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Assessment and Prediction of Long-term Cure in Patients with the Zollinger-Ellison Syndrome: The Best Approach

Vitaly A. Fishbeyn, MD; Jeffrey A. Norton, MD; Richard V. Benya, MD; Joseph R. Pisegna, MD; David J. Venzon, MD; David C. Metz, MD; and Robert T. Jensen, MD
[+] Article and Author Information

From the National Institutes of Health, Bethesda, Maryland. Requests for Reprints: Robert T. Jensen, MD, National Institutes of Health, Building 10, Room 9C-103, Bethesda, MD 20892.


Copyright 2004 by the American College of Physicians


Ann Intern Med. 1993;119(3):199-206. doi:10.7326/0003-4819-119-3-199308010-00004
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Objective: To identify the best method for determining freedom from disease after gastrinoma resection and for predicting long-term disease-free status in patients with the Zollinger-Ellison syndrome.

Design: Prospective study in consecutive patients.

Setting: Referral-based clinical research center.

Patients: Eighty-one consecutive patients with the Zollinger-Ellison syndrome who underwent surgical exploration for gastrinoma resection.

Intervention: Patients were evaluated after gastrinoma resection, before discharge, 3 to 6 months after surgery, and yearly thereafter. Evaluation included secretin provocative testing and fasting serum gastrin determinations. Follow-up examinations after the initial postoperative evaluations included a clinical assessment, acid secretion studies, a calcium provocative test, and various imaging studies.

Measurements and Main Results: Most patients (96%) had gastrinomas. Freedom from disease was defined by improved symptoms, reduced acid output and antisecretory drug requirements, and a normal gastrin level, normal imaging studies, and negative gastrin provocative studies. Fifty-two percent of patients (n = 42) were disease-free immediately after surgery, 44% at 3 to 6 months, 42% at 1 year, and 35% by 5 years (mean follow-up, 39 months). The secretin provocative test was the first test to become positive in 45% of patients with a recurrence, the serum gastrin determination was the first test to become positive in 36%, and both tests became positive at the same time in 18%. No recurrence was first detected by imaging studies or by calcium provocative testing. Fasting serum gastrin levels and secretin provocative test results at different postoperative times can be used to predict the probability of a patient remaining disease free at 3 years. Patients with a normal gastrin level and a normal secretin provocative test immediately after surgery had a 3-year disease-free probability of 75%, and normal results on both tests at 6 months, 1 year, and 2 years yielded respective probabilities of 88%, 95%, and 100%.

Conclusions: Both the secretin provocative test and fasting serum gastrin determination are necessary for the early diagnosis of cases of recurrent disease after gastrinoma resection. The calcium provocative test and imaging studies do not detect any recurrences first. Fasting serum gastrin determinations and secretin provocative testing at different postoperative times can be used to predict the probability of a patient remaining disease free at 3 years.

Figures

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Figure 1.
Relation between the fasting serum gastrin concentration and basal acid output in a patient assessed for recurrence 6 months after resection of a gastrinoma.

This patient was disease free immediately after surgery. At this 6-month assessment, fasting hypergastrinemia was present 1 day after discontinuing ranitidine therapy, 600 mg every 6 hours, suggesting that the disease had recurred; however, achlorhydria was also present at this time. Two days after discontinuing ranitidine therapy, basal acid output (BAO) increased and the fasting serum gastrin level decreased to within the normal range, showing that the patient was still disease free and had instead developed physiologic hypergastrinemia secondary to ranitidine-induced achlorhydria. The dotted line represents the upper limit of normal for the fasting serum gastrin level. See Methods section for definition of recurrence.

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Figure 2.
Proportion of patients remaining disease free at different follow-up times.

Forty-two patients were disease free immediately after surgery. The proportion of patients remaining disease free is shown as a Kaplan-Meier plot. Eleven patients had disease recurrence during a follow-up of up to 72 months.

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Figure 3.
Comparison of the ability of the fasting serum gastrin level, secretin provocative test, calcium provocative test, and imaging studies to first detect recurrence of the Zollinger-Ellison syndrome.

Twenty-seven patients who were disease free immediately after surgery were followed for 36 months, during which time 8 developed recurrence. Seventeen patients who were disease free immediately after surgery were followed from 36 months to 72 months, during which period 3 had a recurrence of disease.

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Figure 4.
Changes over time in fasting serum gastrin level, secretin provocative test results, and imaging studies in two patients who developed recurrent disease.

Top Panel. The time course of changes in this patient is typical of the 45% of patients in whom recurrence was detected initially by a positive secretin provocative test alone and who only later developed elevated fasting serum gastrin levels in association with either positive (9%) (as shown in this patient) or negative (36%) imaging studies. Bottom Panel. The time course of changes in this patient is typical of the 18% of patients who developed both an abnormal fasting serum gastrin level and secretin provocative test as the first sign of recurrence and in whom imaging studies continued to be normal. Dotted lines represent the upper limits of normal for the fasting serum gastrin level and secretin provocative test.

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Figure 5.
Changes over time in fasting serum gastrin levels, secretin provocative test results, and imaging studies in two patients who developed recurrent disease.left panelright panelleft panel

The time course of changes in these two patients is typical of the 36% of patients in whom recurrence was first detected by an abnormal fasting serum gastrin level and who either subsequently had a positive secretin provocative test result (18%) ( ) or continued to have a negative secretin provocative test result throughout the entire follow-up period (18%) ( ). Positive imaging study results were found later in some patients (9%) ( ).

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