Wednesday, January 30, 2013

Why We Need Stomach Acid: The Dangers of Anti-acid Medication

Thanks to Paul Jaminet for helping me with the translation (from Finnish to English).

Heartburn – a burning feeling in chest or throat – is a common modern ailment. It is estimated to afflict 42% of the US population in some way (1), and is nearly as common in other populations worldwide, including Icelanders(2), Taiwanese(3), rural Bangladeshis(4), Belgians(5), Germans(6) and Finns(7).

A variety of conditions, including eosinophilic esophagiti
s (8) or myocardial infarction (9), can cause a burning feeling in the chest. However, heartburn is generally caused by the backward reflux of gastric/intestinal contents, stomach acid being the most well-known but not the only important substance, into the esophagus. The chronic form of acid reflux is known as gastroesophageal reflux disease, GERD. Approximately 10-20% of western populations suffer from GERD (10).

GERD is correlated with age (11) and is often accompanied by other conditions: asthma (12), obesity (13), food intolerances (14) and irritable bowel syndrome (15). It is likely that GERD actually triggers asthma, because anti-acid medications, which suppress acid reflux, offer strong potential relief for asthma (16).

Doctors commonly prescribe stomach acid suppressing medications for GERD: antacids, H2-blockers (such as cimetidine), and proton pump inhibitors or PPIs (such as omeprazole). Antacids do their work by neutralizing stomach acid, but newer medications block the secretion of gastric acid. Anti-acid medications have been a commercial success: In 2004, the US doctors wrote more than 60 million prescriptions (17). Here in Finland, doctors wrote on average 60.8 anti-acid prescriptions in 2009 despite the fact that many drugs for heartburn were also freely available in pharmacies (18).

Doctors who prescribe anti-acid medications may not fully appreciate that the cause of GERD is often not excessive acidity of the stomach (hyperchlorhydria) (19). Rather, heartburn can occur even with low levels of stomach acid if there is a malfunction of the lower esophageal sphincter, allowing the entry of stomach acid or other problematic substances (bile acids etc) to the esophagus.(20)

Anti-acid medications can lower the acidity (=number of protons) of the stomach by more than 99% (21,22). This (for a time anyway) can greatly reduce the damage that acid inflicts upon the esophagus (23). Doctors believe that anti-acid medications are safe even for long-term use (24,25). Given the extensive clinical experience with these medications, it is probably safe to conclude that they do not cause serious problems very quickly.

However, presumably there was a good reason why the human stomach evolved the ability to make gastric acid. Eliminating the acid should therefore lead to harmful consequences. What is the evidence?

Here we go:

Maldigestion of some nutrients. The acidic gastric juice supports the proper digestion of foods by breaking down proteins, aiding the absorption of minerals and vitamins and stimulating the secretion of secretin, a hormone that stimulates the secretion of pancreatic enzymes and bile (26). Studies have shown a reduction in the absorption of non-heme iron (27,28), folic acid (29), zinc (30,31), vitamin B12 (32,33,34) and calcium (35,36) in people on anti-acid medications, though the folic acid and zinc studies are not wholly conclusive. It also seems that oxide minerals (such as magnesium oxide) might be poorly digested in the absence of stomach acid (37,38).

Enteric infections. One of the important roles of gastric juice is to kill foreign bacteria on their way to the intestine. A recent systematic review reported that people using PPI medications have much higher risk for food poisonings:
We describe the available evidence for enhanced susceptibility to enteric infection caused by Salmonella, Campylobacter and C. difficile by PPI use, with adjusted relative risk ranges of 4.2-8.3 (two studies); 3.5-11.7 (four studies); and 1.2-5.0 (17 of 27 studies) for the three respective organisms. (39)

Small intestinal bacteria overgrowth. In Italy, 50% of PPI-users had small intestinal bacterial overgrowth (SIBO) while only 24% of IBS-sufferers (PPI-users excluded) and 6% of healthy people had this condition.(40) This association has also been demonstrated in some clinical studies. One recent study found that PPIs cause dysbiosis in rats.(41) In another smallish study, PPI medication caused duodenal bacterial overgrowth in 7 of 17 human subjects. In H2-blocker cimetidine group, the acid suppression was much less effective and only 3 of 18 patients in this group had duodenal bacterial overgrowth (42). Other studies have found significant jejunal bacteria overgrowth plus dietary fat malabsorption after omeprazole treatment (43,44). Despite the tempting results, some authors suggest that there is still some controversy on this issue (45), based i.a. on the results of a Los Angeles study in which PPI usage didn't correlate with SIBO in IBS-patients and overall the result was strangely very different compared to the Italian study(46).

Allergies. Lack of stomach acid might cause maldigestion of digestion-labile allergens, probably by inhibiting the activity of pepsin and the secretion of secretin. One observational study followed 152 people with no allergy background for three months while they used an anti-acid medication for their GERD. The result was somewhat shocking:
[T]he relative risk for the increase of an IgE response to food allergens after a 3 month anti-acid therapy is 10.5 (95% confidence interval: 1.44–76.48; P=0.0203). (47)
Even though most of the participants did not develop allergies, many did. And there were some people who were found to be allergic to some foods at the beginning of the study. Their allergies became significantly worse during the anti-acid therapy. This figure (Figure 1 from 47) shows how many people had allergies to 19 common food antigens (1: milk, 2: casein, 3: egg white, 4: egg yolk, 5: peanut, 6: walnut, 7: almond, 8: potato, 9: tomatos, 10: celery, 11: carrot, 12: apple, 13: orange, 14: wheat flour, 15: rye flour, 16: sesame seed, 17: soy bean, 18: codfish, and 19: crab) before and after anti-acid therapy:

Atrophic gastritis. Users of proton pump inhibitors have a very high risk of developing atrophic gastritis (an acidless stomach), especially in the presence of H pylori infection (48).

Osteoporosis. Usage of anti-acid medications correlate with a higher risk of osteoporosis and bone fractures, one reason possibly being the impaired absorption of calcium (49,50,51). Vitamin B12 deficiency is another risk factor for osteoporosis (52) and stomach acid is required for B12 absorption.

Mortality. The most important health problem of all! Proton pump inhibitors are associated with a 1.4- to 1.8-fold increased risk of dying in elderly people after the adjustment for comorbidities (53).

Return of the symptoms during long-term PPI use. A 2009 study noticed that in patients that had been using proton pump inhibitors for 3 years in average, approximately 60% reported at least moderate reflux symptoms, the symptoms PPI's were meant to cure!(54)

D’oh!” - Homer Jay Simpson

One plausible mechanism is that in prolonged PPI usage intestinal enzymes and bile acids, instead of gastric acid, reflux to the esophagus (duodeno-gastro-esophageal reflux, DGER).(54) The PPI’s reduce the amount of acid very significantly, but on the other hand all the damaging substances get more easily to esophagus, because sufficient acidity of stomach is one factor keeping lower esophageal sphincter (LES) tightly closed.(56,57)

What else?  Seemingly some diagnosing mistakes are happening often. In one Finnish study, 20 of 150 persons with endogenously acid-free stomachs were using proton pump inhibitors! The authors say:
Extrapolation of the results of this study also allows us to estimate that thousands of Finnish people are currently prescribed PPI medication even though they have a hypochlorhydric or achlorhydric stomach due to ACG." (58)
(On the other hand, these ACGs might have developed after starting the PPI medication because, as mentioned above, PPI’s might cause atrophic gastritis)


It seems that therapies that involve suppressing gastric acid levels might come with some significant downsides, so we should probably find another approach to this interesting disease.

Extra references

Corsonello et al: Proton Pump Inhibitors and Functional Decline in Older Adults Discharged From Acute Care Hospitals (2014) "Use of PPIs was significantly associated with functional decline before (odds ratio (OR) = 1.75, 95% confidence interval (CI) = 1.17–2.60) and after propensity score matching (OR = 2.44; 95% CI = 1.36–4.41)."

Shah et al: Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population (2015) "Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality"

Washi et al: Proton pump inhibitors exacerbate NSAID-induced small bowel injury: A prospective, double-blind, randomized trial. (2015) "The COX-2 SI+PPI group had a significantly increased risk of small bowel injury in comparison to the COX-2 SI group (relative risk 2.67; 95% confidence interval, 1.08-6.58)."

Gomm et al: Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. (Jama Neurol 2016) "The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice."