Proton pump inhibitor and histamine‐2 receptor antagonist use and risk of liver cancer in two population‐based studies

Tran, Kim; McMenamin, Úna C.; Hicks, Blánaid; Murchie, Peter; Thrift, Aaron P.; Coleman, Helen; Iversen, Lisa; Johnston, Brian T.; Lee, Dean A.; Cardwell, Christopher

doi:10.1111/apt.14796

Cited by 41 publications

(36 citation statements)

References 32 publications

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“…The risk of liver cancer in PPI users was recently found to be increased in two different populations, whereas no such risk was seen in H2-blocker users [115]. The underlying mechanism may be similar to that of HE, SBP, and alcohol-induced liver damage, whereby bacterial overgrowth [116] results in increased portal venous concentrations of several proposed harmful substances, including secondary bile acids [117].…”

Section: Resultsmentioning

confidence: 99%

Adverse Effects of Proton Pump Inhibitors—Evidence and Plausibility

Fossmark

Martinsen

Waldum

2019

IJMS

121

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Proton pump inhibitors (PPIs) have been increasingly used over the last decades and there are concerns about overuse and the numerous reported side-effects. It is uncertain whether associations between PPI use and potential side effects are causal. However, important evidence from experimental and mechanistic studies that could support a causal relationship may have been underestimated by epidemiologists and meta-analysists. In the current manuscript we review the combined epidemiological and mechanistic evidence of the adverse effects of PPI use.

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Section: Resultsmentioning

confidence: 99%

Adverse Effects of Proton Pump Inhibitors—Evidence and Plausibility

Fossmark

Martinsen

Waldum

2019

IJMS

121

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“…While the medication use was based on self‐report, the information was verified by a trained nurse. More importantly, in both datasets, we have adjusted for a wide range of covariates including the main risk factors for liver cancer (age, sex, BMI, smoking and alcohol consumption, comorbidities), indications and contraindications of statins (high cholesterol, chronic liver diseases) and medications previously shown to be associated with liver cancer risk (metformin, aspirin, beta‐blockers, proton pump inhibitors and histamine‐2 receptor antagonist).…”

Section: Discussionmentioning

confidence: 99%

Statin use and risk of liver cancer: Evidence from two population‐based studies

Tran

McMenamin

Coleman

et al. 2019

Intl Journal of Cancer

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Epidemiological studies of statin use and liver cancer risk have produced conflicting results. We examined the association between statin use and risk of primary liver cancer in two large independent study populations taking account of important covariates and main indications of statins such as high cholesterol and chronic liver disease. We performed a nested case–control study within the Scottish Primary Care Clinical Informatics Unit (PCCIU) database. Five controls were matched to cases with primary liver cancer and we used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations with statin use. We also conducted a prospective cohort study within the UK Biobank using self‐reported statin use and cancer‐registry recorded primary liver cancer outcomes. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. In the PCCIU case–control analysis, 434 liver cancer cases were matched to 2,103 controls. In the UK Biobank cohort, 182 out of 475,768 participants developed incident liver cancer. Statin use was associated with 39% lower risk of liver cancer in the PCCIU (adjusted OR 0.61, 95% CI 0.43–0.87). When we examined specific subtypes of liver cancer in the UK Biobank, statin use was associated with lower risk of hepatocellular carcinoma (HCC; adjusted HR, 0.48; 95% CI, 0.24–0.94) but not intrahepatic bile duct carcinoma (IBDC; adjusted HR, 1.09; 95% CI, 0.45–2.64). In conclusion, we found a consistent inverse relationship between statin use and risk of primary liver cancer which was only seen for HCC but not IBDC.

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“…In conclusion, there are now both epidemiological and experimental evidence supporting that PPIs could play a role in primary hepatic carcinogenesis.…”

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confidence: 87%

“…In a recent article in Alimentary Pharmacology & Therapeutics , the possibility that PPI's might be associated with hepatocellular carcinoma was raised . Until a few years ago, PPIs were regarded as very safe medication although they induced hypergastrinaemia leading to ECL cell hyperplasia that proceeded to ECL cell neuroendocrine tumours of different degree of malignancy in rodents .…”

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confidence: 99%

“…Except for dementia where we proposed increased risk of prion infection secondary to hypoacidity, no plausible mechanism (hypergastrinaemia or infections due to gastric hypoacidity) was formulated. Therefore, when I first saw the study by Tran and co‐workers describing increased risk of primary liver cancer in PPI users, I thought that this was another study with residual confounding factors. However, they referred to an impressive paper by Llorente and co‐workers describing how gastric acid suppression promoted chronic liver diseases of different aetiology in mice by increasing the concentration and translocation of Enterococcus faecalis.…”

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confidence: 99%

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Editorial: proton pump inhibitors (PPIs) and primary liver cancer

Waldum

2018

Aliment Pharmacol Ther

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with PrOD within the VA system, including 2281 patients with stage 3 and 257 patients with stage 4-5 CKD. Among 137 patients with stage 4-5 CKD treated with SOF-LDV, 71.5% completed treatment and 95.4% achieved SVR. SVR rates were not different regardless of the stage of CKD, similar to those treated with PrOD, but decline in GFR >10 mL/ min/1.7 m 2 occurred more frequently in patients treated with SOF-LDV compared to those treated with PrOD, with the eGFR mostly remaining within the same CKD class. 7 Evidence from this to other small trials suggests safety and efficacy of SOF-based therapy in patients with advanced CKD. This has the potential to fill an unmet need in patients with decompensated cirrhosis and CKD, who should not receive NS3-NS4 containing therapy, and for whom SOF plus an NS5A inhibitor may be useful.Although this study included 4135 patients with cirrhosis, the authors did not categorise them by stages of CKD. The number with cirrhosis among patients with stage 4-5 CKD, and the safety and outcome of therapy in these patients are not presented and would help fill a knowledge gap in this area. ACKNOWLEDGEMENTS Declaration of personal interests:Wael Abdel-Razek: None. Imam Waked has served as investigator and or speaker for: Abbvie, Gilead Sciences, Janssen, Marcyrl, Onxio, Pharco. FUN DING INF ORMATION None. O R C I D W. Abdel-Razekhttp://orcid.org/0000-0003-0114-798XI. Waked http://orcid.org/0000-0002-9857-8972 Editorial: proton pump inhibitors (PPIs) and primary liver cancerProduction of acidic gastric juice developed in primitive fishes and has been preserved during evolution. In individuals, regulatory mechanisms, both central nervous and gastric, control and regulate gastric acidity keeping H+ concentration above a certain level.The gastric juice is a unique, highly acidic liquid with active enzymes, pepsin and lipase. Its main biological function is to kill swallowed microorganisms. The gastric juice is thus an important first line of defence.It is well known that some viruses are resistant to destruction by the gastric juice; leading to access to the gut where for instance, poliovirus can penetrate the gut epithelium and reach the medulla by passage through nerves. The reason why profound drug induced hypoacidity met so little concern when proton pump inhibitors (PPIs) were introduced clinically, must be the apparent few problems seen in patients with anacidity. However, pernicious anaemia is a disease of middle or late parts of life, and experience By realising the difficulties in discrimination between adenocarcinomas and neuroendocrine carcinomas (NECs), we studied gastric carcinomas in man and showed that an important proportion of them is derived from the ECL cell. 4 Therefore, drug-induced hypergastrinaemia was expected to dispose to gastric carcinoma, that indeed was shown half a year ago. 5 However, PPIs were in epidemiological studies incriminated in diseases like stroke, 6 dementia 7 and chronic renal disease. 8 These studies showed significant increases in prevalence in PPI ...

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Proton pump inhibitor and histamine‐2 receptor antagonist use and risk of liver cancer in two population‐based studies

Abstract: We found some evidence that PPI use was associated with liver cancer. Whether this association is causal or reflects residual confounding or reverse causation requires additional research.

Cited by 41 publications

References 32 publications

Adverse Effects of Proton Pump Inhibitors—Evidence and Plausibility

Adverse Effects of Proton Pump Inhibitors—Evidence and Plausibility

Statin use and risk of liver cancer: Evidence from two population‐based studies

Editorial: proton pump inhibitors (PPIs) and primary liver cancer

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