EVALUATION OF POSSIBLE GASTRINOMA

EVALUATION OF POSSIBLE GASTRINOMA      12/28/2015
QUESTION-A patient was referred to me for possible gastrinoma.  She has a history of esophageal rupture repaired with fundoplication and later had a gastric bypass (surgery more than 20 years ago and unable to obtain either operative reports).  She lost almost 100 pounds and had diarrhea following the surgery.  She has had multiple esophageal strictures requiring dilation and more recently was diagnosed with two gastro-gastric fistulas after an episode of melena.  Gastrin (while on PPI, H2 blockers, gabapentin) was 1432.  She has severe indigestion, abdominal pain, watery diarrhea and occasional fecal incontinence which are becoming progressively more bothersome, limiting her ability to participate in activities.  She has had manometry which revealed normal UES but ineffective esophageal motility, chronic gastritis on biopsy of the gastric antrum, negative abdominal CT scan.  Her chromogranin A (on PPI) was 390 ng/mL (normal range 0-95 ng/mL).  Secretin stimulation test was able to be completed (she was off of her PPI, Zofran for three days prior) and baseline gastrin level was 718, 671 pg/mL.  Gastrin level did not increase and in fact decreased after secretin (lowest value at 20 minutes 533 pg/mL).   I have been unable to obtain results of pH monitoring. Thank you for any words of advice that may help with management of the patient.  Barbara Hettinger, MD

RESPONSE--Firstly the gastro-gastric fistulae with GI hemorrhage with elevated gastrins at first glance suggests a gastrinoma. This would be supported by the level of the gastrin and would have been fortified by an increase in acid secretion which unfortunately you do not have the pH or acid secretory state. It is remarkable how difficult it can be to get gastroenterologists who love to put tubes in all orifices yet to get e a pH or acid secretion is just about impossible! Be that as it may the gastrin level fell after the administration of secretin much against a gastrinoma.
This then suggests three other possibilities . One is G cell hyperplasia,  a retained antrum because of the surgery, the third being PPI acid suppression with unbridling of gastrin secretion.  So it would be good to find out the nature of the gastric bypass. Certainly bypass procedures are notorious for the occurrence of proliferation of beta cells and the development of nesidioblastosis and hypoglycemia and you ought to check the fasting glucose and insulin level.
The finding that the gastrin levels fall but not back to normal supports the participation of PPIs in the causation of hypergastrinemia and the only reason that this did not return to normal is that one has to stop the PPI for at least two weeks if not more to allow for acid suppression to return to normal. But this diagnosis is antithetic to the ulcer, hemorrhage and fistula formation and the likely acid hypersecretion.

Now I very much would have like to see what the Stomach anatomy looks like . If the was atrophy of the gastric parietal area and antibody levels and a B12 would help this would support the diagnosis of G cell hyperplasia a consequence of loss of suppression by acid and levels can get awfully high, even in the thousands. But I have alluded to why I do not think this is the case.

So what would fit this constellation of features best of all? I think the clue is in the anatomy of the bypass. My strong suspicion is that there is a retained antrum and that it is overproducing acid ( hyperplasia) which  gives a negative secretin test and remains in physiologic control, hence the response to PPI withdrawal. This would be accompanied by acid hypersecretion, account for the partial response to a PPI yet secreted enough acid to case an ulcer and perforation. I would after getting the information on the new anatomy ask the gastroenterologist to do an upper endoscopy and examine the antrum and biopsy it and have the tissue stained for gastrin, chromogranin, Synaptophysin, and get a mitotic index and KI67. In addition to the gastrin levels obtain levels of CGa, Pancreastatin, neurokinin A to exclude malignancy which I very much doubt.
While you are waiting you might want to see if administration of somatostatin would inhibit the gastrin and the acid and provide relief of the symptoms including the diarrhea and if you find a retained antrum would be best treated by resection.

FOLLOW UP-Here is the summary with some new information I have been able to obtain.
67 year old woman with distant history of traumatic esophageal rupture s/p fundoplication and gastric bypass (mid 1980s); unable to get operative report due to length of time from surgery per the hospital
- multiple esophageal strictures requiring dilation over the past few years
- melena early 2015 prompting EGD revealing two large gastro-gastric fistulas
- midepigastric worsening over past few years, indigestion, watery diarrhea and fecal incontinence at times, some formed stool daily as well
- >10  years of progressively worsening GI symptoms, on high dose PPI
- no pH monitoring ever completed (not available in the small town she is in per her GI there)
- manometery UES normal, disordered peristalsis
- gastrin (on PPI) 1434 pg/mL July 2015
- biopsy gastric antrum performed August with chronic gastritis, negative for H.pylori       per your recommendation, asked pathology to perform gastrin staining
" additional immunostains for gastrin and chromogranin performed and highlight normal distribution of antral G cells, no evidence of gastrinoma identified"; they noted that they did not see cells consistent with neuroendocrine tumor
- chromogranin A 390 ng/mL August 2015 (on PPI, H2 blockers)
- CT scan August 2015 negative for visible pancreatic mass, retroperitoneal lymph nodes, mentions only diverticulosis and a small calcified granuloma
- secretin/gastrin stimulation test (holding H2 blockers, PPI, etc x 72 hours)
baseline gastrin 671; +2 min 683, +5 min 640, +10 min 598, +15 min 624, +20 min 533     baseline chromogranin A 344
I have not had much (any) experience with use of somatostatin for symptoms in cases like this.  Do you have specific recommendations?  Also, if surgery would be indicated, in this complicated lady, is there a particular center you would recommend?  Thank you so much for your help. Barbara Hettinger

FURTHER RESPONSE-Thanks for the further detail. The Secretin test does exclude a gastrinoma although all the evidence was against it. Also seems we can be reassured that the excess gastrin has not stimulated the ECL cells to proliferate and we do not have a gastric carci9noid. The histology of the  "antrum" shows at the most hyperplasia and no tumor which is what we wanted. So\ we have two choices now : medical or surgical or we could  go with sequential depending on the response. Somatostatin therapy is straightforward starting with Somatuline 120mg/month and likely you will be able to reduce and discontinue the PPIs or H2 blockers. You should be checking for mineral and vitamin deficiencies in particularly B12 and folate and Fe, Mg, Mn, Cr and Co  and replace if necessary. Give this up to 3 months and if we do not get marked symptomatic improvement will need to consider surgical reversal of the previous procedure with antyrectomy. Hopefully we will not get to antrectomy but likely will have to do so! All the best,  Aaron I. Vinik, MD  <vinikai@evms.edu