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CLINICAL CASE SEMINAR |
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-5576
Address all correspondence and requests for reprints to: Christopher D. Saudek, M.D., Johns Hopkins University School of Medicine, 600 North Wolfe Street, Osler 576, Baltimore, Maryland 21287-5576. E-mail: csaudek{at}jhu.edu.
Abstract
The work-up of fasting hypoglycemia may be difficult but is crucially important because a wrong diagnosis can lead to either unnecessary pancreatectomy or a missed pancreatic tumor. We describe a patient with severe fasting hypoglycemia [22–32 mg/dl (1.2–1.8 mmol/liter) after 6–10 h of fasting] in which the diagnosis of a secretory islet-cell tumor was obscured, rather than facilitated, by use of a new, highly specific serum insulin assay. Insulin measured by the specific assay suppressed normally during fasting hypoglycemia [undetectable at < 2.0–3.8 µIU/ml (26.4 pmol/liter)], whereas insulin measured by older, less specific assays was diagnostically elevated [34, 73 µIU/ml (236.1, 507.0 pmol/liter)]. Serum proinsulin and C-peptide levels were abnormal, and further work-up revealed an islet-cell tumor that secreted predominantly proinsulin. The tumor was surgically removed, relieving the fasting hypoglycemia. We conclude that insulin levels as measured by new, highly specific insulin assays may obscure the diagnosis of a functional, proinsulin-secreting islet-cell tumor. Because proinsulin cross-reacts with insulin in older insulin assays, C-peptide or proinsulin should be measured to rule out a proinsulin-secreting islet-cell tumor. Normative values for new insulin assays must be established during prolonged fasting.
TRADITIONALLY, THE DIAGNOSIS of insulinoma is established by demonstrating inappropriately high serum insulin concentrations during fasting hypoglycemia. The supervised 72-h fast is the classic diagnostic test (1). It has been well recognized that islet-cell tumors may produce a disproportionately high concentration of proinsulin (2, 3, 4, 5), but this has not presented a diagnostic problem because conventional nonspecific insulin RIAs use polyclonal antibodies that cross-react with proinsulin (6, 7, 8). Therefore, both the inappropriately high insulin and proinsulin levels are measured together as insulin, and the diagnosis is evident.
Newer insulin assays introduced in recent years, however, use monoclonal antibodies with far more specificity for insulin (9, 10). As an unexpected consequence of the improved immunoassay technology, the diagnosis of secretory islet-cell tumors may be more difficult if the tumor secretes predominantly proinsulin. Traditional criteria for establishing the diagnosis and intervening surgically may need revision. We describe herein a patient with severe fasting hypoglycemia and apparently normal insulin/glucose dynamics as measured by a new-generation, highly specific insulin assay.
Case Report
A 37-yr-old African man without history of prior endocrinopathy was referred for evaluation of fasting hypoglycemia. For several years, he reported symptoms of confusion, disorientation, and out-of-body experience on awakening in the morning or after skipping meals. Symptoms resolved with ingestion of food, but they had become more frequent in recent months, requiring his family to awaken him with a glucose-containing drink on multiple occasions and causing motor vehicle accidents. Past medical history revealed sickle cell disease with numerous crises. There was no family history of endocrinopathy or diabetes.
On two occasions, a diagnostic supervised fast was performed. In each case, plasma glucose dropped to 23–32 mg/dl (1.3–1.8 mmol/liter) after 8–10 h (Table 1
), with unequivocal mental status changes. But on both fasts, insulin levels, measured by the hospital laboratory using a highly specific, two-site immunoenzymometric assay (Tosoh Medics, San Francisco, CA), dropped normally from baseline levels of 23.1 and 12.3 µIU/ml (160.4 and 85.4 pmol/liter) to 3.7 and 3.8 µIU/ml (25.7 and 26.4 pmol/liter), respectively. The manufacturer’s reference range is 2.6–24.4 µIU/ml (18.1–169.5 pmol/liter), although normal values during a prolonged fast are not provided. C-peptide level (RIA; Nichols Institute Diagnostics, San Clemente, CA) was not suppressed, and proinsulin level (RIA; Nichols Institute Diagnostics) level was markedly elevated (Table 1) above the noted reference range and well above those found by Service in fasting (1). Serum ß-hydroxybutyrate was undetectable, consistent with hyperinsulinemic hypoglycemia. Insulin antibodies were negative, as were serum sulfonylurea levels. Abdominal ultrasound, spiral computerized tomography, and magnetic resonance imaging of the abdomen were all interpreted as normal, without evidence of pancreatic lesion.
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Lacking data to compare the new two-site immunoenzymometric assay with traditional RIAs during normal or hypoglycemic fast, the patient was admitted to the Johns Hopkins General Clinical Research Center for another supervised fast, collecting sera for several insulin assays simultaneously. The study was approved by the institutional review board, and informed consent was obtained.
Simultaneously drawn serum samples during the fast were assayed for insulin by four different assays, the characteristics of which are summarized in Table 2. Two assays employed monoclonal antibodies highly specific for insulin, and two used less specific antibodies, which cross-react with proinsulin.
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. Severe fasting hypoglycemia again occurred quickly, within 4–6 h. Comparing insulin results from the different assays as documented hypoglycemia developed, the two highly specific insulin assays again measured low insulin concentrations, 1.6 µIU/ml (11.0 pmol/liter) and undetectable level at less than 2.0 µIU/ml (<13.9 pmol/liter), but the two less specific (conventional) assays measured high insulin levels, 73.1 µIU/ml (507.6 pmol/liter) and 34 µIU/ml (236.1 pmol/liter). At the end of the fast, C-peptide level was not suppressed, and proinsulin was again markedly elevated at 5.3 ng/ml (561.8 pmol/liter), with reference range of 0–0.2 ng/ml (0–21.2 pmol/liter).
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Postoperatively the patient had a sickle cell crisis but no longer experienced hypoglycemia. All documented capillary glucose values and plasma glucose values were normal. On discharge, the fasting plasma glucose, insulin, and C-peptide levels were within normal limits, and proinsulin was undetectable (Table 3
).
Discussion
Invasive localization procedures and surgical exploration of the pancreas always carry risks, which in this case were considerably higher, given the patient’s sickle cell disease. Surgical exploration of the pancreas should not be undertaken without biochemical evidence of inappropriate hyperinsulinism. Surgery based solely on an elevated proinsulin has not ordinarily been recommended, and we considered it risky.
Applying traditional criteria to the results of a diagnostic fast using the newer, highly specific insulin assay, this patient had severe fasting hypoglycemia but insulin was appropriately suppressed at or below the published reference range, with plasma glucose as low as 22 mg/dl (1.2 mmol/liter) and mental status changes. No reference ranges are provided by the manufacturer for prolonged fast or hypoglycemia. Service (11) noted that an immunochemiluminometric assay produces somewhat lower values and lists the levels suggestive of insulinoma as 3 µIU/ml or more.
We were reluctant to recommend surgery with such normal insulin suppression during fasting because of the patient’s known sickle cell disease as well as the seriousness of partial pancreatectomy if an islet cell tumor was not found, but the severe, symptomatic hypoglycemia required definitive explanation. The C-peptide levels were borderline according to the manufacturer’s reference range but somewhat elevated, at 1.1–1.5 ng/ml (0.4–0.5 nmol/liter), compared with Service’s (1) upper limit in normal during a prolonged fast of 0.6 ng/ml (0.2 nmol/liter), consistent with endogenous hyperinsulinism. The markedly elevated proinsulin level suggested a functional tumor.
By comparing four insulin assay techniques (two highly specific and two nonspecific) and measuring proinsulin, the quandary of low-insulin but fasting hypoglycemia answer was clarified: This tumor secreted predominantly proinsulin, which was not measured by the highly specific insulin assays. Had we used the nonspecific assays initially, the diagnosis of an islet-cell tumor would have been clear because measured insulin levels with the conventional assays [34.0 and 73.1 µIU/ml (236.1 and 507.6 pmol/liter)] with plasma glucose as low as 22 mg/dl when the fast was terminated would have been immediately recognized as an insulinoma. The new, highly specific insulin assays, however, reported a cross-reactivity of only less than 0.5–2% with proinsulin, compared with an estimated 20% or more cross-reactivity for the nonspecific assays (Table 2). The proinsulin component of the tumor’s secretion, then, is essentially unmeasured by the new insulin assays.
The cross-reactivity of highly specific insulin assays has been assessed by Shimizu et al. (12), and their diagnostic utility is part of the review by Service (11). In the series of six cases reported by Shimizu et al. (12), the insulin levels, measured by highly specific assays, were 14–93% lower than with the nonspecific assays. However, the insulin levels obtained by their specific assays were still significantly elevated in people with insulin-secreting tumors, averaging about twice the normal fasting insulin level.
Plasma proinsulin and C-peptide levels are known to be elevated in patients with insulinomas (13), and the proinsulin content in secretory islet-cell tumors is higher than in normal pancreatic tissues (2, 3, 4, 5, 14). Proinsulin has a hypoglycemic effect (15), and tumors that secrete predominantly proinsulin have been well documented to cause hypoglycemia (12, 13, 16, 17). An unknown fraction of secretory islet cell tumors diagnosed by conventional insulin assays could in fact have been predominantly proinsulin secreting, as in the present case.
The use of proinsulin and C-peptide measurements in diagnosing islet-cell tumors has also been evaluated (16, 17, 18, 19, 20, 21). Kao et al. (20) reported that at the end of a prolonged fast, 85% of the insulinoma patients had proinsulin levels greater than the upper limit of normal reference range, compared with 50% for insulin and 20% for C-peptide. Hirshberg et al. (19) reported that proinsulin level has a diagnostic sensitivity for insulinoma of 90% at the start of a fast and 82% at the end of a fast. Thus, elevated proinsulin has been a slightly more reliable marker than elevated C-peptide in diagnosing a functional islet cell tumor.
The present case was extreme in that the fraction of proinsulin was so high, but specific insulin itself was not only not elevated but was frankly suppressed during fasting, and proinsulin was only modestly elevated. Cross-reactivity of C-peptide with the C-peptide sequence of intact proinsulin is said to be 4.13% (Nichols Institute Diagnostics, personal communication), presumably explaining why C-peptide levels were only slightly high in the face of severe increase in proinsulin with plasma glucose as low as 22 mg/dl. Recombinant proinsulin has a long-acting insulin-like effect and underwent phase II therapeutic trials (22), halted because of possible increase in cardiovascular events. The level achieved in these trials was 100–150 times physiologic, so it is possible that proinsulin itself caused the hypoglycemia in our patient, although this is unproved.
We conclude that using the new highly specific insulin assays, insulin levels may suppress normally despite the presence of a secretory islet-cell tumor causing hypoglycemia. If insulin levels are not diagnostic, proinsulin and C-peptide assays, as proposed by Kao et al. (20, 21), may be helpful in the setting of fasting hypoglycemia. Even when insulin suppresses to undetectable levels, a predominantly proinsulin-secreting tumor may be missed. Finally, normative values during prolonged fasting are needed for the newer insulin assays.
Acknowledgments
We thank Ian Halsall (Department of Clinical Biochemistry, University of Cambridge in Cambridge, UK) for assistance in analyzing one of the insulin assays.
Footnotes
This work was supported by NIH/NCRR Grant M01-RR00052 to the Johns Hopkins University School of Medicine General Clinical Research Center.
Received October 28, 2002.
Accepted January 15, 2003.
References
This article has been cited by other articles:
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  D Vezzosi, A Bennet, J Fauvel, and P Caron Insulin, C-peptide and proinsulin for the biochemical diagnosis of hypoglycaemia related to endogenous hyperinsulinism Eur. J. Endocrinol., July 1, 2007; 157(1): 75 - 83. [Abstract] [Full Text] [PDF]
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