Proton pump inhibitors (PPIs) are a $13 billion-a-year industry in the US. There were 119 million prescriptions written for these drugs in 2009. Omeprazole and lansoprazole are also available over the counter. PPIs are indicated for the treatment of gastroesophageal reflux disease (GERD), Barrett esophagus, and peptic ulcer disease, and to aid in the eradication of Helicobacter pylori overgrowth. They may also be prescribed for symptoms sometimes associated with GERD such as chronic cough, asthma, and chest pain.

Generic and brand names include:
omeprazole (Prilosec)
lansoprazole (Prevacid)
rabeprazole (Aciphex)
pantoprazole (Protonics)
esomeprazole (Nexium)

Effects on Gastric Secretion and Risk of Gastric Polyps
PPIs block the H+/K+ ATPase enzyme system on parietal cells. This action increases pepsinogen and gastrin and lowers pepsin and HCl. Gastric nitrate rendering bacteria levels increase, as do carcinogenic nitrosamines in gastric juice. A pH of less than 3.8 allows gastric bacterial overgrowth. Thirty-five percent of patients on omeprazole had overgrowth compared with 10% of controls (Theisen 2000). Some authors also suggest that the possibility of viral and prion-associated infections may be increased by PPIs. Hypergastrinemia increases the risk of gastric polyps and may be implicated in gastric and colon cancer. "In the long term, hypergastrinemia induced by PPIs causes enterochromaffin-like (ECL) cell hyperplasia and carcinoid" (Waldum 2002).

Gastric hyperplastic polyps are usually multiple, less than 1cm, and sessile, and occur after a mean of 32.5 months on PPIs. Patients on PPIs have an increase in gastric polyp formation. Most carcinoids develop in patients with long-lasting hypergastrinemia and are of ECL origin. It is estimated that, in humans, it takes at least 10 years to induce ECL cell carcinoids (Choudhry 1998). Long-term PPI use increases the risk of atrophic gastritis, which may be a precursor of gastric cancer. According to a Danish study, the incidence of gastric cancer is directly related to the number of PPI prescription refills and duration of use (Poulsen 2009).

Hypergastrinemia decreases intra­gastric vitamin C levels and may increase serum insulin. Whether this is related to increased insulin resistance has not been studied.

Effects on Gastric/Duodenal Mucosa
PPIs decrease mucosal blood flow to the antrum, pylorus, and duodenal bulb. A study of patients taking esomeprazole (Nexium) as a new prescription found a significant transmucosal leak (hyperpermeability) proximal to the duodenum, which occurred within a few days of starting the medication (Mullin 2008). The change reverses within a few days of discontinuing esomeprazole. The hypothesis for the study stemmed from the observation that most Barrett esophagus patients – maintained on PPIs – have gastric hyperpermeability. Murine studies have confirmed this and have found increased transmucosal absorption of bradykinin across the gastric membrane (Gabell 2010). Absorption of digoxin across the gastric mucosa (in mice) was significantly increased by omeprazole. The authors suggest that if extrapolated to humans, this could lead to dangerously high levels in certain situations (Gabello 2010).

Acid Suppression and Food Allergy
Research shows that normal breakdown of food antigens is inhibited when gastric hydrochloric acid is decreased to levels commonly found in patients maintained on PPIs.

Acid-suppressive medications induce gastric hyperpermeability, which may increase the absorption of these antigens (Merwat 2009). Following this trend, adults on PPIs have been shown to have higher IgE antibody levels and to develop food-specific IgE antibodies that were not present prior to 3 months of reduced gastric acid. In addition, eosinophilic esophagitis, an increasingly prevalent food–allergy related pathology, may be induced by PPI administration.

The prevalence of eosinophilic esophagitis has increased in recent years for reasons that are not clear. The gastrointestinal mucosa is regularly exposed to food antigens with the potential to evoke immunological reactions. Other studies have shown that PPIs increase gastrointestinal mucosal permeability (discussed above), which might facilitate the uptake of undegraded peptide allergens. Mice treated with antisecretory medications while being fed a diet of caviar have been found to develop caviar-specific immunoglobulin E (IgE) antibodies, T-cell reactivity, and gastric eosinophilia. These data establish a plausible mechanism whereby acid-suppressive medications, by interfering with the peptic digestion of food allergens and increasing mucosal permeability, might lead to the development of food allergy.
 
Effects on Duodenogastric Reflux (Bile Reflux)
In a study of 23 Barrett esophagus patients on PPIs, acid and bile reflux decreased in most patients, but increased in 12% (Menges 2001). Another study revealed a 48% increase in bile reflux. Only 35% of the subjects had their gastric acid and bile reflux normalized by the treatment (Sarela 2004).

Research suggests that gastrinoma (carcinoid tumor) diagnosis is delayed by PPI suppression of symptoms. More advanced disease is seen and the five-year survival rate decreases in these cases. "Physicians must maintain a high index of suspicion for this disease and not mask a potential malignancy with prolonged control of acid related symptoms without taking steps to diagnose gastrinoma" (Elison 2003).

Gastric adenocarcinoma occurred significantly (50%) more often in rats with bile reflux who were treated with lansoprazole compared with bile reflux controls (27%) (Viste 2004).

Reg protein is expressed in gastric fundic ECL cells. It is stimulated by gastrin, H. pylori overgrowth, and certain cytokines (CINC-2 beta). Its effect is to increase proliferation of gastric mucosal cells. Reg protein is produced in many gastric cancer cells, especially the more advanced and poorly differentiated types. The hypergastrinemia induced by PPIs may increase this proliferation of gastric cancer cells (Kinoshita 2004). On a similar note, a British study investigated the effect of PPI-induced hypergastrinemia on human colonic adenoma when grown in mice. They found that the use of omeprazole and lansoprazole increased the weight of human adenoma grafts by 43% to 70% (Watson 2002).

PPIs and Hip Fracture
Another unfortunate side effect is an increased risk of fracture in women over age 50 on long-term acid suppression therapy. When these women take PPIs for more than a year, they have a 44% increased risk of hip fractures. In addition, long-term high-dose use increases hip fracture by 245% (Geller 2007)! Another study gleaned statistics from the Women's Health Initiative and found no increase in hip fractures, but found a modest association between PPIs and spine, forearm, wrist, and total fractures (Gray 2010). No increase in fracture risk was found for H2 receptor antagonists (cimetadine, etc.).

Pneumonia and PPIs
Use of gastric-suppressive therapy is associated with a 1.89 risk ratio for community acquired pneumonia, while H2 receptor antagonists carry a 1.63 risk ratio (Laheij 2004). Some studies find that this does not extend to hospital acquired pneumonia (Thomsen 2010), while others find up to a 30% increased risk (Herzig 2009). Elderly patients when started on acid-suppressive medication have nearly double the risk of recurrent pneumonia (Eurich 2010).

Antibiotic-Associated Diarrhea and PPIs
PPIs are a significant risk factor for acquiring Clostridium difficile–associated diarrhea while hospitalized (Kim 2010). A Harvard study found it to be dose dependent (Howell 2010). Taking statin drugs along with PPIs may increase the risk – even in patients who have not recently taken antibiotics (McGuire 2009). Acid suppression is a significant risk factor for C. difficile diarrhea in children as well, with either PPI or H2 receptor antagonist administration.

Common Side Effects of PPIs
CNS (7%):   headache, dizziness, asthenia
GI (3%):diarrhea, constipation, abdominal pain, nausea and/or vomiting
Miscellaneous:URI, rash, alopecia, cough, back pain

Drug Interactions
The FDA advises patients taking PPIs to warn their physician or pharmacist if they are also taking diazepam, warfarin, antifungals, digoxin, tacrolimus, clopidogrel bisulfate (Plavix), or atazanavir. "When clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole."

All PPIs except rabeprazole are metabolized by the P450 system enzyme CYP 2C19. The bioavailability of omeprazole and esomeprazole increases after the first week of dosage due to a progressive reduction in their hepatic clearance. In other words, these drugs impair the activity of CYP 2C19 (Horn 2004).

Proton Pump Inhibitors and Altered Laboratory Testing

Effects of Lansoprazole on Lab Values
Increases  
   Transaminases
   Globulin
   LDH
   Creatinine
   Alkaline phosphatase
   Bilirubin
   Eosinophils
   Glucocorticoids
Increases or decreases  
   Electrolytes
   Total cholesterol

Effects of Rabeprazole on Lab Values
Increases 
   Glucose
   Albumin
   Total cholesterol
   Transaminases
   PSA
   CPK
Increases or decreases  
   RBCs
   WBCs
   Platelets

Nutritional Effects
Long-term PPI use may cause deficiencies of folate, B12, iron, zinc, and calcium.

Calcium
Gastric acid is needed for proper absorption of dietary calcium (Graziani 2002).

In vitro calcium carbonate disintegration and dissolution is pH dependent, as pH increases, disintegration and dissolution slows, decreasing from 96% at a pH of 1.0 to 23% at a pH of 6.1. Proton pump inhibitors effectively reduce gastric acid production and increase gastric pH to an average of 5.5 with 19% of the day spent above a pH of 6.0. (O'Connell 2005)

Dietary supplementation with lactic acid or lactic acid dairy products improves calcium absorption in hypochlorhyric rats (Chonan 1998). Compared with placebo, omeprazole decreased calcium absorption by 41% in a seven-day trial. A study at Tufts University found no decrease in calcium absorption in subjects exposed to a single dose of omeprazole even though it induced transient hypochlorhydria (Serfaty-Lacrosniere 1995).

Iron
Long-term use of PPIs increases the risk of iron malabsorption. This is especially important in patients who are iron deficient prior to commencing acid suppression (Sharma 2004). Treatment of H. pylori overgrowth has cured several cases of chronic iron deficiency anemia in children and adults (Duque 2010, Sugiama 2002). Perhaps this is due to correction of the hypochlorhydria induced by many cases of H. pylori infection.
Vitamin B12

Case reports of B12 in patients taking long-term PPIs indicate a gradual decrease in serum levels (Termanini 1998). Some studies find no significant decline. Research using more accurate markers than serum cyanocobalamin such as methyl-malonic acid, holotranscobalamine II, homocysteine, or neutrophilic segmentation index may be more definitive and should be pursued.

Zinc
Omeprazole decreases intestinal zinc absorption (Ozutemiz 2002). A Jordanian study found that zinc, copper, and cobalt form complexes with omeprazole (Hamdan 2001).

Proton Pump Inhibitors and Rebound Hypersecretion
Significant rebound acid hypersecretion lasts from 8 to 26 weeks after long-term proton pump inhibition (Fossmark 2005, Waldum 1996).

Naturopathic Treatment of GERD
Clearly, the naturopathic approach to digestive wellness with a focus on improving function is a treatment worth pursuing. Optimizing the tone of the lower esophageal sphincter and the parasympathetic nervous system as well as normalizing gastric and pancreatic secretions often result in normalization of reflux symptoms.

According to the 2006 edition of the Merck Manual, over 40% of Americans have a sliding hiatal hernia. The Townsend Letter published my article on natural treatment of hiatal hernia in February 2009. Many cases of gastroesophageal reflux can be resolved with the techniques that I detailed.

Diet, medications, and hormonal balance are key factors in reflux.

Consider Dr. Sherry Rogers's organizational system – "Cut out the CRAP" (2000). I have made a few additions to her mnemonic device:

CRAP
C   Coffee   • Cigarettes • Chocolate
R   Refined carbohydrates
A   Acid-containing foods • Alcohol • Aspirin
   Allergy or intolerance to foods
P   Pop (soda) • Peppermint (menthol)
   Packin' food in at bedtime
   (eating within 3 hours of bedtime)
   Progesterone

Methyl xanthines such as coffee and chocolate may induce heartburn by decreasing the tone of the lower esophageal sphincter. Consuming peppermint, drinking excessive alcohol, and smoking tobacco probably cause heartburn by this same mechanism.

Refined carbohydrates and soda pop may cause GERD by inducing insulin resistance, which delays gastric emptying. The extreme example is gastroparesis, which may prevent the stomach from emptying for up to 8 to 10 hours. A full stomach is much more likely to reflux its partially digested contents into the lower esophagus. This gastric fullness mechanism applies to eating within 3 hours of bedtime as well. During sleep, gravity does not support the acid esophageal clearance and salivary secretion is decreased, leading to less lower esophageal neutralization of gastric acid. In addition, there are fewer esophageal contractions. A left lateral sleep position is more protective than sleeping on the right side (Dantas 2002).

High-progesterone states – the menstrual luteal phase, pregnancy, and the use of progesterone-containing medications – downregulate smooth muscle tone, decreasing peristalsis in the small intestine (Aytug 2001). Less active phases of the migrating motor complex (MMC) of the small intestine lead to decreased gastric emptying (Medhus 1995). It is important to note that the MMC was measured in 75% of breast-fed infants but only 17% of formula-fed infants (Tomomasa 1987).

A large French study of low-dose daily aspirin use revealed a 15.4% incidence of upper gastrointestinal symptoms with 70% of the symptoms being gastroesophageal reflux (Cayla 2010). Antiretroviral therapy for AIDS also increases the incidence of reflux and H. pylori infection (Nkuize 2010).

Nutritional and botanical medicines are highly effective in relieving heartburn and healing reflux esophagitis. These include aloe vera, glycine, glutamine, zinc, N-acetyl glucosamine, gamma oryzanol, and deglycyrrhizinated licorice root. These are best used in a nonencapsulated form to insure contact with the lower esophageal mucosa. Others improve the tone of the lower esophageal sphincter, thereby preventing reflux from the stomach into the esophagus. These include phosphatidyl choline (lecithin), plant enzymes, and huperzine A from the Chinese herb Huperzia serrata (Lamson 2003).

I agree with the following quote from the Digestive and Liver Disease journal:

The relatively common use of acid inhibitors in uncomplicated GERD or in the prevention of NSAID and steroid gastropathy is often unsubstantiated and should be limited to very specific situations. (Machetti 2003)

References
Aytug N et al. Gender influence on jejunal migrating motor complex. Am J Physiol Gastrointest Liver Physiol. 2001 Feb;280(2):G255–G263.
Cayla G et al. Prevalence and clinical impact of upper gastrointestinal symptoms in subjects treated with low dose aspirin: the UGLA survey. Int J Cardiol. 2010 Nov 17.
Chonan O et al. Effect of L-lactic acid on calcium absorption in rats fed omeprazole. J Nutr Sci Vitaminol (Tokyo). 1998 Jun;44(3):473–481.
Choudhry U et al. Proton pump inhibitor-associated gastric polyps: a retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics. Am J Clin Pathol. 1998 Nov;110(5):615–621.
Dantas RO, Aben-Athar CG. Aspects of sleep effects on the digestive tract. Arq Gastroenterol. 2002 Jan–Mar;39(1):55–59.
Duque X et al. Effect of eradication of Helicobacter pylori and iron supplementation on the iron status of children with iron deficiency. Arch Med Res. 2010 Jan;41(1):38–45.
Ellison EC, Sparks J, Zollinger-Ellison syndrome in the era of effective acid suppression: are we unknowingly growing tumors? Am J Surg. 2003 Sep;186(3):245–248.
Eurich DT et al. Recurrent community-acquired pneumonia in patients starting acid-suppressing drugs. Am J Med. 2010 Jan;123(1):47–53.
Fossmark R et al. Rebound acid hypersecretion after long-term inhibition of gastric acid secretion. Aliment Pharmacol Ther. 2005 Jan 15;21(2):149–154.
Freeman HJ et al. Proton pump inhibitors and an emerging epidemic of gastric fundic gland polyposis. World J Gastroenterol. 2008 Mar 7;14(9):1318–1320.
Gabell M et al. Omeprazole induces gastric transmucosal permeability to the peptide bradykinin. World J Gastroenterol. 2010 Mar 7;16(9):1097–1103.
Gabello M et al. Omeprazole induces gastric permeability to digoxin. Dig Dis Sci. 2010 May;55(5):1255–1263.
Geller JL, Adams JS, Proton pump inhibitor therapy and hip fracture risk. JAMA. 2007 Apr 4;297(13):1429.
Gray SL et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. Arch Intern Med. 2010 May 10;170(9):765–771.
Graziani G et al. Calcium and phosphate plasma levels in dialysis patients after dietary Ca-P overload. Role of gastric acid secretion. Nephron. 2002 Jul;91(3):474–479.
Hamdan II et al. In vitro study of the interaction between omeprazole and the metal ions Zn(II), Cu(II), and Co(II). Pharmazie. 2001 Nov;56(11):877–881.
Herzig SJ et al. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA. 2009 May 27;301(20):2120–2128.
Horn J, Review article: relationship between the metabolism and efficacy of proton pump inhibitors – focus on rabeprazole. Aliment Pharmacol Ther. 2004 Nov;20 Suppl 6:11–19.
Howell MD et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010 May 10;170(9):784–790.
Kim JW, et al. Proton pump inhibitors as a risk factor for recurrence of Clostridium-difficile-associated diarrhea. World J Gastroenterol. 2010 Jul 28;16(28):3573–357.
Kinoshita Y et al. Reg protein is a unique growth factor of gastric mucosal cells. J Gastroenterol. 2004 Jun;39(6):507–513.
Laheji RJ et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004 Oct 27;292(16):1955–1960.
Lamson DW. The problem of gastroesophageal reflux disease. Integ Med. 2003;2(2).
Machetti F et al. Proton pump inhibitors in children: a review. Dig Liver Dis. 2003 Oct;35(10):738–746.
McGuire T et al. Clinically important interaction between statin drugs and Clostridium difficile toxin? Med Hypo. 2009 Dec;73(6):1045–1047.
Medhus A et al. The migrating motor complex modulates intestinal motility response and rate of gastric emptying of caloric meals. Neurogastroenterol Motil. 1995 Mar;7(1):1–8.
Menges M et al. Increased acid and bile reflux in Barrett's esophagus compared to reflux esophagitis, and effect of proton pump inhibitor therapy. Am J Gastroenterol. 2001 Feb;96(2):331–337.
Merwat SN et al. Might the use of acid-suppressive medications predispose to the development of eosinophilic esophagitis? Am J Gastroenterol. 2009 Aug;104(8):1897–1902.
Mullin JM, Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase. Aliment Pharmacol Ther. 2008 Dec 1;28(11–12):1317–25.
Nkuize M et al. Upper gastrointestinal endoscopic findings in the era of highly active antiretroviral therapy. HIV Med. 2010 Jul 1;11(6):412–417.
O'Connell MB et al. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med. 2005 Jul;118(7):778–781.
Ozutemiz AO et al. Effect of omeprazole on plasma zinc levels after oral zinc administration. Indian J Gastroenterol. 2002 Nov–Dec;21(6):216–218.
Poulsen AH et al. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br J Cancer. 2009 May 5;100(9):1503–1507.
Rogers S. No More Heartburn. Kensington Publishing Corp; 2000.
Sarela AI et al. Persistent acid and bile reflux in asymptomatic patients with Barrett esophagus receiving proton pump inhibitor therapy. Arch Surg. 2004 May;139(5):547–551.
Serfaty-Lacrosniere C et al. Hypochlorhydria from short-term omeprazole treatment does not inhibit intestinal absorption of calcium, phosphorus, magnesium or zinc from food in humans. J Am Coll Nutr. 1995 Aug;14(4):364–368.
Sharma VR et al. Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia. South Med J. 2004 Sep;97(9):887–889.
Sugiyama T et al. Improvement of long-standing iron-deficiency anemia in adults after eradication of Helicobacter pylori infection. Intern Med. 2002 Jun;41(6):491–494.
Termanini B et al. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. Am J Med. 1998 May;104(5):422–430.
Theisen H et al. Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids. J Gastrointest Surg. 2000 Jan–Feb;4(1):50–54.
Thomsen AB et al. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol. 2010 May 21;16(19):2323–2330.
Tomomasa T et al. Gastroduodenal motility in neonates: response to human milk compared with cow's milk formula. Pediatrics. 1987 Sep;80(3):434–438.
US Food and Drug Administration. Information for healthcare professionals: update to the labeling of clopidogrel bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC) [online document]. Available at: www.fda.gov.
Viste A et al. Lanzoprazole promotes gastric carcinogenesis in rats with duodenogastric reflux. Gastric Cancer. 2004;7(1):31–35.
Waldum HL et al. Long-term safety of proton pump inhibitors: risks of gastric neoplasia and infections. Expert Opin Drug Saf. 2002 May;1(1):29–38.
Waldum HL et al. Marked increase in gastric acid secretory capacity after omeprazole treatment. Gut. 1996 Nov;39(5):649–653.
Watson SA et al. Potential role of endocrine gastrin in the colonic adenoma carcinoma sequence. Br J Cancer. 2002 Aug 27;87(5):567–573.

Steven Sandberg-Lewis, ND, DHANP, is a professor at the National College of Natural Medicine (NCNM) in Portland, Oregon. He has taught pathology and gastroenterology since 1996 and has been in continuous practice since graduating from NCNM in 1978. He supervises student clinicians at the NCNM Natural Health Center with a focus on digestive and musculoskeletal health. His emphasis is on diet; myofascial, visceral and spinal manipulation; and functional analysis and mind-body clearing techniques. Dr. Sandberg-Lewis's first textbook is entitled Functional Gastroenterology – Assessing and Addressing the Causes of Functional Gastrointestinal Disorders and is available from NCNM Press – www.ncnm.edu/bookstore.