Gastric neuroendocrine carcinoma after long-term use of proton pump inhibitor

Jianu, Constantin S.; Lange, O.; Viset, Trond; Qvigstad, Gunnar; Martinsen, Tom Christian; Fougner, Reidun; Kleveland, P. M.; Fossmark, Reidar; Hauso, Øyvind; Waldum, Helge L.

doi:10.3109/00365521.2011.627444

Cited by 74 publications

(56 citation statements)

References 13 publications

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“…The first published report involved endochromaffin cell‐derived (ECL cell‐derived) neuroendocrine carcinoma. The authors postulated whether carcinoma was secondary to hypergastrinemia due to PPI use over a 15‐year course 25. As found in this study, long‐term use of PPI was associated with the risk of periampullary cancers.…”

Section: Discussionsupporting

confidence: 56%

Proton pump inhibitors and risk of periampullary cancers—A nested case–control study

Chien

Huang

Shao

et al. 2015

Intl Journal of Cancer

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Considerable attention has been focused on long‐term use of proton pump inhibitor (PPI) medications in relation to increased risk of cancer via stimulation of DNA‐damaged cells. The aim of this study is to examine the dose‐dependent effect of PPI on periampullary cancers in a national population‐based cohort. A nested case–control analysis was constructed based on Taiwan's National Health Insurance Research Database and the Taiwan Cancer Registry between the years 2000 and 2010. Cases involving patients diagnosed with periampullary cancers were selected and controls were matched to cases according to age, sex and observational period. A “PPI user” was defined as any patient receiving more than 28 cumulative defined daily doses as measured by prescription drug claims. Conditional logistic regression analysis was conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) according to the level of PPI exposure. A total of 7,681 cases and 76,762 matched controls were included with a mean follow‐up period of 6.6 years (SD: 2.0). The odds of PPI exposure in patients with periampullary cancers were higher than that of control patients with an adjusted OR of 1.35 (95% CIs: 1.16–1.57). Our results also showed that PPI exposure was slightly linked to periampullary cancers in dose‐dependent manner. A similar association was observed in patients who solely took PPI but no eradication therapy for Helicobacter pylori infection. Long‐term PPI use was associated with an increased risk of periampullary cancers in the current population‐based study. Physicians must weigh potential risks of long‐term maintenance against therapeutic benefit.

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Section: Discussionsupporting

confidence: 56%

Proton pump inhibitors and risk of periampullary cancers—A nested case–control study

Chien

Huang

Shao

et al. 2015

Intl Journal of Cancer

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“…Therefore the LEVA-induced upregulation of lysozyme activity is consistent with its immunostimulatory effect. In addition, prolonged use of proton pump inhibitors (PPI) has been associated with the development of gastric neuroendocrine carcinoma (37), which has recently been attributed to the inhibitory effects of PPI on lysozyme enzyme activity and may result in immunosuppression (36). The stimulatory effect of GO on lysozyme activity when administered alone, and its inhibitory effect when administered with LEVA, indicated that GO has an immunomodulatory balancing effect, which may counteract any immune system deviation.…”

Section: A B C D E F G H I Discussionmentioning

confidence: 99%

Modulatory effects of levamisole and garlic oil on the immune response of Wistar rats: Biochemical, immunohistochemical, molecular and immunological study

et al. 2016

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Abstract. Levamisole (LEVA) and garlic are prevalent immunomodulators in humans and animals. Therefore, the present study aimed to examine the immunomodulatory effects of LEVA and garlic oil (GO) alone or in combination on the immune response of Wistar rats. A total of 24 male Wistar rats were allocated into four equal groups: Control group, which was given ad libitum access to food and water; and groups 2-4, which were orally administered LEVA [2.5 mg/kg body weight (BW) every 2 days], GO, (5 ml/kg BW daily), or LEVA plus GO, respectively for 4 consecutive weeks. Serum immunoglobulin (Ig)G and IgM levels were measured using a radial immunodiffusion assay. Serum cytokine levels, including interferon (IFN)-γ, interleukin (IL)-5 and tumor necrosis factor (TNF)-α, were measured using enzyme-linked immunosorbent assay kits. Total blood counts were measured automatically using a cell counter. Serum lysozyme enzymatic activity was determined by measuring the diameters of the zones of clearance relative to lysozyme. Immunohistochemical detection of CD4 and CD8 was carried out using the streptavidin-biotinperoxidase method. Furthermore, the mRNA expression levels of IL-4, IL-5 and IL-12 were measured in the leukocytes and thymus gland by semi-quantitative polymerase chain reaction. The results revealed that LEVA increased serum levels of IFN-γ, IL-5 and TNF-α cytokines, whereas co-administration of LEVA and GO decreased the stimulatory action of LEVA alone. LEVA and GO alone increased the serum levels of IgG, IgM and total blood cell counts, and co-administration of GO and LEVA inhibited the effects of LEVA. At the cellular level, in the spleen, LEVA increased immunoreactivity of CD4 and CD8, whereas co-administration of GO with LEVA decreased this strong expression. At the molecular level, in leukocytes, LEVA upregulated the mRNA expression levels of IL-2, IL-4 and IL-5, whereas GO alone downregulated mRNA expression. Co-administration of GO with LEVA inhibited the LEVA-induced upregulation of IL-2, IL-4 and IL-5 mRNA expression. In the thymus, both LEVA and GO upregulated the mRNA expression levels of IL-4 and IL-5, whereas LEVA alone did not affect IL-12 mRNA expression. Co-administration of GO with LEVA inhibited LEVA-induced upregulation of IL-4 and GO-induced upregulation of IL-12 expression, and had an additive upregulatory effect on IL-5 expression. In conclusion, LEVA stimulated T-helper (Th)1 cytokines, whereas GO stimulated a Th2 response, and co-administration of GO with LEVA inhibited the stimulatory effects of LEVA and balanced the Th1/Th2 response.

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“…From these data, it was discovered that achlorhydria and secondary hypergastrinemia from PPI therapy can lead to ECL cell hyperplasia [Lamberts et al 1988]. While the theory for decades has argued against the potential for carcinoma due to long-term PPI therapy, the first case of ECL cell-derived neuroendocrine carcinoma due to hypergastrinemia secondary to PPI use for more than 15 years has just been described [Jianu et al 2012].…”

Section: Introductionmentioning

confidence: 99%

Overutilization of proton-pump inhibitors: what the clinician needs to know

Heidelbaugh

Kim

Chang

et al. 2012

Therap Adv Gastroenterol

275

206

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Proton-pump inhibitors (PPIs) remain the leading evidence-based therapy for upper gastrointestinal disorders, including gastroesophageal reflux disease, dyspepsia, and peptic ulcer disease. The effectiveness of PPIs has led to overutilization in multiple treatment arenas, exposing patients to an increasing number of potential risks. The overutilization of PPIs in ambulatory care settings is often a result of failure to re-evaluate the need for continuation of therapy, or insufficient use of on-demand and step-down therapy. PPI overutilization in the inpatient setting is often a result of inappropriate stress ulcer prophylaxis (SUP) in nonintensive care unit patients, and failure to discontinue SUP prior to hospital discharge. Potential consequences of prolonged PPI therapy include hypergastrinemia, enterochromaffinlike cell hyperplasia, and parietal cell hypertrophy, leading to rebound acid hypersecretion. PPIs have been linked via retrospective studies to increased risk of enteric infections including Clostridium difficile-associated diarrhea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with metabolism of antiplatelet agents. Reducing inappropriate prescribing of PPIs in the inpatient and outpatient settings can minimize potential for adverse events, and foster controllable cost expenditure.

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Gastric neuroendocrine carcinoma after long-term use of proton pump inhibitor

Cited by 74 publications

References 13 publications

Proton pump inhibitors and risk of periampullary cancers—A nested case–control study

Proton pump inhibitors and risk of periampullary cancers—A nested case–control study

Modulatory effects of levamisole and garlic oil on the immune response of Wistar rats: Biochemical, immunohistochemical, molecular and immunological study

Overutilization of proton-pump inhibitors: what the clinician needs to know

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