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Forty-Eight-Hour Fast: The Diagnostic Test for Insulinoma

Division of Intramural Research, National Institute of Diabetes, Digestive and Kidney Diseases (B.H., A.L., M.C.S.); Surgical Metabolism Section, National Cancer Institute (D.L.B., S.K.L., H.R.A.); and Department of Diagnostic Radiology (J.L.D.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Boaz Hirshberg, Division of Intramural Research, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 85-235B, Bethesda, Maryland 20892.

	Abstract

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Insulinoma causes fasting hypoglycemia due to inappropriate insulin secretion. Its diagnosis is based on demonstrating Whipple’s triad during a supervised 72-h fast. For 75 yr, the 72-h fast has been the cornerstone for the diagnosis; however, it has never been critically assessed using newer assays for insulin, C peptide, and proinsulin. Thus, the aim of the current study is to assess the need for a full 72-h fast for the diagnosis of insulinoma. Patients with suspected hypoglycemia with documented glucose concentrations below 45 mg/dL were admitted to the NIH. Data obtained during the supervised fast of patients with pathologically proven insulinoma over a 30-yr period (1970–2000) were reviewed. We identified 127 patients with insulinoma. The average age of patients was 42.7 ± 15.9 yr, with a predominance of females (62%). 107 patients had a benign tumor, 20 had malignant insulinoma, and 15 patients had multiple endocrine neoplasia type 1. The fast was terminated due to hypoglycemia in 44 patients (42.5%) by 12 h, 85 patients (66.9%) by 24 h, and 120 (94.5%) by 48 h. Seven patients fasted beyond 48 h despite subtle neuroglycopenic symptoms and glucose and insulin concentrations diagnostic of insulinoma. Immunoreactive proinsulin was elevated at the beginning of the fast in 90% of 42 patients. Proinsulin in noninsulinoma, in contrast to insulinoma, patients is usually suppressible; therefore, samples taken in the suppressed state have the greatest diagnostic value. We conclude that with the current available insulin and proinsulin assays, the diagnosis of insulinoma can be made within 48 h. Thus, the 48-h fast should replace the 72-h fast in textbooks and hospital protocols as the new diagnostic standard.

	Introduction

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HYPOGLYCEMIA and neuroglycopenic symptoms that are corrected by the administration of carbohydrate are the hallmarks of the diagnosis of insulinoma (1, 2, 3, 4, 5, 6, 7, 8). Fasting, therefore, is the major maneuver used in the diagnosis of insulinoma and has two important purposes. The first is to document hypoglycemia and its relationship to the patient’s symptoms, and the second is to demonstrate inappropriate insulin concentrations in the face of hypoglycemia. The diagnosis of insulinoma has centered on the 72-h fast that was introduced long before it was possible to measure insulin or insulin-related components (1, 8, 9). Clearly, it is desirable to modify the diagnostic test as described in textbooks and protocols, to be conducted over a less protracted period if that can be justified by clinical experience.

The purpose of the present study was 3-fold: 1) to determine the optimal duration of the diagnostic fast in the light of other modern biochemical laboratory measurements such as plasma insulin; 2) to determine the diagnostic value of direct measurement plasma proinsulin; and 3) to compare our large patient population with other large patient populations that have used similar criteria.

	Subjects and Methods

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Patients

We have identified 127 subjects with a pathological diagnosis of insulinoma and reviewed data collected during the diagnostic fast. These patients are part of a cohort recruited to a protocol approved by the institutional review board of the clinical center of the NIH. An additional 22 patients were studied over the same period, but did not meet criteria for diagnosis of insulinoma and are used for comparison. This protocol was intended to study the diagnosis, treatment, and natural history of diseases that cause hypoglycemia. Patients with suggestive history of hypoglycemia as well as documented glucose levels below 45 mg/dL were admitted to the Warren Grant Magnuson Clinical Center at the NIH. All patients had a complete history and physical examination, routine blood examination, and urine chemistries. Patients were fasted for up to 72 h under close medical supervision. Blood glucose levels, insulin, C peptide, and proinsulin were collected every 4–6 h. Serum samples were also screened for insulin antibodies. In addition, at the beginning and end of the fast, blood samples were taken for sulfonylurea screen, cortisol, and GH. The test was continued until the patient developed hypoglycemia, defined as plasma glucose below 40 mg/dL (2.22 mmol/L) accompanied by neuroglycopenic symptoms, such as confusion or blurred vision, or for a maximum of 72 h. Patients with documented hypoglycemia accompanied by inappropriate insulin and C peptide levels and negative sulfonylurea screen underwent localization studies and surgery when appropriate.

Assays

The assay procedure for measurement of insulin, C peptide, and proinsulin has been previously described (10). Results of determination of percent proinsulin and preliminary results of direct immunoreactive proinsulin have been presented (10).

	Results

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Characteristics of insulinoma patients

Over a 30-yr period, from 1970–2000, 127 patients were diagnosed with insulinoma. Surgical pathology confirmed the diagnosis in each case. The patients’ average age during their first hospitalization at the NIH was 42.7 ± 15.9 yr; the youngest patient was 13 yr, and the oldest 81 was yr. There were 79 (62%) females and 48 (38%) males. The average delay between the initial symptoms and final diagnosis was 3.6 ± 5.2 yr. One hundred and seven patients (84%) had benign insulinoma, 20 (16%) had malignant insulinoma, and 15 (12%) patients had multiple endocrine neoplasia type 1 (MEN1). For the entire patient group, the average weight was 77.6 ± 22.2 kg, and the height was 167.8 ± 9.9 cm. The average body mass index (BMI) was 27.7 ± 7.4, and 62% of the patients had a BMI greater than 25.

Diagnostic testing in insulinoma patients

One hundred and nineteen patients completed a supervised fast. An additional 7 patients were constantly experiencing hypoglycemic episodes during the first 4 h after a meal (Fig. 1). Fifty-four patients (42.5%) became hypoglycemic within the first 12 h, and 85 patients (66.9%) became hypoglycemic within the first 24 h of the fast. The fast was concluded within 48 h in 120 (94.5%) of the patients. Seven patients in whom the fast was continued beyond 48 h are shown in Table 1. After reviewing the clinical as well as the laboratory data obtained during the fast, it is apparent that each of these 7 patients achieved glucose and insulin concentrations that were consistent with the diagnosis of insulinoma by 48 h. The fast was continued because in the judgment of the physician the patient did not exhibit neuroglycopenic symptoms. Four of these patients (including the 2 who completed 72 h) had MEN1. These 4 patients with MEN1 had initially been evaluated for features of the syndrome that were unrelated to hypoglycemia, and a fast was performed due to a high index of suspicion. There was no association between the BMI and the length of the fast or the baseline insulin and proinsulin levels (results not shown).

View larger version (10K): [in this window] [in a new window]   Figure 1. Diagnostic fast in 127 patients with insulinoma. On the vertical axis is shown the percentage of patients reaching a diagnostic end point for the fast, and on the horizontal axis is shown the duration of the fast.

We have previously reported in 98 patients that the plasma percent proinsulin component was equal to or higher than 25% of the total immunoreactive insulin level in 87% of patients (10). In the present study we obtained direct measurements of plasma proinsulin in 42 patients from samples taken from the beginning of the fast [preliminary results were reported for a subset of 20 of these patients (10)]. In 38 of 42 patients (90%), immunoreactive proinsulin was equal to or greater than 0.2 ng/mL (22 pmol/L), which is the upper level of normal for this test. (Fig. 2) Samples from 50 patients taken at the end of the fast were available for measurement. There was a complete overlap in values from the basal to the suppressed state, but in the suppressed state 41 of 50 values (82%) were equal to or greater than 0.2 ng/mL (22 pmol/L). In 28 patients paired basal and suppressed samples were available for analysis (Fig. 3A). In general, immunoreactive proinsulin is poorly suppressible during the fast, and only 3 patients suppressed to 0.2 ng/mL. The calculated sensitivity of proinsulin for the diagnosis of insulinoma in the basal state is 89%, and that in the suppressed state is 90%.

View larger version (18K): [in this window] [in a new window]   Figure 2. Direct immunoreactive proinsulin measurements in patients with and without insulinoma. Basal refers to the beginning of the fast, and suppressed refers to the end of the fast. Note that samples were available in 42 insulinoma patients (basal) and 50 suppressed patients. Twenty-eight of these samples have been previously reported and correlated with measurements of plasma proinsulin-like component (10 ). In the noninsulinoma patients, there were 16 samples obtained in the basal state, and 21 in the suppressed state.

View larger version (21K): [in this window] [in a new window]   Figure 3. Direct immunoreactive proinsulin measurements in paired samples taken at the beginning and the end of the diagnostic fast in insulinoma patients (A) and in noninsulinoma patients (B). Note the change in scale from A to B.

In a previous study we presented the relationship of proinsulin-like activity in plasma to the direct method of measuring proinsulin in plasma (10). In the present study we expanded on these results. To better understand the specificity of direct measurements of proinsulin in insulinoma patients, we present data for 21 patients who were studied using the same protocol as the insulinoma patients, but did not meet the diagnostic criteria and hence are termed noninsulinoma patients.

Sixteen patients had proinsulin measurements in the basal state, and 50% had values below 0.2 ng/mL. In the suppressed state, 95% of the patients had values below 0.2 ng/mL (Fig. 2). The calculated specificity is thus 50% in the basal and 95% in the suppressed state. In 16 patients paired basal and suppressed samples were available for measurement (Fig. 3B).

All 16 subjects suppressed their proinsulin values, and all but 1 suppressed below 0.2 ng/mL (Figs. 2 and 3B). In 1 additional patient (not shown in Fig. 2) with MEN-1 whose blood glucose value was 33 mg/dL at 29 h of fasting, the basal proinsulin was 0.9 ng/mL and the suppressed value was 0.49 ng/mL, whereas the suppressed insulin value was 0.4 µU/mL. We suspect that this patient may have an insulinoma and represents the rare group of patients who suppress insulin during the fast to a much greater extent than proinsulin.

	Discussion

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In the present study we verify that a 48-h fast provides sufficient information for the diagnosis of insulinoma. Thus, by 48 h in all patients studied, hypoglycemia was observed in the presence of inappropriately elevated insulin concentrations. Approximately 95% of our patients had their fast terminated by 48 h, and the other 5% (seven patients) could have had their fast terminated on or before 48 h because they met the required glucose and insulin criteria. In these seven patients, the delay in the termination of the fast was due to inconsistency in the evaluation of neuroglycopenia. Careful review of the nursing as well as the physician notes revealed clear, although subtle, neuroglycopenia before 48 h, symptoms that corresponded with low glucose levels and inappropriately high insulin concentrations. Furthermore, in six of the seven patients with a fast longer than 48 h, the proinsulin levels were elevated, adding further supporting evidence for the diagnosis of insulinoma.

Our data are in good agreement with studies of insulinoma patients from the Mayo Clinic and the Cleveland Clinic (6, 11). In a series of 51 patients reported by Service et al. (6) in 1976, 92% developed hypoglycemia by 48 h. A previous series from the Mayo Clinic published in 1960 (2), reported that 59 of 79 patients (74%) developed hypoglycemia within 24 h of induction of the fast, and in only 2 patients was it necessary to continue the fast longer then 48 h. Both series used the classical Whipple’s triad as the criteria for a positive fast, as insulin, C peptide, and proinsulin measurements were not available. Dizon et al. (11) reported a series of 59 patients seen at the Cleveland Clinic Foundation. Of the 49 patients who underwent a fast, only 1 patient did not achieve the glucose/insulin levels required by their protocol within first 48 h.

Service (9) reported that several patients have been unnecessarily fasted for the full 72-h period, as subtle signs of neuroglycopenia had been overlooked. This is in agreement with our analysis of the seven patients in whom the fast test was extended beyond 48 h. A careful quantitative study has demonstrated a diminished responsiveness in insulinoma patients that is reversible (12).

Proinsulin has been shown to be of diagnostic value in the diagnosis of insulinoma (10, 13, 14). We previously reported that 87% of our insulinoma patients had a plasma proinsulin component equal to or greater than 25% of the total immunoreactive insulin (10). In the present study we extend the number of patients previously reported in whom direct measurement of proinsulin is available. Ninety percent (38 of 42) had a value equal to or greater than the cut-off point of 0.2 ng/mL (22 pmol/L) at the start of the fast, and 82% (41 of 50) had values that met this criteria at the end of the fast. Our proinsulin measurements are also in clear agreement with the results reported from the Mayo Clinic (13). Direct measurement of proinsulin is now generally available and will replace the more laborious measurement of percent proinsulin component (for further discussion of the column method of measuring proinsulin-like component and direct measurement of proinsulin, see Ref. 10). Inappropriately elevated or nonsuppressed insulin values associated with hypoglycemia are the cornerstone of diagnosis of insulinoma. We now show that proinsulin values are poorly suppressible in these patients, whereas in noninsulinoma patients both insulin and proinsulin are readily suppressible. In fact, we have encountered 3 patients in whom insulin values, but not proinsulin values, are suppressed during the diagnostic fast. It is useful to have both a basal and a suppressed sample for proinsulin, as this markedly increases the specificity of the diagnosis of insulinoma.

We believe that the 48-h fast and the measurement of proinsulin are sufficient for the diagnosis of insulinoma and that more prolonged fasting or other stimulation or suppression tests are unnecessary. The fast must be carried out in a supervised setting, and insulin should be determined every 6 h (1, 3, 9). This is because there may be some fluctuation in values during the fast, and the overall pattern is useful in the final analysis. Normal subjects may lower their glucose levels below 45 mg/dL in 48 h, but the corresponding insulin levels should be very low or undetectable (15).

There are several other caveats that are important. Rarely, patients with insulinoma may suppress their insulin levels as their glucose levels fall. In fact, only three patients had insulin values below 10 µU/mL at the end of their fast but still had elevated proinsulin concentrations (16, 17; see Ref. 10 for further discussion of insulin RIAs). In addition, patients with MEN1 may be confusing. This is due in part to the fact that these patients may present other manifestations of MEN1 and be asymptomatic with respect to glucose levels. These patients may be fasted due to a high index of suspicion, including random low glucose measurements, vague symptoms, or even direct measurements of high insulin levels during venous sampling, but still, in a way that is not clear, have minimal or any symptoms. Thus, the interpretation of fasting results in MEN1 patients without clear symptoms may pose a challenge. Furthermore, during surgery multiple tumors that secrete insulin or other hormones are the rule, but are rare in sporadic insulinomas (18).

In our experience, that spans more then 30 yr, we have not convincingly seen islet hyperplasia or nesidioblastosis that could be etiologically related to the patients’ hypoglycemia. Thus, we only carry out pancreatic resection or enucleation when an insulinoma is clearly localized during surgery. We believe that former recommendations of distal blind pancreatectomy when localization is not possible are not appropriate. This is again based on the excellent sensitivity of preoperative calcium stimulation test and intraoperative ultrasound in localization of the tumor (19, 20, 21, 22, 23). It should be emphasized that invasive localization studies should be carried out only in patients in whom the biochemical diagnosis of insulinoma is confirmed.

Recently, Service et al. (24) have described five patients with severe postprandial hypoglycemia in whom partial pancreatic resection guided by calcium stimulation was carried out. These patients did not have insulinoma, and the postprandial nature of the hypoglycemia differentiates these patients from patients with fasting hypoglycemia. We have not, to date, recognized patients with this syndrome.

In our experience the most difficult differential diagnosis for insulinoma is factitious hypoglycemia, especially when oral hypoglycemic medications are used. In these cases levels of insulin and C peptide will be high as in insulinoma. This is farther complicated by the fact that current sulfonylurea assays fail to detect the new generation nonsulfonylurea hypoglycemic agents (25, 26).

The 72-h fast became central to the diagnosis of insulinoma well before insulin and proinsulin determinations became available. Now that insulin and proinsulin measurements are widely available, all of the necessary information from a fast can be derived in the first 48 h. Thus, the 48-h fast should replace the 72-h fast in textbooks and hospital protocols and become a new standard. Certainly this will reduce cost, but it is imperative for both private insurers and clinical research centers to recognize that the fast must be carried out under supervised conditions.

Received May 4, 2000.

Revised June 1, 2000.

Accepted June 5, 2000.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hirshberg, B. Articles by Gorden, P. Search for Related Content PubMed PubMed Citation Articles by Hirshberg, B. Articles by Gorden, P.