Insulinoma

New Protocol Cuts Fasting Time to Rule Out Insulinoma

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 Use of a new protocol — sequential beta-hydroxybutyrate testing with a cut-off for ruling out insulinoma in patients with hypoglycemia — may allow for a shortening of the gold-standard 72-hour fasting time normally required for this diagnosis, therefore yielding significant hospital cost savings, new data suggest.

Insulinomas are small, rare types of pancreatic tumors that are benign but secrete excess insulin, leading to hypoglycemia. More than 99% of people with insulinoma develop hypoglycemia within 72 hours, hence, the use of a 72-hour fast to detect these tumors.

But most people who are evaluated for hypoglycemia do not have an insulinoma and fasting in hospital for 3 days is burdensome and costly.  

As part of a quality improvement project, Cleveland Clinic endocrinology fellow Michelle D. Lundholm, MD, and colleagues modified their hospital’s protocol to include measurement of beta-hydroxybutyrate (BHB), a marker of insulin suppression, every 12 hours with a cutoff of ≥ 2.7mmol/L for stopping the fast if hypoglycemia (venous glucose ≤ 45mg/dL) hasn’t occurred. This intervention cut in half the number of patients who needed to fast for the full 72 hours, without missing any insulinomas.

“We are excited to share how a relatively simple adjustment to our protocol allowed us to successfully reduce the burden of fasting on patients and more effectively utilize hospital resources. We hope that this encourages other centers to consider doing the same,” Lundholm told Medscape Medical News.

“These data support a 48-hour fast. The literature supports that’s sufficient to detect 95% of insulinomas…But, given our small insulinoma cohort, we are looking forward to learning from other studies,” she added.

Lundholm presented the late-breaking oral abstract on May 5 at the American Association of Clinical Endocrinology Annual Meeting.

Asked to comment, session moderator Jenna Sarvaideo, MD, told Medscape Medical News: “We’re often steeped in tradition. That’s why this abstract and this quality improvement project is so exciting to me because it challenges the history…and I think it’s ultimately helping patients.”

Sarvaideo, of Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin, noted that, typically, although the fast will be stopped before 72 hours if the patient develops hypoglycemia, “often they don’t, so we keep going on and on. If we just paid more attention to the beta-hydroxybutyrate, I think that would be practice-changing.”

She added that more data would be optimal, given that there were under 100 patients in the study, “but I do think that devising protocols is…very much still at the hands of the endocrinologists. I think that this work could make groups re-evaluate their protocol and change it, maybe even with a small dataset and then move on from there and see what they see.”

Indeed, Lundholm pointed out that some institutions, such as the Mayo Clinic, already include 6-hour BHB measurements (along with glucose and insulin) in their protocols.

“For any institution that already draws regular BHB levels like this, it would be very easy to implement a new stopping criterion without adding any additional costs,” she told Medscape Medical News.

All Insulinomas Became Apparent in Less Than 48 Hours

The first report to look at the value of testing BHB at regular intervals was published by the Mayo Clinic in 2005 after they noticed patients without insulinoma were complaining of ketosis symptoms such as foul breath and digestive problems toward the end of the fast.

However, although BHB testing is used today as part of the evaluation, it’s typically only drawn at the start of the protocol and again at the time of hypoglycemia or at the end of 72 hours because more frequent values hadn’t been thought to be useful for guiding clinical management, Lundholm explained. 

Between January 2018 and June 2020, Lundholm and colleagues followed 34 Cleveland Clinic patients who completed the usual 72-hour fast protocol. Overall, 71% were female and 26% had undergone prior bariatric surgery procedures. Eleven (32%) developed hypoglycemia and stopped fasting. The other 23 (68%) fasted for the full 72 hours.

Lundholm and colleagues determined that the fast could have ended earlier in 35% of patients based on an elevated BHB without missing any insulinomas.

And so, in June 2020 the group revised their protocol to include the BHB ≥ 2.7mmol/L stopping criteria. Of the 30 patients evaluated from June 2020 to January 2023, 87% were female and 17% had undergone a bariatric procedure.

Here, 15 (50%) reached a BHB ≥ 2.7mmol/L and ended their fast at an average of 43.8 hours. Another seven (23%) ended the fast after developing hypoglycemia. Just eight patients (27%) fasted for the full 72 hours.

Overall, this resulted in approximately 376 fewer cumulative hours of inpatient admission than if patients had fasted for the full time.

Of the 64 patients who have completed the fasting protocol since 2018, seven (11%) who did have an insulinoma developed hypoglycemia within 48 hours and with a BHB < 2.7 mmol/L (median, 0.15).

Advantages: Cost, Adherence

A day in a general medicine bed at Cleveland Clinic was quoted as costing $2,420, based on publicly available information as of January 1, 2023. “If half of patients leave one day earlier, this equates to about $1,210 per patient in savings from bed costs alone,” Lundholm told Medscape Medical News.  

The revised protocol required an additional two to four blood draws, depending on the length of the fast. “The cost of these extra blood tests varies by lab and by count, but even at its highest does not exceed the amount of savings from bed costs,” she noted.

Patient adherence is another potential benefit of the revised protocol.

“Any study that requires 72 hours of patient cooperation is a challenge, particularly in an uncomfortable position like fasting. When we looked at these adherence numbers, we found that the percentage of patients who prematurely ended their fast decreased from 35% to 17% with the updated protocol,” Lundholm continued.

“This translates to fewer inconclusive results and fewer readmissions for repeat 72-hour fasting. While this was not our primary outcome, it was another noted benefit of our change,” she said.

Persistent hypoglycemia despite oral therapy

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An 82-year-old woman was brought to the ED after a fall. Her medical history was significant for hypertension, recurrent urinary tract infections, atrial fibrillation and recently diagnosed dementia.

Her medication list included Pradaxa (dabigatran, Boehringer Ingelheim), Aricept (donepezil, Pfizer), atenolol, lisinopril, and calcium and vitamin D supplements.

She was found to be combative and disoriented. Her capillary blood glucose level was 31 mg/dL, and after the IV administration of dextrose, her mental status returned to baseline. She was admitted to the hospital for further evaluation.

Laboratory testing, imaging

Her family reported an 8-month history of forgetfulness and a 3-month history of recurrent falls. After hospital admission, she was found to have bradycardia and persistent hypoglycemia despite a continuous infusion of fluids with 5% glucose. Atenolol was discontinued because of the potential to block glucagon secretion. Hypoglycemia was attributed to low oral intake; however, her symptoms persisted in the hospital despite adequate food consumption. Her husband reported that the patient had no personal or family history of diabetes and that no insulin or oral hypoglycemic agents were kept at home.

On initial laboratory testing, a random blood glucose measurement was 46 mg/dL, insulin level 20.3 mIU/L and C-peptide 3.7 ng/mL. Serum sulfonylurea panel was negative. Morning cortisol level was 12 µg/dL, and after a cosyntropin adrenal stimulation test, the patient showed a normal adrenal response with a cortisol of 26 µg/dL at 30 minutes and 30 µg/dL at 60 minutes. Her thyroid-stimulating hormone level was normal at 1.5 mIU/L. The remainder of a routine complete blood count and chemistry panel were unremarkable.

Abdominal CT (Figure) showed an 8-mm arterially enhancing lesion within the body of the pancreas near the junction with the tail, which was concerning for neuroendocrine tumor.

The patient was transferred to our tertiary care hospital for further management. On physical exam, her BMI was 24.6 kg/m2. She was oriented to person, but not to place and time. She did not show wasting or hyperpigmentation.

On admission, random serum glucose was 47 mg/dL. Because her random serum glucose levels had been low, she was not started on a 72-hour fast but kept on regular diet. Her capillary glucose levels were checked every 2 hours. Repeat laboratory tests revealed hypoglycemia with a serum glucose level of 30 mg/dL, insulin 15 mIU/L (normal, 2-15 mIU/L), C-peptide 3.62 ng/mL (normal, 0.8-3.1 ng/mL), proinsulin 244 pmol/L (normal, < 18.8 pmol/L) and beta-hydroxybutyrate 0.08 mmol/L (normal, < 0.28 mmol/L).

The patient did not have neuroglycopenic symptoms. She was started on IV dextrose infusion because blood glucose remained less than 70 mg/dL with intermittent serum glucose levels dropping to the 40s. Laboratory testing suggested an endogenous excess insulin consistent with an insulinoma.

After a hand-assisted laparoscopic distal pancreatectomy and splenectomy, the patient experienced rapid resolution of her hypoglycemia. Pathology revealed a well-differentiated neuroendocrine tumor with positive staining for synaptophysin and chromogranin and negative staining for insulin. On follow-up, the patient’s blood glucose levels have remained within normal limits.

Figure 1. Contrast-enhanced CT scan with arterial and delayed capillary phase sequences. (A) Arterial phase. (B) Delayed capillary phase. The small, rounded 8-mm nodule (red
arrow) within the body of the pancreas enhances compared with the normal pancreas.

Diagnosing, treating insulinoma

The diagnosis of insulinoma is likely if the patient has neuroglycopenic symptoms, a fall in plasma glucose to less than 45 mg/dL (< 2.5 mmol/L), inappropriately elevated beta-cell polypeptides (insulin, proinsulin and C-peptide levels) and a beta-hydroxybutyrate level of less than 2.7 mmol/L. Insulinomas are the most common functioning pancreatic endocrine tumors, but they are rare tumors that occur in one to four people per million in the general population. Insulinomas cause hypoglycemia, and patients present with related autonomic and neuroglycopenic symptoms. Diagnosis is based on endocrine tests confirming hypoglycemia and excess endogenous insulin secretion and imaging procedures.

Surgical resection is the best treatment with a cure rate of 85% to 95%. Tumor localization is an essential step in surgical planning. Multiple noninvasive imaging techniques are available, including transabdominal ultrasonography, CT and MRI. Because insulinomas tend to be small, the sensitivity of transabdominal ultrasound in the localization of insulinomas is poor. CT and MRI can detect 30% to 66% of these tumors. MRI has a slight superiority in the detection of extrapancreatic extensions. Typically, insulinomas are hypervascular. CT imaging will show a significant enhancement compared with normal pancreatic parenchyma during the arterial and capillary phases of contrast bolus (Figure). On MRI, these tumors demonstrate low-signal intensity on T1-weighted images and high-signal intensity on T2-weighted images.

If these noninvasive tests fail to localize the insulinoma, invasive modalities, such as endoscopic ultrasonography and arterial stimulation venous sampling, should be performed and may have superior abilities to localize the tumor. Selective percutaneous transhepatic venous sampling can localize an insulinoma to the head, body or tail of the pancreas, and selective arteriography is also often helpful in localizing insulin-secreting lesions. Nuclear octreotide scans can localize somatostatin receptors on insulinomas in approximately 50% of cases. Preoperative identification of the tumor location allows an uninterrupted surgery, decreasing the probability of reoperation and limiting perioperative complications.

The nuclear option for insulinomas.

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Although insulinomas are rare tumours, they have fascinated clinicians for many years because of the variety in clinical presentation, close association between symptoms and biochemistry, and striking response to surgical cure. In a patient who is otherwise healthy, and in the absence of a history of diabetes mellitus, intermittent hypoglycaemia is usually attributable to inappropriate insulin activity.1 If other causes can be excluded—which is not always easy if, for example, patients are knowingly injecting insulin or taking drugs that stimulate insulin release—insulinoma should be seriously considered as a diagnosis. Diagnosis can be proven by confirmed hypoglycaemia in the presence of inappropriate insulin secretion; however, threshold criteria for measurements of glucose and insulin are somewhat controversial. Recent guidelines suggest that blood glucose concentrations should be lower than 3 mmol/L to be regarded as hypoglycaemia,1 but at the Churchill Hospital in Oxford, UK, we noted that this cutoff produced too many false positives and have reverted to a stricter threshold of 2·2 mmol/L. Equally, the inappropriate level of insulin in the presence of hypoglycaemia has been set at 3 mIU/L, but because insulin assays have become more specific, this crucial concentration of insulin has decreased. Indeed, we have reported a confirmed insulinoma in a patient with an insulin concentration of 2·7 mIU/L.2 As in other areas of endocrinology, improved assays have led to more difficult diagnostic decisions. However, a C-peptide concentration of more than 200 pmol/L is a useful and potentially robust determinant of inappropriate insulin secretion.

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After the diagnosis of insulinoma has been made, localisation of the tumour is the biggest challenge. Most tumours are benign and small, with almost all less than 2 cm in maximum diameter, so identification can be problematic. Previously, surgeons would operate and trust that they could feel the tumour by direct palpation, but nowadays this technique is rarely practised (although intraoperative ultrasound is still used). CT scanning has good resolution but the difference in tissue density might not allow clear discrimination of the tumour. We reported that MRI was the most sensitive discriminatory imaging technique, identifying about 75% of tumours, and this sensitivity might be improved with diffusion-weighted imaging.3 Other groups have emphasised the role of endoscopic ultrasound.4 Intra-arterial injection of calcium with measurement of hepatic vein insulin is often used, but is invasive and only regionalises rather than localises the tumour; however, it can help confirm an anatomically identified abnormality.3—5 Thus, a need remains for precise localisation of these tumours. Nuclear medicine has been suggested to be useful in this context because it depends on functional aspects rather than simple anatomical size, but somatostatin scintigraphy and 18F-fluorodeoxyglucose (18F-FDG) PET have not proved useful for these benign tumours.

In The Lancet Diabetes & Endocrinology, Emanuel Christ and colleagues6 ingeniously speculated that because most insulin cells contain receptors for incretins—specifically the glucagon-like peptide-1 receptor (GLP-1R)—injection of radiolabelled exendin-4, a GLP-1R agonist, might identify these tumours where other techniques have failed. Following on from an initial pilot study7 showing the feasibility of this technique, the group now report on 30 patients who were referred for exendin-4 scanning in centres in Switzerland, Germany, and the UK. All patients had either no lesion or only a suspicion of one on CT or MRI scanning, to exclude patients with evidence of malignant insulinoma. Christ and colleagues were able to report on 25 patients who had histological confirmation of insulinoma after surgery; of these, 23 had both CT/MRI and 111In-DTPA-exendin-4 scanning.6 CT/MRI correctly identified 47% (95% CI 27—68) of insulinomas in this study and endoscopic ultrasound correctly diagnosed seven of nine patients assessed using this technique. 111In-DTPA-exendin-4 scanning was 95% (75—100) sensitive, and was the only modality to correctly identify the tumour in all ten instances of histologically confirmed insulinoma where the other imaging was negative, although there were four false positives. Patients had a mean fall in blood glucose concentrations of 1·3 mmol/L (IQR 0·8—2·1) during the study so glucose infusions are required with the technique. Notably, the investigators used a different chelating agent, DPTA, in this study than in previous studies,7 which might cause fewer side effects (such as nausea and hypoglycaemia).

The radiotracer technique seems to be less effective for malignant tumours than benign tumours (radiolabelled octreotide might be more useful) and is not yet commercially available.8 However, it might allow for the identification of tumours not otherwise readily visualised, and should decrease the number of blind laparotomies, decreasing surgical morbidity, and could also allow for an increased rate of laparoscopic removal. Furthermore, some 5—10% of these tumours are a manifestation of multiple endocrine neoplasia type 1 (MEN1), in which multiple lesions frequently occur in the pancreas and identification of insulinomas is difficult. In Christ and colleagues’ study, two patients had MEN1 and their insulinomas were identified and successfully removed after 111In-DTPA-exendin-4 scanning.

A few points warrant emphasis. All patients in the study were selected for inclusion and had uncertain imaging, and at some point a direct comparison against optimum MRI and possibly endoscopic ultrasound and calcium-stimulated venous catheterisation should be done. At the moment, the new radiotracer technique is probably best reserved for those cases in which conventional localisation techniques have not worked. In time, PET isotopes might become available that are more sensitive and can reduce scan times (although whether this would work well for the pancreas is unknown). Endocrinologists should nevertheless regard the nuclear technique as offering great potential benefit to our patients in the future.

Source: Lancet