Adverse Effects of PPIs

The Untold Perils of Proton Pump Inhibitors (PPIs)

As we learned in the last article, gastroesophageal reflux disease (GERD) is an extremely prevalent condition in our society.  It has been estimated the prevalence of GERD symptoms in the general population may be up to 30% in the U.S.[125] but other studies show it could be as high as 34% to 40%.[126]  The standard treatment for this condition continues to be the use of a powerful class of medications known as proton-pump inhibitors (PPIs).  PPIs are block-buster drugs that make the pharmaceutical companies billions of dollars annually.  This class of medication represents the third-highest selling class of drugs in the United States, with $13.9 billion in annual sales.[127]  Sales of Nexium (the “purple pill” by Astra Zeneca) topped $6.1 billion in 2013 alone, the second highest prescribed medication in the U.S.[128]  In this article we take a closer look at the known risks associated with the use of PPIs, according to the most recent literature.

drug-muggersPPIs and Nutrient Absorption

Since stomach acid plays a role in nutrient absorption, PPIs and other acid suppressing medications have a significant impact on vitamin and mineral absorption.  The literature reveals that absorption of various vitamins and minerals are impacted as a result of acid suppression.

vitamin-B12-functionsPPIs and Vitamin B12 Absorption

Vitamin B12, also called cobalamin, is a crucial water-soluble vitamin that is used for many functions in the body, including brain function, nerve function, red blood cell production, methylation and liver detoxification.  B12 deficiency is associated with a number of chronic diseases, including heart disease and cancer.  Our primary source of B12 is our diet, and it is found in animal products such as meat.  However, in its dietary form, B12 is bound to animal-derived protein which requires stomach acid to cleave off the protein so that it can be absorbed after it becomes bound to intrinsic factor in the intestines.  B6-B12-pathwayIf stomach acid is insufficient, B12 may not be cleaved off from dietary proteins and lead to absorption problems.

“The use of H(2)-receptor antagonists and/or PPIs may impair the absorption of protein-bound dietary vitamin B12 and could contribute to the development of vitamin B12 deficiency with prolonged use.”[189]

“The studies reviewed in this article clearly show that omeprazole therapy will decrease the absorption of vitamin B12 by preventing its cleavage from dietary proteins.”[190] 

benefits-B12A number of studies have shown an association of decreased B12 absorption with prolonged PPI use.[189,190]  However, PPIs have been shown to affect B12 absorption in very short periods of time as well.[191,192]  One study showed a 72% decrease in B12 absorption on 20 mg of omeprazole (Prilosec) and an 88% decrease in B12 absorption on 40 mg of omeprazole after only 2 weeks of treatment!  The authors made the following conclusion:

“Omeprazole (PPI) therapy acutely decreased cyanocobalamin (B12) absorption in a dose-dependent manner.”[191]

symptoms-B12-deficiencyB12 absorption issues worsen in patients with atrophic gastritis, which is a common condition in the elderly.  In one study of 359 elderly people aged between 60 and 99 years of age, the prevalence of atrophic gastritis was found to be 31.5% and increased significantly with advancing age.  Subjects with atrophic gastritis exhibited a lower mean serum vitamin B12 level, indicating decreased absorption.

“It is concluded that…atrophic gastritis is common in an elderly population, and that atrophic gastritis is associated with vitamin B12 deficiency and anemia.”[193] 

3-functions-of-iron-in-human-healthPPIs and Iron Absorption

Iron is an essential element for red blood cell production. About 70% of your body’s iron is found in the red blood cells of your blood called hemoglobin and in muscle cells called myoglobin. Hemoglobin is essential for transferring oxygen in your blood from the lungs to the tissues.  It has long been known that conditions of low stomach acid (hypochlorhydria) such as atrophic gastritis and partial gastrectomy cause iron-deficiency anemia.[194]  Studies have shown that patients who undergo gastric bypass surgeries are at much higher risk of iron deficiency, in fact, iron deficiency is extremely frequent in this patient population.[195]

iron-rich-foodsIron can be found in the heme (ferrous) form or nonheme form but only the ferrous form can be absorbed.  Nonheme iron requires gastric acid for conversion to the ferrous form of iron for absorption.[196]  90% of dietary and 100% of oral iron supple-mentation is in the nonheme form.[197]  So not surprisingly, several review studies in the literature conclude that PPI use leads to decreased iron absorption.[198,199]  In one study, all markers of iron deficiency were decreased among patients on PPI therapy as compared to controls.

impaired-iron-absorption“Among patients on PPI therapy, all hematologic indices decreased from baseline, including hemoglobin (-0.19 g/dL, P=0.03), hematocrit (-0.63%, P=0.02), and mean corpuscular volume (-0.49 fL, P=0.05). PPI users had significant decreases in mean hemoglobin and hematocrit (P<0.01 for both) compared with matched controls. Among adult patients receiving chronic PPI therapy, there is a significant decrease in hematologic indices from baseline.”[200]

Another study looked at the effects of omeprazole on iron supplementation in patients with iron-deficient anemia.  It found that:

role-of-iron-in-body“…the profound hypochlorhydria induced by omeprazole may indeed impair the optimal absorption of orally administered iron in iron-deficient individuals…”[201]

In fact, PPI therapy is so reliable in reducing iron absorption from food, it is now being used as a treatment for decreasing iron absorption from food in conditions of excess iron stores in the body called hemochromatosis.

“Proton pump inhibitor therapy reduces the absorption of non-heme iron and this effect has been employed in the management of hemochromatosis. It may also retard clinical response to iron supplementation.”[202]

functions-of-calciumPPIs and Calcium Absorption

Calcium performs a number of basic functions in your body. Your body uses 99% of its calcium to keep your bones and teeth strong, thereby supporting skeletal structure and function. The rest of the calcium in your body plays key roles in cell signaling, blood clotting, muscle contraction and nerve function but calcium levels for these functions is usually tightly-regulated. So anything that effects calcium absorption from food will likely have a negative impact on bone density, primarily.  Numerous human studies show that gastric acid secretion aid in calcium absorption and that acid suppressants such as PPIs can decrease calcium absorption and decrease bone density.[203-210] An acidic environment in the stomach facilitates the release of ionized calcium from calcium salts, which is important for calcium absorption.[203-210] A number of conditions that cause hypochlorhydria are associated with an increased occurrence of osteoporosis and bone fracture, and it is assumed that this is secondary to the effect of low gastric acid levels on calcium absorption.[203-210]

FDA-PPI-warningThere were two large, case control studies from 2006 which led to considerable concern that chronic PPI use could lead to an increase in bone fractures and speculation of the possible mechanisms involved.  Both of these studies associated long-term use of PPIs with bone fractures with one of them showing the risks were particularly increased with high-dose PPI use and the risk progressively increased with the duration of PPI treatment.[205,211]

These studies and others led the U.S. Food and Drug Administration to issue a warning in 2010 of the “possible increased risk of fractures of the hip, wrist, and spine with high doses or long-term use of a class of medications called proton pump inhibitors.” (U.S. FDA News Release, May 25, 2010).  fda-warningSince then, PPIs and other acid-suppressing medications have been shown in numerous studies to decrease calcium absorption [208, 212-214] with omeprazole causing a 41% decrease in one study [208] and long-term PPI usage has been increasingly associated with an increased occurrence of bone fractures. [210,211,215-217] The most widely-assumed mechanism is that long-term PPnexium-and-hip-fracturesI use leads to decreased intestinal absorption of calcium resulting in increased osteoporosis, increased bone loss and increased fractures. [205,206, 210,212,218-220]

A large retrospective analysis done in 2008 matched 15,792 cases of osteoporosis-related fractures with 47,289 controls during an 8 year period between 1996 and 2004.  The researchers concluded the following:

“Use of proton pump inhibitors for 7 or more years is associated with a significantly increased risk of an osteoporosis-related fracture. There is an increased risk of hip fracture after 5 or more years exposure.”[221]

functions-of-magnesium-in-the-bodyPPIs and Magnesium Absorption

Magnesium is needed for more than 300 biochemical reactions in the body. It helps to maintain normal nerve and muscle function, supports a healthy immune system, keeps the heart beat steady, and helps bones remain strong. It also helps regulate blood glucose levels and aids in the production of energy and protein.  So anything that impacts magnesium, can potentially cause a wide range of symptoms related to the muscles, nerves, brain, heart, bone and the immune system.

symptoms-magnesium-deficiencyHypomagnesemia (low magnesium levels in the blood) was reported for the first time in the medical literature as a potential side effect of proton-pump inhibitors (PPIs) in 2006.  Since then, numerous studies have shown that magnesium deficiency associated with the use of PPIs results in a wide variety of serious disorders affecting multiple organ systems.[222-229]  In 2011, the U.S. Food and Drug Administration released a warning about low serum magnesium levels associated with long-term use of PPIs.  Symptoms include seizures, arrhythmias, low blood pressure, severe muscle contraction (tetany), and death.[230]

symptoms-of-magnesium-deficiencyIn a recent review of 10 cases, the elderly patients had been taking PPIs for an average of 8.3 yrs.[226]  They suffered from severe symptoms of low magnesium and there was significant morbidity related to fatigue, unsteadiness, severe muscle contraction, seizures, cardiac arrhythmias, and multiple hospitalizations. The low magnesium condition promptly resolved when the PPI therapy was stopped and recurred if the PPI therapy was reintroduced.

“There were 18 emergency hospital admissions with severe hypomagnesemia (low magnesium). Oral and parenteral magnesium supplements were relatively ineffective at correcting the problem, but stopping PPI therapy lead to prompt resolution of the hypomagnesemia (within 2 weeks in five carefully monitored patients), with symptomatic benefit. Hypomagnesemia recurred if PPI therapy was re-introduced…”[226]

symptoms-of-magnesium-deficiencyAnother recent review of 4 cases examined the clinical consequences and mechanisms of electrolyte disorders that resulted from the elderly patients taking a PPI for a period of 1 to 13 years.[227]  They developed severe low magnesium levels  with low calcium levels, hypoparathyroidism (low parathyroid hormone), and extremely low urinary calcium and magnesium excretion. One patient developed encephalopathy (brain dysfunction) after a collapse likely caused by cardiac arrhythmia. The others had cardiac abnormalities identified by electrocardiogram.  Low potassium levels were considered the cause for these arrhythmias. The low potassium levels were believed to be due to excess potassium excretion by the body resulting from the low magnesium.

stomach-acid-blockers“This series of PPI-induced hypomagnesemia shows that this is a generic effect. It also indicates that hypomagnesemia may occur within 1 year of PPI therapy initiation and can have serious clinical consequences…”[227]

At present the mechanism of the PPI-induced low magnesium levels is not known. It was concluded in one study that it is not specific to a given PPI, but is a generic problem with the PPI class of drugs, because it recurs even when PPIs are interchanged.[82]  It is believed that low magnesium levels resulting from PPI use is likely due to gastrointestinal malabsorption of magnesium secondary to hypochlorhydria.[222]

ppis-side-effectsSummary of PPIs and Nutrient Absorption

As you can see, the evidence supporting the risk of critical vitamin and mineral malabsorption secondary to acid suppression by PPI use is alarming and unfortunately often overlooked by doctors and patients.  In addition to risk of vitamin B12, calcium, iron and magnesium malabsorption, there is evidence that acid suppression by PPIs increases risk of malabsorption of other important vitamins and minerals as well, including vitamin C, zinc and folic acid.[231- 235]

vitamin-C“Proton pump inhibitor therapy lowers the concentration of vitamin C in gastric juice and the proportion of the vitamin in its active antioxidant form i.e., ascorbic acid. There is also some evidence that proton pump inhibitors may reduce the bioavailability of ingested vitamin C.” [231]

“Zinc absorption decreased (about 42%) after omeprazole (Prilosec) administration compared with pre-omeprazole values.  Suppression of gastric acid secretion by omeprazole reduces intestinal absorption of zinc.”[232]

infographic-zinc-deficiency“This study indicates that intragastric pH and salt solubility-dissolution are important in the oral absorption of zinc.”[233]

“Further, in vitro studies have confirmed the dependency of folate absorption on intraluminal pH.”[235]

In one study, when folate was given to achlorhydric patients (with no stomach acid) along with an HCl supplement, absorption of folate increased by 54%.[235]  Although there is currently no available research on PPI risk of malabsorption of other nutrients, given that gastrointestinal pH plays an important role in absorption of various vitamins and minerals, one has to consider the probability that the absorption of other nutrients are affected as well.

proton-pump-inhibitors-and-bacterial-overgrowthPPIs and SIBO

Small intestinal bacterial overgrowth (SIBO) commonly occurs in patients on omeprazole (PPI) and in atrophic gastritis (a condition leading to very low stomach acid).[183]

“SIBO…occurs significantly more frequently among long term PPI users than patients with IBS or control subjects.”[184]

ppi-sibo-ibsConsidering that low stomach acid is an important risk factor for the development of SIBO, recent research has focused on the mechanism by which PPIs lead to SIBO.  The mechanism appears to be related to a shift in the balance of the intestinal bacteria that occurs in PPI use.  This should not be surprising, given the important role that acid plays in preventing bacterial infection.

prevalence-of-sibo-by-duration-PPI-therapy“Use of proton pump inhibitors (PPIs) could predispose individuals to small intestinal bacterial overgrowth (SIBO) by altering the intraluminal environment and bacterial flora.”[185]

In conclusion, omeprazole is associated with a microbiota shift and functional change in the distal gut in patients with compensated cirrhosis that could set the stage for bacterial overgrowth.”[186]

PPIs-and-C. diffPPIs and Colonic Infections

PPIs have also been shown to increase risk of Clostridium difficile (known as C. diff) infection, which is commonly seen in patients on long-term antibiotic therapy.

“Omeprazole treatment decreases the expression of genes that have important functions in colonocyte integrity. Such impairment in colonocyte function may promote Clostridium difficile infection (CDI).”[236]

ppis-side-effectsPPIs and Immune Responses

PPIs have also been shown to affect normal immune responses and clotting mechanisms.

“One potential toxicity mechanism of PPIs as suggested from this systematic PPI-specific gene expression analysis is that PPIs are enriched in acidic organelles where they are activated and inhibit V-ATPases and acid hydrolases, and consequently block the pathways of antigen presentation, the synthesis and secretion of cytokines, and complement component proteins and coagulation factors.”[237]

Related Articles

Hypochlorhydria (Low Stomach Acid)


Gastroesophageal Reflux Disease (GERD)

Intestinal Permeability/Leaky Gut

NSAID-Induced Enteropathy

Irritable Bowel Syndrome (IBS)

Small Intestinal Bacterial Overgrowth

The Neuroendocrine System of the Gut and the Brain-Gut Axis


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