The diagnostic challenge of

hyperinsulinaemic hypoglycaemia

Kawther Alhussain and Amal Alsadiq

 Hypoglycemia

- Physiologic Responses to Hypoglycemia :

1- When glucose levels approach the low 80s, insulin levels decrease.

2- As glucose levels decrease further, glucagon levels increase (glucagon is the

first line of defense against more severe hypoglycemia).

3- Epinephrine is the next hormone to combat hypoglycemia Cortisol and other

catecholamines also play a role.
 Clinical features of hypoglycemia

1. Symptoms occur at a blood glucose level of 40 to 50 mg/dL

2) Elevated epinephrine levels cause sweating, tremors, increased BP and pulse, anxiety, and
palpitations.

3) Neuroglycopenic symptoms-decreased glucose for the brain (CNS dysfunction), resulting in

irritability, behavioral changes, weakness, drowsiness, headache, confusion, convulsions,
coma, and even death.
 Differential diagnosis of hypoglycemia

1 Drug-induced.
2-Factitious hypoglycemia.
3-Insulinoma
4-Ethanol ingestion.
5-Postoperative complications after gastric surgery (due to rapid gastric emptying)
6-Reactive (idiopathic) hypoglycemia
7- Adrenal insufficiency
8-Liver failure
9-Critical illness
10-Disorders of carbohydrate metabolism (e.g., glycogen storage diseases) diagnosed at a much
younger age usually
 Diagnosis

-Blood glucose level-Symptoms generally begin when levels drop below 50. However,
there is no cutoff value to define hypoglycemia

- Plasma insulin .
- C-peptide.
- Anti-insulin antibodies
- Plasma and urine sulfonylurea level.
 Treatment

1-Acute treatment of hypoglycemia:

A-If the patient can eat, give sugar-containing foods
B-if not, give 1/2 to 2 ampules of D50W intravenously.
Repeat administration of D50W as necessary, but switch to D10W as clinical condition
improves and glucose level is approximately >100 mg/dL.

2-Appropriate management of underlying cause

3-If reactive hypoglycemia is suspected, dietary interventions are appropriate.

4. If the patient is an alcoholic (or suspected alcoholic), give thiamine before

administering glucose. ( why ? )
Insulinoma

● insulin producing tumor originating from the pancreatic beta-cells,

cause hyperinsulinaemic hypoglycaemia in adults .
● Associated with MEN1 syndrome.
● Usually benign ( 90%) , (50%) <1 cm .
● Symptoms :

Palpitation diaphoresis weakness irritability

Confusion seizure personality changes coma

● Diagnosis :
72-hour fasting test which reveals decreased plasma glucose (<2.2
mmol/l), increased insulin, C-Peptide and/or proinsulin, and symptoms
of hypoglycaemia that are compensated by glucose infusion (Whipple’s
triade).
● Localization tests :

CT EUS venous catheterization

 ● Treatment :

Medical : Diazoxide , to suppress insulin release .

Primary treatment is surgery for both benign and malignant

insulinoma
If not possible
● anti-tumoural treatments such as ,chemotherapy, everolimus,
sunitinib, and radionuclide
● Treatment of persistent hypoglycemia is a challenge, but
everolimus may prevent episodes of hypoglycemia.
● Prognosis : 80% pt have benign solitary adenoma that is cured by
surgical resection
 Case 1

A 62-year-old Caucasian woman .

1994 - distal pancreatectomy for insulinoma.
1999 - recurrence of hypoglycaemia .
2004 - re-resection of the left pancreas and a pancreatico-duodenectomy.
However, hypoglycaemia persisted and an additional abdominal exploration
and treatment with diazoxide, octreotide and norditropin were unsuccessful.
2005 - positive fasting test after 19 hours. Figure 2

6 mm lesion in the bed of the resected pancreas detected by EUS and pancreatic CT .
Pt treated with chemotherapy with streptozotocin and 5-fluorouracil .

2007-2010 - unchanged lesion in the pancreatic bed.

2010 - minor residual pancreatic tissue was resected.
Histology demonstrated multiple neuroendocrine islets, but no insulinoma.
2011- 14 mm lesion in the pancreatic bed in CT .
A laparotomy was performed and a lymph node was resected, which
contained neuroendocrine tissue.
The patient was euglycaemic at the time of discharge but episodes of
hypoglycaemia recurred and treatment with somatostatin analogues or
everolimus were refused by the patient .
Discussion

Diagnosis initially :
Benign Insulinoma

5y later :
Presented with Metastatic cancer
-Most patients with malignant insulinoma have lymph node or liver
metastasis

concurrent nesidioblastosis is likely, since an increased number of

islet cells were found in the surgical specimens.
 Case report 2

A 59-year-old Caucasian woman.

In 2011- she was admitted to our NET Centre after episodes of loss of consciousness and
seizure.

European Journal of Case Reports in Internal Medicine © EFIM 2015

 Diagnostic tests

- Blood glucose was 1.6 mmol/l (normal range [NR] 4-7 mmol/l)

- Plasma insulin (p-insulin) 400 pmol/l (NR 10-125 pmol/l)

- C-peptide 6000 pmol/l (NR 265– 1026 pmol/l)

- Plasma glucagon (p-glucagon) 119 pg/ml (NR < 60 pg/ml).

- A fasting test was positive.

European Journal of Case Reports in Internal Medicine © EFIM 2015

 MRI was done
( shows hypervascular neuroendocrine
tumour of 2 cm in the pancreatic tail. )

European Journal of Case Reports in Internal Medicine © EFIM 2015

 - At CT and endoscopic ultrasonography (EUS), a further lesion in the body of the
pancreas was suspected

- Octreotide scintigraphy showed no pathological uptake.

- Selective intra-arterial calcium stimulation with hepatic venous sampling demonstrated a

moderate increase of p-insulin following calcium injection into the splenic artery, suggesting an
insulinoma in the pancreatic tail.

European Journal of Case Reports in Internal Medicine © EFIM 2015

 Management

-Intraoperative ultrasound demonstrated a lesion in the pancreatic tail, and

a distal pancreatectomy was performed .

- Pathological examination revealed a 1.7 cm neuroendocrine cystic tumour in

the pancreatic tail and diffuse pancreatic beta-cell hyperplasia.

- The tumour was immunohistochemically

European Journal of Case Reports in Internal Medicine © EFIM 2015

 Surprisingly , it was positive for glucagon, but negative for proinsulin
and insulin.

Plasma levels of insulin, C-Peptide, glucose, and glucagon normalized

postoperatively, and have remained with the normal range ever since.

European Journal of Case Reports in Internal Medicine © EFIM 2015

 DISCUSSION

- Diagnosis initially :Insulinoma

-The patient underwent 6 diagnostic tests, of which 4 disclosed the tumour.

Surprisingly, the histological examination revealed a glucagonoma and nesidioblastosis – but no

insulinoma.

- It is uncertain whether there was a causal relationship between the glucagonoma and nesidioblastosis, or
it was a coincidental finding.

- Of note, the patient was diagnosed with diabetes mellitus and had taken metformin until 2 weeks prior to admission;
metformin was discontinued due to side effects, but did not have migratory necrolytic erythema.
Glucagonomas : originate from the alpha-2 cells of the
pancreas and secrete glucagon, which causes:
Glucose intolerance, diabetes, weight loss and migratory
necrolytic erythema.
Diagnosis requires demonstration of an inappropriately
elevated p-glucagon (diagnostic at levels above 500-1000
pg/ml).
(It is important to note that not all cases of hyperglucagonemia will lead to a diagnosis of glucagonoma)
-10% of cases are associated with multiple endocrine neoplasia type 1 (MEN-1) syndrome.

- About 60% of people diagnosed with glucagonoma are women.Most of those that are diagnosed
are between 45–60 years of age.

-Treated by surgical resection.

- Heightened glucagon : octreotide, a somatostatin analog, which inhibits the release of glucagon.
Doxorubicin and streptozotocin have also been used successfully to selectively damage alpha cells of
the pancreatic islets. These do not destroy the tumor, but help to minimize progression of symptoms
 Adult nesidioblastosis

-A rare form of abnormal islet cell proliferation arising from the pancreatic ductal
epithelium, affects approximately 4% of adults with hyperinsulinaemic
hypoglycaemia.

The histopathological criteria include : beta-cell hypertrophy, islet hyperplasia,

and an increase in the beta-cell mass.
(The patients have elevated insulin and C-peptide levels).

- When radiological studies do not show a pancreatic mass, nesidioblastosis

should be suspected.

-Most surgeons perform 60-80% distal pancreatectomy in patients with

nesidioblastosis, which results in cure in about half on the patients.
CONCLUSION

Insulinomas are rare and often present both diagnostic and therapeutic
challenges. Referral to specialised NET centres with a multidisciplinary
approach is recommended.
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