Proton Pump Inhibitors Raise Risk of Liver CancerMay 2019
By John Verona
For decades, people have been taking proton pump inhibitor drugs (PPIs) like Prilosec OTC® and Nexium® to treat heartburn, acid reflux, ulcers, and other related ailments.
But now a new study establishes a disturbing link between taking those drugs and the rate of developing liver cancer.1
In a shocking finding, individuals’ PPI use was associated with an 80% increased risk of liver cancer, compared with people who did not use PPIs.1
There have been other ominous findings about this drug category previously. Studies have shown that PPIs can reduce nutrient absorption, cause bacterial overgrowth, and are associated with increased risk of cardiovascular, kidney, and neurodegenerative brain diseases.2-6
The new findings are the most alarming yet. While PPIs, which reduce the production of stomach acid, have a role in short-term symptom management, the list of troubling issues linked to their long-term use is growing. Now liver cancer has been added to that list.
In this Research Update, we review the new epidemiological study to see precisely what the researchers found, and we explore safe alternatives to relieve symptoms.
Study Links PPI Use to Liver Cancer
Many scientists have become concerned about potential adverse effects of PPIs. Recent animal studies have shown increased stomach cancer risk and the potential for liver damage.7-9
In another animal study, PPI use demonstrably promoted liver cancer in rats.10 So cancer epidemiologists—scientists who study diseases within populations, searching for patterns and causes—teamed up in the United Kingdom and Texas to conduct a study of the impact of PPI use on liver cancer in people.
Of course, scientists can’t expose people to a substance they believe may cause cancer. What the researchers did was combine 2 proven epidemiological techniques to examine associations between PPI use in humans and the risk of liver malignancies. This let them cross-check their data and made the overall study exceptionally thorough and strong.1
In the first part, a case-control study was carried out. Using this method, scientists identify people with a disease (in this case, primary liver cancer), then select control subjects without the disease. They then compare each group’s exposure to a potential risk factor (in this instance, PPI drugs).1
The participants in this study were 434 people with confirmed cases of liver cancer and 2,013 control subjects. The groups were carefully matched for age, gender, and a primary care physician, assuring the reliability of any findings.1
The second part was a prospective cohort study. Using this method, a very large group of people is identified, and wide-ranging data are collected about their health. In this way, associations between specific exposures (such as PPI use) can be identified among those who do or do not ultimately develop the particular disease (primary liver cancer).1
A link between PPIs and liver cancer was demonstrated in both parts of the study.
In the case-control study, PPI use was associated with an 80% increased risk of liver cancer. The strongest PPI drug-specific association, with an 83% increased risk of liver cancer1 was with omeprazole, most commonly sold as Prilosec® or Zegerid®.
In the prospective cohort study, which looked at nearly 500,000 participants, those individuals who had used PPIs nearly doubled their risk of liver cancer compared with people who had never used them.1
Potential Mechanisms Linking PPI Use to Liver Cancer
Even the strongest epidemiological studies cannot determine causality. Does exposure to drug X cause disease Y?
The main study we review here does not prove that PPIs cause liver cancer. But it does establish a close connection between exposure to the drugs and development of the cancer.
Since we can’t do direct experiments to prove causality in humans, we must rely on laboratory and animal studies to demonstrate credible mechanisms for any link.
Here is what we know from such basic scientific studies about PPIs and liver cancer risk:1
- Direct experiments in rats show that PPIs can promote liver tumors.10
- Long-term PPI use can cause excessive secretion of gastrin, a stomach-produced hormone that has
known, cancer-inducing effects, especially on liver
- By reducing stomach acid, PPIs can permit the overgrowth of bacteria and other microorganisms in the stomach that may cause the formation of carcinogenic compounds.13,14
Safer Alternatives to Treat Stomach Issues
In 2013, an estimated 15 million Americans used PPIs.15 Considering the association of PPIs with increased incidence of liver cancer—and the tragically high death rate associated with that cancer—it’s wise to consider less potentially harmful alternatives.
Studies have shown that supplements containing deglycyrrhizinated licorice and a zinc-carnosine compound protect the stomach from acid damage, while raft-forming alginates help to protect the esophagus against acid/reflux erosion.16-19
Licorice root and zinc-carnosine are used to treat both ulcers and heartburn, and they actively promote healing of the stomach’s lining. Raft-forming alginates block acids, enzymes, bile and foods from entering the esophagus and causing painful and damaging effects. All 3 supplements have an excellent safety record and have been used for decades to help with stomach and esophagus problems.
Proton pump inhibitors are intended to be used for a short period of time. However, many individuals use them regularly for years, and this creates a challenging dilemma for those with severe esophageal reflux.
If you are considering alternative therapies, do not discontinue PPIs without physician guidance. Discuss and review any alternative therapies with your physician for a successful transition.
Heartburn hurts, and people who suffer from it will try just about anything to get relief.
The most common medications available to heartburn sufferers over-the-counter in the U.S., proton pump inhibitors (PPIs), are often used inappropriately, and come with a growing list of potentially adverse effects.
A new and thorough study from the U.K. has shown a shocking increase in liver cancer risk associated with PPI use.
That comes on top of previous studies associating PPIs with heart disease, dementia, and kidney disorders, along with the disruption of healthy intestinal bacteria. Caution is clearly advised in pursuing relief through long-term PPI use.
Alternatives to PPIs can be found in flavonoid-rich deglycyrrhizinated licorice extracts, zinc-carnosine, and protective raft-forming alginates. The benefits of all these alternatives are supported by scientific evidence and should be discussed with your physician.
If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.
- Tran KT, McMenamin UC, Hicks B, et al. Proton pump inhibitor and histamine-2 receptor antagonist use and risk of liver cancer in two population-based studies. Aliment Pharmacol Ther. 2018 Jul;48(1):55-64.
- Davis TME, Drinkwater J, Davis WA. Proton Pump Inhibitors, Nephropathy, and Cardiovascular Disease in Type 2 Diabetes: The Fremantle Diabetes Study. J Clin Endocrinol Metab. 2017 Aug 1;102(8):2985-93.
- Gomm W, von Holt K, Thome F, et al. Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA Neurol. 2016 Apr;73(4):410-6.
- Sukhovershin RA, Cooke JP. How May Proton Pump Inhibitors Impair Cardiovascular Health? Am J Cardiovasc Drugs. 2016 Jun;16(3):153-61.
- Tai SY, Chien CY, Wu DC, et al. Risk of dementia from proton pump inhibitor use in Asian population: A nationwide cohort study in Taiwan. PLoS One. 2017;12(2):e0171006.
- Corsonello A, Lattanzio F, Bustacchini S, et al. Adverse Events of Proton Pump Inhibitors: Potential Mechanisms. Curr Drug Metab. 2018;19(2):142-54.
- Cheung KS, Chan EW, Wong AYS, et al. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut. 2018 Jan;67(1):28-35.
- Brusselaers N, Wahlin K, Engstrand L, et al. Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a nationwide population-based cohort study in Sweden. BMJ Open. 2017 Oct 30;7(10):e017739.
- Llorente C, Jepsen P, Inamine T, et al. Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus. Nat Commun. 2017 Oct 16;8(1):837.
- Hayashi H, Shimamoto K, Taniai E, et al. Liver tumor promoting effect of
omeprazole in rats and its possible mechanism of action. J Toxicol Sci. 2012;37(3):
- Fossmark R, Sagatun L, Nordrum IS, et al. Hypergastrinemia is associated with adenocarcinomas in the gastric corpus and shorter patient survival. APMIS. 2015 Jun;123(6):509-14.
- Caplin M, Khan K, Savage K, et al. Expression and processing of gastrin in hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma. J Hepatol. 1999 Mar;30(3):519-26.
- Thorens J, Froehlich F, Schwizer W, et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut. 1996 Jul;39(1):54-9.
- Lewis SJ, Franco S, Young G, et al. Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole. Aliment Pharmacol Ther. 1996 Aug;10(4):557-61.
- Lazarus B, Chen Y, Wilson FP, et al. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Intern Med. 2016 Feb;176(2):238-46.
- Inaba T, Ishikawa S, Toyokawa T, et al. Basal protrusion of ulcers induced by endoscopic submucosal dissection (ESD) during treatment with proton pump inhibitors, and the suppressive effects of polaprezinc. Hepatogastroenterology. 2010 May-Jun;57(99-100):678-84.
- Larkworthy W, Holgate PF. Deglycyrrhizinized liquorice in the treatment of chronic duodenal ulcer. A retrospective endoscopic survey of 32 patients. Practitioner. 1975 Dec;215(1290):787-92.
- Mahmood A, FitzGerald AJ, Marchbank T, et al. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut. 2007 Feb;56(2):168-75.
- Sweis R, Kaufman E, Anggiansah A, et al. Post-prandial reflux suppression by a raft-forming alginate (Gaviscon Advance) compared to a simple antacid documented by magnetic resonance imaging and pH-impedance monitoring: mechanistic assessment in healthy volunteers and randomised, controlled, double-blind study in reflux patients. Aliment Pharmacol Ther. 2013 Jun;37(11):1093-102.
- Ladep NG, Khan SA, Crossey MM, et al. Incidence and mortality of primary
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- Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol. 2013 May;11(5):483-90.