs because of clinical reports inferring increased risk for bone fractures. The FDA revised this warning in March of 2011 to release over-the-counter PPIs, which are intended for short-term use. This revision was said to have come due to conflicting data regarding the risk of fractures and that even the risk is the short-term use would not cause an increase. How releasing over the counter PPIs prevents long term use is still not clear… A 2011 meta-analysis study in The Annals of Family Medicine reported that high doses or long-term usage of proton pump inhibitors (PPIs) have been linked to an increased risk of osteoporosis-related fractures of any type, including wrist, spine, and hip.

Magnesium
There have been several cases of hypomagnesemia that were associated with long-term PPI use. The patients generally presented with profound hypomagnesemia that required hospitalization. In approximately 25% of these cases, the patients had persistent hypomagnesemia despite magnesium supplementation and prompt resolution of magnesium levels following discontinuation of the PPIs. Furthermore, in a few cases patients who were restarted on a PPI, the hypomagnesemia recurred. Clearly this demonstrated a PPI-related effect. The exact mechanism for this magnesium depletion is not well understood, but health care providers need to aware of this side effect.

Zinc
Zinc is needed in several metabolic processes that are involved in maintaining and stabilizing cell membranes, form new bone, immune defense, night vision, and tissue growth. In one controlled trial, Tagamet and Pepcid, which can raise gastric pH to over 5 reduces zinc absorption by about 50 percent.

The Immune Function

The mouth, the esophagus and the intestines house approximately 400-1,000 species of bacteria. Healthy stomach contents however, are almost completely sterile. This is because acid kills bacteria. The acid of the stomach actually creates a two-way barrier. Stomach acid kills harmful bacteria present in the air, food and drink we take in from entering the intestine. At the same time, stomach acid also prevents normal gut flora in the intestines to move into the stomach and esophagus. Although harmless in the intestine gut flora can cause problems if it spreads beyond the intestine into stomach, esophagus or respiratory tract. The acidic stomach contents are one of the major non-specific immune mechanisms. When the pH of the stomach is 3 or lower, the normal between-meal “resting” level, bacteria are killed in fifteen minutes. As gastric pH rises above 5, many bacteria thrive. Tagamet and Zantac significantly raise the pH of the stomach from about 1 to 2 before treatment to 5.5 to 6.5 after, respectively. Prilosec is even worse as it can reduce stomach acidity to near zero. High pH promotes bacterial overgrowth and makes patients are more vulnerable to infection.
A recent systematic review of gastric acid-suppressive drugs suggested that there is an increase susceptibility to some infections:

C. Difficile
Community Acquired and Hospital Acquired Pneumonia
Salmonella
Campylobacter
Cholera
Listeria
Giardia

Acid suppressing drugs weaken our immune system. In vitro studies have shown that PPIs impair neutrophil function, and inhibit neutrophil phagocytosis. When you decrease acid secretion in the stomach, you boost the risk of infection. Without adequate stomach acid present, large amounts of undigested food pass into the intestines, contributing to the growth of opportunistic organisms, an increase in toxins, and an imbalance in intestinal flora. Studies published in the Journal of the American Medical Association revealed that when taking a proton pump inhibitor drug, the risk of developing pneumonia increases up to 89%, and the risk of developing a potentially deadly chronic infection from the intestinal bacterium Clostridium difficile increases also. A randomized, double-blind, controlled trial published in Gastroenterology shows that withdrawal from acid blockers can lead to rebound acid hyper secretion, which then forces the patient to immediately go back to the acid blocker drug. This becomes a vicious cycle. As we mentioned in an earlier article, acid secretion declines with age. In 1996, a British physician noted that age-related stomach acid decline is due to a loss of parietal cells that produce the HCL. Chronic inflammation of gastric mucosa leads to atrophy of parietal cells and eventually mucosa is replaced with fibrous tissue. This condition is called atrophic gastritis. A host of illnesses is associated with atrophic gastritis. This includes the following:

Allergies
Asthma
Depression, anxiety, mood disorders
Pernicious anemia
Skin diseases, including forms of acne, dermatitis and eczema
Cholelithiasis
Autoimmune diseases, such as Rheumatoid arthritis and Graves disease
Irritable bowel syndrome (IBS), Crohn’s disease (CD), Ulcerative colitis (UC)
Stomach cancer
Osteoporosis

Stomach Cancer

Atrophic gastritis is a major risk factor for stomach cancer. H. Pylori is the leading cause of atrophic gastritis. Moreover, long-term use of proton pump inhibitors by people with H. pylori may reduce acid secretion enough to cause atrophic gastritis (chronic inflammation of the stomach). Atrophic gastritis is a well-established risk factor for stomach cancer. To compound concerns, long-term use of PPIs may mask symptoms of stomach cancer and thus delay diagnosis.

Dr. Julie Parsonnet, M.D. of Stanford University Medical School wrote an editorial on this subject stating:

In principle, current [acid suppressing drug] therapies might be advancing the
cancer clock by converting relatively benign gastric inflammation into a more destructive, premalignant process.

PPIs increase the risk of cancer is by inducing above-normal secretion of the hormone gastrin. PPI induced hypochlorhydria results in an elevated gastrin level in an attempt to compensate for increased pH in the stomach. A daily 20 mg dose of Prilosec typically results in up to a three-to-fourfold increase in gastrin levels. Increased expression of gastrin is also seen in Helicobacter infections. Chronic infection of the gastric mucosa with Helicobacter pylori has long been recognized as a significant risk factor for gastric cancer (specifically adenocarcinoma). Recent studies have expanded the role for gastrin and related peptides in inflammation and inflammation-associated cancers, suggesting that their expression in immune cells contributes to the initiation and progression of GI cancers. H. Pylori induces the systemic elevation of serum gastrin through several mechanisms:
H. Pylori infection suppresses gastric acid secretion by parietal cells, causing a loss of feedback inhibition by acid and a compensatory increase in gastrin production by the G cells in the antrum.

Chronic infection and inflammation results in loss of parietal cells (atrophic gastritis). Loss of parietal cell results in reduced acid production, which also triggers the G cells to overexpress gastrin.

A smaller percent of patients (~15%) with chronic gastritis also have decreased somatostatin, also resulting in increased gastrin production by removing the normal feedback inhibition of G cells.

H. Pylori-induced inflammatory cytokines stimulate also G cells to release gastrin.

The combination of hypochlorhydria and hypergastrinemia results in gastric bacterial overgrowth, lack of parietal cell differentiation, development of gastric metaplasia, and eventual progression to gastric carcinoma.

Another mechanism for carcinogenesis involves elevated concentration of nitrites in the gastric contents. Normally, vitamin C removes nitrite from gastric contents by converting it to nitric oxide. This process is dependent upon the pH of the stomach being less than 4. As mentioned previously, acid-reducing medications can increase PH well above that.

These are two distinct mechanisms through which medication induced hypochlorhydria can increase risk of cancer.

Irritable bowel Disorders (IBD)

Adenosine is an important modulator of GI tract inflammation and its anti-inflammatory effects have been well established in humans and in animal models. High levels of extracellular adenosine suppress and resolve chronic inflammation in IBD including Crohn’s disease and Ulcerative Colitis. Increased extracellular adenosine levels activate reduce cytokines responsible for chronic inflammation (by activating A2a receptor). More information is available in this article Adenosine: An immune modulator of inflammatory bowel diseases Jeff Huaqing Ye and Vazhaikkurichi M Rajendran. World J Gastroenterology. 2009 Sep 28; 15(36): 4491–4498. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751993/
Chronic use of PPIs has been shown to decrease extracellular concentration of adenosine, resulting in an increase in inflammation in the digestive tract. More information on this topic can be found in this article: Possible mechanism for the inhibition of gastric (H+ + K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749. H Nagaya, H Satoh, K Kubo and Y Maki Journal of Pharmacology and Experimental Therapeutics.

As discussed in previous articles acid suppressors contribute to bacterial overgrowth. Likewise the connection between irritable bowel syndrome (IBS) and small bowel bacterial overgrowth (SIBO) has been established. There is a striking similarity between the symptoms of IBS and SIBO. It has been theorized that SIBO may be responsible for the symptoms of at least some patients with irritable bowel syndrome. The estimates run as high as 50% of patients with irritable bowel syndrome. Support for the SIBO theory of IBS comes from the observation that many patients with IBS are found to have an abnormal hydrogen breath test, and some patients with irritable bowel syndrome have improvement of their symptoms after treatment with antibiotics, the primary treatment for SIBO. Therefore, it is plausible that chronic use of acid suppressing drugs could contribute to the development of IBS healthy patients, and could certainly exacerbate the condition in those already suffering with IBS.

Mood Disorders, Depression and Anxiety

Specific research connecting antacids to mood disorders is lacking. However, as discussed above, some connections are clear. Stomach acid secretion triggers the release of pepsin. Pepsin is an enzyme that cleaves protein into component essential amino acids and peptides. With out pepsin the proteins we eat are not broken down into peptide components. Essential amino acids, such as phenylalanine and tryptophan, play a crucial role in mental health. In addition low stomach acid may predispose people towards developing deficiency in vitamin B12. The combination of these factors can lead to depression, anxiety and insomnia.

Autoimmune diseases

Low stomach acid and consequent bacterial overgrowth cause the intestine to become permeable, allowing undigested proteins to find their way into the bloodstream. This process is known as “leaky gut syndrome”. Both trans-cellular and Para-cellular intestinal permeability is substantially increased in patients with atrophic gastritis.

Undigested proteins that enter the bloodstream, they are treated as pathogens by the immune system. This results in chronic low-level immune response activation. As a result there is constant strain on the immune system. This immune response against proteins we eat contributes to food allergies. A similar mechanism that is not fully understood predisposes people with a leaky gut to develop more serious autoimmune disorders such as lupus, rheumatoid arthritis, Graves disease, and inflammatory bowel disorders. The connection between rheumatoid arthritis (RA) and hypochloridia has been established. A study found that people with RA have decreased stomach acidity and an extremely high rate of atrophic gastritis associated with low stomach acid when compared with normal individuals.

Asthma

Recently, the connection between asthma and acid reflux has been extensively studied. In addition to wheezing, gastro-esophageal reflux is one of the most common features seen in asthma suffers. It is estimated that between up to 80 percent of people with asthma also have GERD. Compared with healthy people, those with asthma also have significantly more reflux episodes and more acid-induced irritation of their esophageal lining.

When acid gets into the respiratory tract, the lungs ability to breathe air in and out is reduced. This association caused physician to prescribe acid more and more stopping drugs to asthma patients suffering from GERD.

Conclusion

GERD is most often caused by diminished – rather than excessive – stomach acid. In addition to GERD, hypochloridia is associated with bacterial overgrowth, decreased resistance to infection and impaired absorption of nutrients. Hypochlorhydria is also linked to an increased risk of stomach cancer, ulcers, IBS, depression, autoimmune disease, and asthma. Chronic use of acid stopping medications dramatically reduces stomach acid, thus increasing the risk of the above conditions.