The use of heartburn medications like Nexium is widespread. These medications suppress the symptoms of acid reflux and give symptomatic relief – but doesn’t fix the problem! Recent research should be of concern as to what the long-term use of these medications may be doing.

With up to 17% of Australians experiencing heartburn or dyspepsia on a weekly basis, it is no wonder that it is one of the 10 most highly prescribed medications by Australian doctors. As these medications only offer symptomatic relief, it should also be no surprise that long-term treatment is very common. Medications used to treat hyperacidity and reflux, commonly referred to as proton pump inhibitors (PPIs), are sold under brand names such as Nexium, Losec and Somac. Patients are prescribed these medications to get relief of their symptoms, unaware that these medications may be causing them widespread long-term problems. Doctors are not aware that they should be monitoring their patients for signs of these adverse effects.

The list of adverse effects from long-term PPI use is quite long. Patients are told that the risk is small. That may be so, unless it is YOU that that develops them. You develop a new medical condition. Is your medication suspected? No. And so you now have a new condition (that is a drug side effect) that needs to be pharmaceutically treated. This is how patients end up with a bag full of prescription medications when they walk into my clinic.

The list of adverse effects of PPIs listed in MIMS, the doctor’s desktop guide to medicines, include: headache, dizziness, GI upset, dry mouth, paraesthesia, somnolence, insomnia, vertigo, peripheral oedema, hepatic effects, rash increased GI infection risk (possibly) and others.

In 2016 and also this year, I am seeing more articles being published on the adverse effects of long-term PPI use. Two possible adverse effects of PPIs that are being discussed currently in the literature, are the link with kidney disease and with dementia.

Kidney Damage and PPI Use

A new study assessed new patients prescribed PPIs. They were followed up for 5 years, looking at their kidney outcomes. None of these users had kidney disease at baseline, 18.24% of new PPI users developed acute kidney injury (AKI) over this time. Even when patients with AKI were excluded, PPI users still had an excess risk for chronic renal outcomes.

These results show that new users prescribed PPIs were significantly more likely to develop chronic kidney disease or end-stage renal disease, and more than half of those on PPIs who developed disease initially showed no sign of acute kidney injury after starting therapy.

Dementia and PPI Use

Another study has confirmed an association between PPIs and increased risk for dementia in older patients. An earlier study by the same researchers found a connection between PPI use and dementia risk. The current study is larger and based on information from a pharmaceutical database rather than on medical records, as the previous one was.

The study used the largest mandatory public health insurer in Germany, which included one third of the overall population and as much as 50% of the elderly population. These users had a significantly higher risk (1.44 fold) for dementia compared with those not taking this drug.

Researchers are not clear on how PPI use might raise dementia risk. Evidence suggests some PPIs may cross the blood–brain barrier and interact with brain enzymes and, in mice, may increase beta amyloid levels in the brain. The current study did not include vitamin B₁₂ levels, other research has linked PPI use to vitamin B₁₂ deficiency, which has been shown to be associated with cognitive decline.

But wait, of course there is more! If you look for it, you will find it.

These research articles prompted me to have a more detailed look at the research into long-term PPI use. Below is a summary, and it is not an extensive review, however the data should be put out there so that patients, as well as practitioners are aware of the long-term side effects of these PPIs. Also, remember that these PPIs are also prescribed to children.

Bone Strength and PPI Usage

Studies have shown an association between chronic PPI use and fractures of the hip or other sites, including spine, wrists and forearms. The risks seem to increase with the dose of drug and duration of use. It is not clear whether it is due to drug-related calcium malabsorption or decreases in bone density. However, in some vulnerable individuals, PPI use contributes to an increased risk of fractures at various sites, in a manner related to dose of drug and duration of therapy. Much of the fracture risk may ultimately prove to arise from widespread use of PPIs in very sick people whose comorbid illnesses and polypharmacy collectively increase the risk of fracture.

Infection Risk and PPI Usage

The principal function of gastric acid in humans is, to sterilise all contents entering the digestive tract. Reduction in acidity is associated with increased risks of both enteric and systemic infection. The only organism uniquely adapted to surviving the acid milieu is Helicobacter pylori, and the effects of PPIs in inhibiting gastric acidity/elevating pH are significantly greater in Helicobacter pylori-infected individuals than in controls. Helicobacter pylori gastritis is likely to be an important confounding factor in our understanding of an apparent increase in risk and severity of Clostridia difficle infections in the elderly, especially when treated with acid suppressive drugs.

There is a consistent association between PPI usage and an increased risk of Clostridium difficle associated diarrhoea. The risk for Salmonella, Shigella or other enteric infection is also increased. The occurrence of Clostridium difficle associated diarrhoea increases from 0.3% in patients receiving no acid suppression, to 0.9% in those receiving once daily PPI and to 1.4% in those receiving more frequent PPI therapy.

A number of early studies suggested a weak association between pneumonia and PPI use. A review of the literature found no association, although about half the studies showed a trend toward significant increases. In a more recent study, there appears to be a high risk of pneumonia in the first 30 days of therapy.

There is suspicion that acid-suppressive therapy increases the risk of small intestinal bowel overgrowth (SIBO), whether this risk is uniform in all users or is perhaps restricted to certain subgroups, such as the elderly, the Helicobacter pylori-infected or those with irritable bowel syndrome (IBS) is uncertain. There is growing acceptance of the presence of SIBO in 25–40% of patients with IBS-type symptoms, particularly gaseous bloating, excessive flatus and diarrhea, but also to a lesser extent in those in whom constipation or pain are dominant symptoms. The type of overgrowth due to PPIs may be caused more by the oral flora rather than by the usual flora of the more distal gut and give rise to a different clinical picture. A study of 450 patients with a positive glucose hydrogen breath test (GHBT), among 200 gastroesophageal reflux disease patients on PPIs, GHBT was positive in 50% compared with 24.5% among 200 PPI nonusers with IBS and 6% among 50 normal controls.

It seems likely that chronic use of PPIs increases the risk of SIBO in a sizable number of individuals, the risk increasing with length of time on the drug. This number may be influenced by a number of other factors including the presence of IBS, chronic gastritis, Helicobacter pylori infection, other comorbid conditions and exposure to antibiotics or to drugs or diseases that affect gastric emptying.

Cardiovascular Risk and PPI Usage

One study reviewed more than 16 million clinical documents on 2.9 million individuals and found that PPIs, appear to be associated with an elevated risk for myocardial infarction (MI). Specifically, patients with gastroesophageal reflux disease who were exposed to PPIs had a 16% increased risk of MI. The investigators also documented a twofold increase in risk for cardiovascular mortality.

Gastric Malabsorption and PPI Use

Inhibition of gastric secretion of acid, pepsin, intrinsic factor, vitamin C and other substances has given rise to concerns about a number of clinical nutritional deficiency states. Both hydrochloric and ascorbic acids secreted by the stomach are involved in converting ferric to ferrous iron. Ascorbic acid, whether of dietary or gastric origin, also chelates nonheme iron and keeps it in solution until absorbed. PPIs inhibit secretion of both hydrochloric and ascorbic acids. Therefore, conditions for iron absorption are significantly suboptimal during PPI therapy, particularly in the presence of Helicobacter pylori gastritis. PPI use has also been linked with the possible development of painful restless legs syndrome, long associated with iron deficiency and low serum ferritin concentrations.

Long-term use of acid-suppressing therapy has been linked to vitamin B12 malabsorption. Patients taking these medications for more than four years should be monitored for vitamin B 12 status.

Over the last several years, low serum magnesium levels have been in found in patients who were on long-term PPI’s. Patients were experiencing a number of symptoms, such as muscle cramps, tetany, cardiac arrhythmia, vertigo, convulsions and seizures. There have also been reports of an increase in hip fractures in patients using PPI’s over long periods (as discussed above). Studies of these patients show low serum magnesium as well as low serum calcium, which responded to magnesium therapy and discontinuation of the PPI.

Food Allergies and Eosinophilic Oesophagitis Linked to PPI Usage

A number of ingested potential food allergens that are normally broken down by acid digestion, become antigenic when the gastric pH rises to values seen during PPI therapy. Investigations have shown that PPIs dose dependently increase mucosal permeability to small molecules that could include peptide antigens. Adults treated with PPIs for 3 months develop a rise in plasma IgE levels, new food-specific IgE antibodies and a mucosal immune response to offending allergens. A recent hypothesis generating much interest proposes that PPIs may play a key etiologic role in causing eosinophilic esophagitis, as both PPI use and the incidence of eosinophilic esophagitis have risen over closely similar periods.

Carcinoid Tumours and PPI Use

PPIs inhibit acid secretion, leading gastric cells to release gastrin, causing hypergastrinemia. Gastrin, in turn, binds to gastric mucosal cells, causing them to release chromogranin, histamine and other substances. The acid-secretory effects of gastrin are inhibited by PPI, but the potential proliferative effects on mucosal cells or cancers are not. In rodents given PPIs, hypergastrinemia leads to the development of gastric carcinoids. In heartburn patients, long-term PPI use is associated with the development of focal areas of hyperplasia (abnormal cell changes) in 10–30% of patients. Whether or not PPI therapy leads to the development of gastric or other carcinoids in humans has never been formally studied, despite large recent increases in the incidence of these comparatively rare tumours in many sites. These increases in incidence rates have been observed in several large analyses in Western countries. The scientific basis for expecting long-term PPI use to cause carcinoid tumours is quite strong and merits serious attention. Hypergastrinemia may also stimulate carcinoid development or growth in other sites. At a minimum, it seems reasonable to discontinue PPI therapy in patients with carcinoid tumours.

Other Medications and PPI Use

Rises in pH and lack of gastric acid have been shown to impair the absorption of various drugs in common use, including ketoconazole, indinavir, midazolam, didanosine and methadone. Following absorption, some but not all PPIs inhibit various components of the cytochrome P-450 (CYP) enzyme detoxification system in the liver and intestine. PPIs also variably affect the hepatic catabolism of thyroxine by UDP-glucuronyl transferase, increasing TSH slightly and in some cases requiring an increase in the dose of thyroxine.

Rebound Hyperacid Secretion

This is an effect of acid suppression recognized for many years that daily PPI therapy leads to increased gastric acid-secretory capacity that is not apparent during PPI therapy, but that appears promptly when the drug is stopped. In normal volunteers, treated for 8 weeks with esomeprazole 40 mg per day, stopping the drug was followed by the development of dyspeptic symptoms in more than 40% of previously symptomless patients. Depending on the dose and duration of exposure, it can take 2–3 months for rebound acid hypersecretion to return to pre-PPI basal levels. This implies that a post-PPI-therapy period of difficulty should be anticipated.

Who is Monitoring Patients on PPIs?

The widespread use of PPIs for almost two decades is gradually increasing concern that their benefits may be accompanied by a variety of risks that until recently have received little attention. Although patients on long-term proton pump inhibitor (PPI) therapy are at increased risk for micronutrient deficiency, clinicians aren’t routinely checking for this, even in high-risk patients. At a poster session presented at United European Gastroenterology Week in Vienna in 2016, “even though gastroenterologists know about micronutrient deficiency, they aren’t looking for it”. The researchers reviewed the electronic health records of 41 patients with Barrett’s esophagus who were on long-term PPI therapy to see if their levels of vitamin B₁₂, ferritin, or magnesium were ever tested.

• The micronutrient levels of 20 patients (48.8%) had not been tested in the previous 5 years
• Only a single patient had undergone micronutrient testing in the previous 12 months
• Six patients (14.6%) had an incidental micronutrient deficiency detected on routine blood testing (vitamin B₁₂, folate, phosphate, ferritin)
• Serum magnesium level was not checked in the previous year for 38 patients (92.7%), and had never been checked for 15 patients (36.6%)
• Serum ferritin and vitamin B₁₂ levels were not checked in the previous year for 32 patients (78.1%), and had never been checked for nine patients (21.5%)
• The median level of magnesium in the study cohort was at the low end of normal, and median ferritin level was normal. There was one case of vitamin B₁₂ deficiency (2.4% of all patients)

There are reports in the literature of “serious” problems from PPI-induced micronutrient deficiency, including seizures and cardiac arrhythmias secondary to hypomagnesemia. The US Food and Drug Administration lists hypomagnesemia as a potential adverse effect of PPI therapy, and recommends that clinicians consider monitoring serum magnesium in long-term users.

Patients on PPIs presenting to my clinic rarely have had any blood work done to assess nutrient levels. From the study data, it would be prudent for patients on PPIs to have a comprehensive nutritional workup done. If your doctor refuses to order any tests, then for your well-being,  perhaps it is time to find one that will.

Alternatives to PPIs

There are alternatives to acid suppressive drugs, like PPIs, to treat heartburn or dyspepsia. Identify triggers and avoid them. Chocolate for example has been found to trigger symptoms in 40% of patients. Strengthening the lower oesophageal sphincter with herbal remedies. It is interesting that there is research to show that melatonin can help to strengthen the tone of the lower oesophageal sphincter in reflux patients. A specific form of zinc has been used in Japan for over 10 years for its unique properties in healing inflamed gut mucosa.

If you are suffering from reflux related symptoms, or on acid suppressive medication, and would like to come off, just contact me for more details. There are effective solutions that can help without the worry of long-term side effects.