In contrast to PPIs, with longterm treatment with H2R antagonists in ZES patients, higher dosing and/or more frequent dosing, are almost always needed than they are generally used to treat the typical patient with idiopathic GERD/PUD [33,59,79,80,217,222,223], thus helping to raise the suspicion that the patient may have ZES as a possible diagnosis. This evidence concerns the gene HRH2 and Zollinger-Ellison syndrome.