Using Proton Pump Inhibitors Increases the Risk of Hepato-Biliary-Pancreatic Cancer. A Systematic Review and Meta-Analysis

Abstract

Background: More and more studies are focusing on the adverse effects and damage caused by PPI abuse, we carried out a systematic review and meta-analysis for assessing whether the proton pump inhibitor (PPI) leads to liver-biliary-pancreatic cancer.

Methods: PubMed, EMBASE and Web of Science were searched until July 1, 2022, 24 studies (16 case-control and 8 cohort studies; 274, 0958 individuals) included in this study. Pooled Odd Ratios (ORs) were used for random effect models. Sensitivity analysis and dose-response analysis, subgroup analysis were all conducted.

Results: The aggregate OR of the meta-analysis was 1.69 (95% confidence interval (CI): 1.23-2.22, P = 0.01) and heterogeneity (I² = 98.9%, P < 0.001) was substantial. According to stratified subgroup analyses, the incidence of hepato-biliary-pancreatic cancer was associated, expect for study design, study quality and region. Risk of hepato-biliary-pancreatic cancer is highest when people is treated with normal doses of PPI. The risks decrease and become insignificant when the cumulative defined daily dose (cDDD) increases.

Conclusion: The use of PPI may be associated with an increased risk of hepato-biliary-pancreatic cancer. Hence, caution is needed when using PPIs among patients with a high risk of hepato-biliary-pancreatic cancer.

1. Introduction

Proton pump inhibitors have been the most widely used drugs since the 1980s for treating gastroesophageal reflux disease (GRED), H. pylori infection, Zollinger-Ellison syndrome and a number of other diseases caused by hyperacidity irreversibly inhibiting H+/K+-ATPase in stomach cells (1). These diseases usually require long-term treatment, which leads to the consequence of overdose.

However, there is still no consensus on whether long-term use of PPI can induce malignant tumors. Current research suggests that long-term PPI may lead to impaired absorption of vitamin B12, iron and calcium, while low gastric acid leads to an increased risk of gastrointestinal infections, these mechanisms may be strongly associated with tumor development. However, PPI may be a protective factor against the developing of esophageal and gastric cancer (2, 3) and high-quality evidence of an association between the use of PPI and hepato-biliary-pancreatic cancer is still needed. Therefore, evidence is needed to help doctors address the adequacy of the prescription and the patient's dose abnormalities during treatment.

We have clarified the association between PPI and risk of hepato-biliary-pancreatic cancer by including known studies in this meta-analysis. We likewise evaluated whether the risk of hepato-biliary-pancreatic cancer aggravates when the dose of PPI increases.

2. Methods

2.1 Search strategy

This study is based on the aloe system assessment and analysis criteria (PRISMA) and the optional reporting items in the Corcoran manual (Appendix S1). This research plan registered in the international prospective systematic evaluation register is NO.CRD 420211103, and can access the PubMed, EMBASE and web of science databases, research collections of proton pump inhibitors and hepato-biliary-pancreatic cancer, as well as comparative studies, this was done by the two researchers themselves. The search strategy is set out (Appendix S2). In order to identify other articles, additional manual searches were conducted for references in research reports and related reviews

2.2. Inclusion and exclusion criteria

Including criteria: (1) observational studies which include case-control (nested case-control and aggregated analysis of case-control studies) or cohort studies (aggregated analysis of cohort studies); (2) Exact records of PPI users; (3) Defined results of pancreatic, liver and biliary carcinoma; (4) Odds ratio (OR), Relative risk (RR) and hazard ratio (HR) reported for selected neoplasms and 95% CI.

Excluding criteria: (1) literature review or comments; (2) evaluate cancer recurrence or survival. We did not exclude based on the quality of the literature; therefore, no studies were excluded due to poor study design or low data quality.

2.3 Data extraction

Two auditors independently examined titles meeting the including and excluding criteria and examined whether the information of study is insufficient. Subsequently, the full text of the selected articles was evaluated and two auditors extracted critical information which includes first author, year of publication, region/country, study design, exposure definition, cDDD. independently. Any disagreement has been resolved by consensus between the two auditors or arbitrated by the third auditor. The quality of the observational studies was assessed by two authors using the Newcastle-Ottawa scale.

2.4 Data analysis and integration

ORs were used as a common measure of association between studies. Statistical analyses were performed using R (4.2.1). We derived aggregated risk estimates, which were expressed with 95% CI in total hepato-biliary-pancreatic cancer and in each cancer. Random effect models were used to take into account the heterogeneity of aggregate estimates. We used Cochran Q test to evaluate heterogeneity between studies, quantified using Cochran Q and I² statistics.

Subgroup analysis and meta-regression was performed (classification by study design (case-control or cohort), region (Western or Asia), and the Newcastle-Ottawa Scale (NOS) score (< 7 or ≥ 7)).

We also investigated a potential nonlinear dose-response relationship between cDDD and hepato-biliary-pancreatic cancer via restricted cubic splines and fractional polynomial models reported in Bagnardi et al (4). Dose-response study was conducted by mean cDDD values reported in the included articles.

3. Results

3.1 Description of included studies

The flowchart of study selection was demonstrated in Fig. 1. 24 articles and a population of 274, 0958 individuals were finally included in our analysis, an article of these contains 2 population-based studies (Primary Care Clinical Informatics Unit [PCCIU] and UK biobank studies) which has different study designs, many of the original studies included in this analysis had different subgroup analyses. Therefore, we analyzed them separately in our article. Table 1 provides the details of the study characteristics. Table S1 demonstrates the quality assessment and New-castle Ottawa scale scores of the included studies. Scored 7 is considered as high-quality in our study.

3.2 Association between PPI use and hepato-biliary-pancreatic cancer

All of the 24 studies (16 cases control (5–20) and 8 cohort studies (21–28) contained association between PPIs and hepato-biliary-pancreatic cancer risk. Results from both cohort and case-control studies were reported in two studies (9, 14), four studies report an association between PPI and multiple tumors (5, 11, 20, 21). An aggravated risk and the subgroup analysis by the types of pooled estimates indicated that the pooled estimates were similar numerically and can be seen in Fig. 2, with significantly increased risks in studies reporting ORs (OR = 1.69, 95%CI:1.23-2. 20). I² > 50% was found by heterogeneity test, we identified evidences of publication bias by the visual the results of Egger test(P༜0.001) (Figure S1), corrected (OR = 1.26 95% CI: 1.05–1.522) after adding 13 studies by subtractive complementation using trim and filling method. The heterogeneity was obvious (Cochran’s Q = 4478.36, I2 = 98.9%, P < 0.001). Subgroup analysis and meta-regression in different subgroups were performed (Table S2). Differences in study design, region, and NOS score were not sources of heterogeneity. An overall sensitivity analysis revealed that the heterogeneity originated from the study of Brusselaers et al. and Lassalle et al. and Shao et al. (Figure S2), a rereading of these studies revealed that the Brusselaers' study was biased by a smaller sample size, while the latter two were biased by different definitions of long-term PPI use. When these studies were excluded and re-analyzed, it was found that I² ༜50%。

3.3 PPI use and different cancers

A total of 12 studies reported the risk of liver cancer (3 studies reported intrahepatic bile duct cancer as an outcome and 9 studies reported the risk of hepatocellular carcinoma), which were analyzed separately and found that long-term PPI use increased the risk of liver carcinoma (OR = 1.69, 95% CI: 1.37–2.08), hepatocellular carcinoma (OR = 1.69, 95% CI: 1.30–2.20) were at risk of development. six case-control studies and five cohort studies (one case-control study reported the results of the cohort study) showed a significant association between long-term PPI use and the development of liver cancer when subgroup analysis was performed (OR 1.91, 95% CI:1.48–2.46 for case-control, OR = 1.51, 95% CI: 1.09–2.07 for the cohort study), and the risk of increased incidence of liver cancer after long-term PPI use was found in different geographical regions (Asia: OR = 1.75, 95% CI: 1.39–2.21; Western: OR = 1.66, 95% CI: 1.30–2.13) ( Table S2).

A total of 4 studies reported the risk of long-term PPI use and the risk of biliary system carcinoma, of which 2 reported the risk of gallbladder cancer (OR = 1.63, 95% CI: 1.31–2.04) and 3 reported the risk of intrahepatic and extrahepatic biliary tract cancer (OR = 1.83, 95% CI: 1.60–2.09), respectively, while the long-term use of PPI was associated with the overall risk (OR = 1.79, 95% CI: 1.63–1.97), and long-term PPI use was significantly associated with the overall biliary tract cancer (OR = 1.79, 95% CI: 1.63–1.97).

14 studies (12 case-control, 2 cohort studies) showed that long-term use of PPI drugs increased the risk of developing pancreatic malignancies (OR = 1.69, 95% CI: 1.30–2.20) and that PPI uses increased the incidence of pancreatic tumors in different geographical populations (Asia: OR = 1.67, 95% CI: 1.29–1.77; Western: OR = 1.45, 95% CI: 1.17–1.78).

3.4 cDDD, duration of PPI uses, and cancer risks

The WHO developed the anatomical therapeutic chemical (ATC) classification system in 1969, which established the defined daily dose (DDD) as the unit of medication frequency analysis. It is defined as the average daily dose of a drug used for the primary therapeutic purpose in adults (29). Information on hepato-biliary-pancreatic cancer risks correlated with cDDD of PPIs was provided in ten studies(Fig. 3).

Fourteen studies provided information on hepato-biliary-pancreatic cancer risks correlated with cDDD of PPIs.

The OR was highest at about 500 cDDD/per patient (Fig. 3A), which may mean that long-term normal dose of PPI use makes the risk of malignant tumor development significantly higher. The OR declined and became not apperant at around 1400 cDDD per patient or higher. The risk of hepatocellular and pancreatic cancers is highest at a cDDD of 300–400, while the risk of bile duct cancer is highest at a cDDD of about 120. The results of the dose-response study for hepatocellular carcinoma and pancreatic cancer were similar to the overall results.

4. Discussions

After analyzed 24 studies using a random effects model, including a total of 274, 0958 patients. This meta-analysis aimed to clarify that long-term use of PPI may increase the risk of hepato-biliary-pancreatic cancer.

Based on the results of our study, a normal dose of PPI is associated with an increased risk of developing hepato-biliary-pancreatic cancer. We found no correlation between higher dose of PPI use (cDDD > 2000/per patient) and the risks of hepato-biliary-pancreatic cancer.

Several mechanisms suggest a potential oncogenic effect of PPI in hepato-biliary-pancreatic cancer. These effects include an increase in levels of abnormal gastrointestinal hormones and intestinal microbiota, as well as the production of carcinogens.

4.1 Abnormal levels of gastrin and cholecystokinin

Prolonged use of PPI leads to a rise in gastric pH and an increase in gastrin production by G-cells with negative feedback. In addition to stimulating the secretion of digestive glands and accelerating nutrient absorption, gastrin seems to induce the development and growth of gastrointestinal cancers by binding to CCK-BR on the surface of the enterochromaffin-like cells (ECL) (30). In hepatocellular carcinoma, CCK-BR and a precursor form of gastrin are expressed in tumor cells (31), and this expression may be associated with apoptosis (32). Gastrin-releasing peptide promotes hepatocellular carcinoma cell growth not only by interacting with homologous receptors of gastrin-releasing peptide co-expressed in tumor cells but also by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) pathway through a non-dependent mechanism of the epidermal growth factor receptor (EGFR) (32), it can also inhibit the growth of normal liver cells by blocking the activation of ER (33). A DNA vaccine targeting gastrin-releasing peptide has been shown to inhibit the growth of blood vessels in liver tumors and to destroy tumor cells (34, 35). However, in cholangiocarcinoma, gastrin appears to have the opposite effect to that of hepatocellular carcinoma, inhibiting the proliferation of cholangiocarcinoma cells and inducing apoptosis via the Ca2 + dependent protein kinase C (PKC)-α pathway (36). However, when gastrin receptors are the target of pancreatic cancer treatment, specific antagonists can inhibit the growth of pancreatic cancer cells by blocking the cellular stimulatory effect of gastrin. Current clinical studies have demonstrated that these drugs have the potential to prolong survival and are no less effective than conventional treatments for pancreatic cancer (37), however, further research is needed on their safety and long-term efficacy (38).

A current study has proved long-term PPI use may pose a risk for gallbladder dysfunction and biliary complications (39), a retrospective analysis of stone recurrence in patients after endoscopic retrograde cholangiopancreatography (ERCP) found that PPI may pose a risk for recurrence of common bile duct stone (CBDS) in ERCP patients (40). long-term PPI use may be associated with the abnormal secretion of CCK, a gastrointestinal peptide released from the upper part of the small intestine, which has a similar peptide structure to gastrin. CCK has functions that include stimulation of intestinal motility, stimulation of pancreatic enzyme secretion, and stimulation of gastric acid secretion (41). Its primary function is to trigger gallbladder emptying by binding to the CCK A-type receptor (CCKAR) and mediating the activation of post-membrane signaling pathways in smooth muscle, defects in CCKAR are a key point of impairment of gallbladder motility, which in turn may form the background for GBC (42, 43), abnormal level of CCK results in reduced or delayed postprandial gallbladder contraction, leading to bile stagnation and creating an environment for cholesterol supersaturation and subsequent gallstone formation (41, 43–46). Both CCK and its receptor CCKAR are important in the pathogenesis of biliary tract tumors, CCK is currently thought to exhibit growth-stimulating effects on biliary tract-derived cancer cell line (44), an analysis of the biliary tract tumor in Shanghai, China, found that women with the CCKAR genotype were at increased risk of gallbladder cancer, and biliary tumorigenesis may be inhibited when CCKAR is in an antagonistic state (45). However, CCKAR receptors are more highly expressed in patients with cholelithiasis than in the normal population, while CCKAR expression is reduced in patients with GBC (46), it may be because CCK remains chronically high in CA patients, leading to a decrease in receptor number and activity responsiveness. However, Kazmi observed a significant increase in CCKAR mRNA and protein expression in GBC tissues (47). Furthermore, gastrin or CCK showed a definite growth stimulating effect on biliary tract-derived cancer cell lines, and CCKAR and CCK-BR mRNA were detected in all biliary and pancreatic cancer (48). CCK also has a pro-pancreatic function in the normal gastrointestinal environment, and high CCK levels have been found to stimulate abnormal pancreatic growth and promote early carcinogenesis and malignant tumor growth by binding to CCKAR, pro-carcinogenic effect of CCK can be inhibited by antagonizing CCKAR (49). Although CCKR expression has been widely reported in many tumors (31), relevant studies have shown that none of the cancer samples had statistically higher CCKR expression than all normal samples (50). Therefore, the association between CCK and Hepato-biliary-pancreatic cancer still needs to be further investigated (51).

4.2 Abnormal gut microbiota

The distribution of microorganisms in the gastrointestinal tract depends mainly on the pH gradient and the abundance of oxygen, and the changes in pH due to long-term PPI use are limited to the duodenum and proximal small intestine (52), this part of the gastrointestinal tract is more closely related to the hepatobiliary and pancreas, bacteria may enter the body circulation through portal vein transfer and activate pro-inflammatory pathways organs (53), which may induce solid tumor growth if these pathways are activated over time (54). When the inflammatory pathway is activated, it may lead to the abnormal metabolism of bile acids, thus inducing cholestatic liver cancer (55). Bacteria can disrupt the normal DNA repair by producing toxins and alter the bile acid metabolism process by enzymes on the surface of bacteria, thus leading to local inflammation and vascular proliferation in the tissues and increasing the possibility of biliary tract stone formation, which are potential biliary tumor carcinogenic mechanisms (56–58).

long-term PPI reduces gastrointestinal microbial diversity by blocking gastric acid secretion and affecting gut microbiota diversity (59, 60), it can increase the growth of potentially pathogenic bacteria such as Clostridium difficult, Enterococcus, Streptococcus, Staphylococcus, and E. coli (61, 62), as well as the disruption of the intestinal barrier and the alteration of intestinal permeability, these changes in the normal structure and microbiota can lead to excessive accumulation of lipopolysaccharides (LPS) and increased levels of deoxycholic acid in the tumor microenvironment, and hyper-deoxycholic acidemia can induce the development of HCC by damaging DNA (63), LPS promotes HCC pathogenesis and metastasis and affects prognosis by upregulating toll-like receptor (TLR4) expression, thereby increasing cell proliferation, inhibiting apoptosis and producing a specific systemic inflammatory response. Activation of TLR2 by lipid wall phosphate in bacteria and ursodeoxycholic acid leads to upregulation of the senescence-associated secretory phenotype (SASP) and cyclooxygenase 2 (COX-2), which mediates prostaglandin 2 inhibition of antitumor immunity via EP4 receptors, thereby inducing HCC progression (64).

As an important secretory organ of the body, the pancreas requires the assistance of intestinal microorganisms for the application of its digestive enzymes. The antimicrobial activity of pancreatic fluid protects the pancreas from retrograde infection and contributes to the diversity of the gut microbiota. However, intestinal microorganisms can reach the pancreas via the circulatory system or the biliary/pancreatic duct, especially in the case of abnormal gut microbiota (65). The current study suggests that the abnormal distribution of Enterococcus faecalis and Escherichia coli may be associated with the progression of pancreatic tumors associated with pancreatitis (66). Microorganisms promote tumor development, invasion and migration by activating the inflammatory response, increasing pro-inflammatory cell recruitment and cytokine secretion, increasing exposure to oxidative stress, altering energy dynamics, and damaging DNA, ultimately leading to molecular alterations and tumor transformation. In addition, chronic inflammation caused by non-pathogenic bacteria can induce the production of angiogenic factors, which increase the oxygen as well as nutrient supply to tumor and directly accelerate cancer cell growth. Alterations in several molecular mechanisms: oncogene mutations, oncogene inactivation, loss of heterozygosity, and chromosomal and microsatellite instability are also involved in inflammation-mediated oncogenesis. Cells within the microenvironment control tumor growth through the production of autocrine, paracrine, and endocrine mediators (67). It is believed that abnormal gut microbiota is an important cause of weight-related tumors, weight abnormalities aggravate the homogeneity of the gut microbiota by increasing deoxycholic acid production, which can lead to DNA damage, and activate the K-RAS pathway to induce pancreatic cancer (68). LPS on the cytosolic surface of bacteria are involved in the progression and invasion of pancreatic cancer through a cascade reaction generated by LPS-TLR, but no studies have shown this mechanism increases the risk of pancreatic cancer (69–71).

Bile acid concentrations in the digestive tract are significantly higher in GERD patients receiving long-term PPI therapy than in healthy individuals (72), Bile acids can directly disrupt the plasma membrane and cause activation of the PKC and p38 MAPK pathways, which result in a cascade reaction that activates the downstream IL-6 and Janus kinase (JAK) - signal transducer and activator of transcription 3 (STAT3) pathways, then leading to HCC (73), and persistently high bile acid levels can stimulate the development of HCC (74).

Insufficient gastric acid leads to microbiota translocation and overgrowth in the digestive tract leading to dysbiosis, and an increased pH leads to bacterially catalyzed N- nitrosamine leading to nitrosamine reduction and rapid nitrosamine production in the lumen. Faster nitrosation triggers the production of potentially carcinogenic N-nitrosamines in the digest tract (75). The association between nitrosamines and various types of cancer has been extensively studied (76). The association between nitrosamines and various types of cancer has been extensively studied (77), which can increase the risk of pancreatic cancer by affecting β2-AR signaling and upregulating HIF-1α expression (78), it also caused DNA damage and decreased repair capacity in the pancreatic duct epithelium in synergy with glucagon (79, 80), however, a meta-analysis of the association between nitrosamine exposure and pancreatic cancer development did not report a direct association (81, 82). In hepatocellular carcinoma, nitrosamine induces apoptosis in human normal liver cell lines through endogenous and exogenous pathways of caspases (83), nitrosamine has been shown to induce hepatocellular carcinoma in mouse models (84). Therefore, it is reasonable to assume that nitrites produced by gut microbiota disorders have varying degrees of induction in Hepato-biliary-pancreatic cancer.

Long-term abnormal hormonal stimulation, decreased diversity of gut microbiota, production of carcinogenic substances, chronic inflammation, and activation of tumor pathways may all be biologically linked to long-term PPI use, and therefore the amplification of these biological mechanisms and the synergy between them should be further investigated.

4.3 Significance of the study

Current guidelines for GERD, hemorrhagic ulcers and H. pylori infection use IPPs as the drug of choice, but PPI also have the potential to alter the structure of upper gastrointestinal pH, which has potential links to previous studies on the pathogenesis of hepato-biliary-pancreatic cancer, and our study supports the view that excessive use of PPI increases the risk of hepatobiliary-pancreatic cancer. This may lead clinicians to be more careful in choosing indications and to control the dose of the drug so that the disease population is treated properly without worrying about increased tumor risk.

5. Limitations

Although the results of this study corroborate the conclusion that long-term PPI may increase the risk of hepato-biliary-pancreatic cancer. However, there are still some shortcomings: if some measurement uniformities were available, we could have performed a dose or response duration analysis to evaluate the linear relationship, which would have helped quantify the association more accurately. and the dose and duration inconsistencies mentioned above may have contributed to this heterogeneity. Third, the relationship between long-term PPI use and biliary system cancer may be biased, the bias may be caused by the number of cDDD in the studies. In addition, the meta-analysis included only studies published in English, with smaller studies with cumulative results often unpublished, leading to potential biases.

6. Conclusions

In conclusion, the results of this study corroborate the argument that the risk of hepatobiliary and pancreatic cancer is higher among IPP users, an increased risk of biliary tract cancer was found in people with higher levels of exposure, but no significant association was found with the risk of pancreatic and hepatocellular cancer. But further studies are needed to clarify and validate the mechanism. However, health professionals should carefully consider the prescription of PPI for patients at high risk of hepato-biliary-pancreatic cancer and control the misuse of medications.

7. Declarations

7.1 Competing interests

All authors have no conflicts of interest to disclose. Ethical statement This is a meta-analysis; ethical approval is not required.

7.2 Availability of data and materials

The datasets generated and/or analyzed during the current study are available in the PubMed, EMBASE and Web of Science.

7.3 Authors' contributions

 CXL performed the literature search, data organization and article writing, FQG performed the data analysis and image review, YHC performed the literature search and article review, and JWK and ZWC provided writing ideas and performed article review.

7.4 Funding

There was no funding source for this study.

7.5 Acknowledgements

We thank Home for Researchers editorial team (www.home-for-researchers.com) for language editing service.

7.6 Ethics approval and consent to participate

Not applicable. 

7.7 Consent for publication

Not applicable

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