Insulinoma diagnostic criteria

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

## Overview

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The diagnosis of insulinoma is based on the Whipple's triad, which includes blood glucose < 55 mg/dL, symptoms of hypoglycemia that can be neuroglycopenic (visual disturbances, confusion, weakness, seizures, coma) or adrenergic symptoms (sweating, tremors, palpitations, and hyperphagia) and resolution of symptoms after ingestion/infusion of glucose. It is also diagnosed on the basis of radioimmunoassay (RIA) and Immunochemiluminescent assay (ICMA) in the absence of hypoglycemia causing agents e.g. insulin and oral hypoglycemic agents (e.g. sulfonylureas) by insulin level (>6 μU/mL (43 pmol/L by RIA and ≥ 3 μU/mL by ICMA, glucose level of < 2.5mmol/L (55mg/dL) and C-peptide level of ≥ 200 pmol/L and/or proinsulin level ≥ 25% or ≥ 22pmol/L. The gold standard for the diagnosis of insulinoma is 72-hour fasting test.

## Diagnostic Criteria

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* The classical diagnosis of insulinoma is based on the Whipple's triad (1935), which includes:[1][2][3][4]

1. Hypoglycemia (fasting blood glucose < 55 mg/dL)
2. Symptoms of hypoglycemia
* Neuroglycopenic symptoms including visual disturbances (blurring of vision, diplopia), confusion, weakness, behavioral changes, seizures and coma.
* Adrenergic symptoms including sweating, palpitations, tremors and hyperphagia/obesity.
3. Improvement of symptoms after glucose infusion

* The diagnosis of insulinoma is based on the biochemical assay with radioimmunoassay (RIA) and immunochemiluminescent assay (ICMA) in the absence of plasma sulfonylureas (or drug causing hypoglycemia) as below: [5][6]
* Insulin level > 6 μU/mL (43 pmol/L by RIA and ≥3 μU/ml by ICMA
* Glucose level < 2.5mmol/L (55 mg/dL)
* C-peptide level ≥ 200 pmol/L
* Proinsulin level ≥25% or ≥22pmol/L is also included in some criteria
* The gold standard for diagnosis classically had been 72-hour fasting test.[6][5]
* 33% patients develop symptoms in 12 hours, 80% at 24 hours, 90% after 48 hours and 100% after 72 hours of fasting.

Algorithm used commonly[7]

| Suspicion of Insulinoma|

|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|

| Whipple's triad confirmed|

| 72 hour fast|

| Positive|

| Negative

| MRI/CT|

| Prolonged OGTT or mixed meal

| No visible lesion|

| Visible
lesion(s)|

| Unresectable
liver metastasis|

| No
hypoglycemia|

| Hypoglycemia

| No follow up|

| Differential diagnosis of
postprandial hypoglycemia|

| EUS|

| Treat metastatic disease

| |

| No visible lesion(s)|

| Visible lesion(s)|

| GLP-1 Scan or ASVS|

| No lesion(s)|

| Identified lesion(s)|

Medical control
and reevaluation|

| Surgical exploration
(intraoperative US)|

| Single lesion(s)|

| Multiple lesion(s)|

| Excision|

| ASVS|

| Excision based on ASVS|

Abbreviations: EUS: Endoscopic ultrasound, ASVS: Arterial stimulation venous sampling, GLP-1: Glucagon-like-peptide 1, OGTT: Oral glucose tolerance test

## References

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1. ↑ Whipple AO, Frantz VK (1935). "ADENOMA OF ISLET CELLS WITH HYPERINSULINISM: A REVIEW". Ann. Surg. 101 (6): 1299–335. PMC 1390871. PMID 17856569.
2. ↑ Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER; et al. (2009). "Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 94 (3): 709–28. doi:10.1210/jc.2008-1410. PMID 19088155.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
3. ↑ Metz DC, Jensen RT (2008). "Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors". Gastroenterology. 135 (5): 1469–92. doi:10.1053/j.gastro.2008.05.047. PMC 2612755. PMID 18703061.
4. ↑ Boukhman MP, Karam JH, Shaver J, Siperstein AE, Duh QY, Clark OH (1998). "Insulinoma--experience from 1950 to 1995". West J Med. 169 (2): 98–104. PMC 1305178. PMID 9735690.CS1 maint: Multiple names: authors list (link)
5. ↑ 5.0 5.1 Metz, David C.; Jensen, Robert T. (2008). "Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors". Gastroenterology. 135 (5): 1469–1492. doi:10.1053/j.gastro.2008.05.047. ISSN 0016-5085.
6. ↑ 6.0 6.1 Grant CS (2005). "Insulinoma". Best Pract Res Clin Gastroenterol. 19 (5): 783–98. doi:10.1016/j.bpg.2005.05.008. PMID 16253900.
7. ↑ Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, Kos-Kudla B, Kwekkeboom D, Rindi G, Klöppel G, Reed N, Kianmanesh R, Jensen RT (2016). "ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors". Neuroendocrinology. 103 (2): 153–71. doi:10.1159/000443171. PMC 4849884. PMID 26742109.

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