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. 2019 Oct 16;20(20):5128. doi: 10.3390/ijms20205128

Table 1.

Summary of potential side-effects of PPIs and insights from studies of patients with gastrinomas causing ZES with chronic hypergastrinemia (Chr. HG) and with acid hypersecretion controlled by very long-term treatment with PPIs.

Potential PPI Side-Effect Potential Mechanism Insights from ZES Studies
General
Why ZES useful model of Chr HG 		Chronic hypergastrinemia (Chr. HG)
  1. ZES patients have lifelong Chr. HG
    1. Delayed diagnosis-6yrs
    2. Less 20% cured lifelong
    3. 30–40% = FSG levels in range of PPIs in non-ZES pts, rest have > FSG levels

  2. All forms of circulating gastrin including amidated, NH2,COOH extended forms
General
Why ZES useful model of long-term PPI use 		Lifelong need for potent gastric antisecretory drugs—PPIs drug of choice

  1. >80% ZES patients take PPI lifelong

  2. Frequently take hi doses PPI

  3. Regularly followed for acid control and other side-effects
ECL hyperplasia/gastric carcinoids Chronic hypergastrinemia
(Chr. HG)

  1. All ZES patients have ECL hyperplasia

  2. Advanced ECL changes including dysplasia is seen both sporadic and MEN1/ZES

  3. ECL changes are more advanced in MEN1/ZES

  4. Carcinoids are very uncommon in sporadic ZES which resemble non-ZES PPI users

  5. 23% of MEN1/ZES have gastric carcinoids

  6. Sporadic ZES more resembles chronic PPI users than CAG/PA patients which have high incidence of inflammation ± atrophy and frequently develop carcinoids
Esophageal, gastric, pancreatic adenocarcinomas Chronic hypergastrinemia
(Chr. HG)

  1. Limited data but no evidence for increased incidence in ZES
Colorectal cancer Chronic hypergastrinemia
(Chr. HG)

  1. Limited data but no evidence for increased incidence in ZES2

  2. Two studies show increased rectal/colonic mucosal increased proliferative rates in ZES
Nutrient malabsorption (Fe, Ca) PPI-induced Hypo-/Achlorhydria

  1. Limited data but no evidence for malabsorption in ZES
Nutrient malabsorption (VB12) PPI-induced Hypo-/Achlorhydria

  1. Two studies report decreased VB12 levels in in ZES2

  2. One ZES study correlates low serum levels in VB12, but not folate levels with use of PPIs, duration of PPI use and with the degree of PPI-induced acid hyposecretion.
Hypomagnesemia Unclear = mechanism

  1. Uncommonly reported in ZES patients showing that it is not dose-related or related to length of treatment with PPIs
Bone fractures Unclear = mechanism

  1. No data in ZES2

  2. ZES poor model to study this in as 20–25% have MEN1 with hyperparathyroidism, which causes bone disease; a proportion have malabsorption prior to diagnosis which could contribute to bone disease, and high proportion had low VB12 levels from long-term PPI that could contribute
Rebound hypersecretion after stopping PPI Unclear = mechanism

  1. Studies of ZES patient’s post-curative resection of gastrinoma have provided insights into very long-term effects of PPI treatment/Chr HG on post drug acid secretory effects.

Abbreviations: Chr HG—chronic hypergastrinemia, ZES—Zollinger–Ellison syndrome, PPI—proton pump inhibitor, ECL—gastric enterochomaffin-like cell, MEN1/ZES—Zollinger–Ellison syndrome in patients with Multiple Endocrine Neoplasia-Type 1, VB12—vitamin B12, Fe—Iron, Ca—calcium, Mg—magnesium, pts—patients.