A 19-year-old student of 10th class was admitted to our ward with a history of recurrent abnormal movements, confusion and altered state of consciousness for 2 years. While attending school, he was unable to concentrate and developed mental cloudiness after 12:00 PM in school almost every day. These symptoms persisted and were ignored by the patient until the month of Ramzan begins. On 1st Ramzan, while fasting he became unconscious and resuscitated at home. He developed similar episodes on 2nd Ramzan. Now attendants tried to dig out the problem and consulted different psychiatrists for possible malingering

The psychiatrist prescribed him olanzapine, divalproex sodium, propranolol, Escitalopram, risperidone, procyclidine, a combination of olanzapine and fluoxetine on different visits over 1 year. All these medicines did not help and patient symptoms continued. He took medicines prescribed by a neurologist for fits and abnormal movements, no record of medication was available. For a recent episode, the patient became unconscious and they took him to THQ hospital. During the evaluation, blood sugars were recorded at 45 mg/dl and all the symptoms alleviated within one hour after infusion of 25% dextrose and blood sugar rose to 165 mg/dl. This is what we call Whipple’s triad

The patient was referred to a tertiary care hospital for further evaluation. After admission, 72 hours fasting test was done and the patient developed symptomatic hypoglycemia of 38 mg/dl with 6 hours. Blood sugar, C-peptide, and insulin levels were sent and a diagnosis was made

Causes of hypoglycemia in apparently healthy individuals:

  1. Possibility of physiological response to prolonged fasting?

Lean people may have low glucose levels while fasting. Glucose supply is physiologically regulated and such patients don’t develop any symptoms of hypoglycemia. Our patient has hypoglycemia in the context of poor oral intake but symptomatic hypoglycemia rules out this possibility

  1. Factitious hypoglycemia: (Hypoglycemia due to accidental or purposeful administration of insulin or oral hypoglycemic agents) This patent was not using any medication, there is no chance of error in medication dispensation. Another possibility is Munchausen’s syndrome, but the patient and attendants strongly negated the disappearance of medication of DM or any such abnormal behavior. Results of C-peptide and insulin levels are available to rule out
    1. Exogenous insulin: There should be elevated insulin levels and suppressed C-peptide levels. But this patient has normal insulin and C peptide levels
    2. Oral hypoglycemic agents: Insulin and C peptide levels are increased (as it happens in insulinoma). If suspected, screening of oral hypoglycemic drugs is the only means of detection. Our patient has normal insulin and C-peptide level
  1. Insulinoma: Patients with insulinoma develop symptomatic hypoglycemia on fasting in 90% of patients, but 10% may have postprandial hypoglycemia as well. Insulin and C-peptide levels in insulinoma are inappropriately elevated as compared to low blood glucose levels. This patient has a blood sugar level of 38 mg/dl and insulin [15.2 µU/mL (2-25 µU/mL)] and C-peptide [2.34 ng/mL (0.9 – 4.3)]are within normal limits which are inappropriate for severe hypoglycemia. Normal levels are not normal here. These levels are expected in euglycemic patients
  1. Addison’s disease: Recurrent Hypoglycemia may occur in Addison’s disease. But such patients are usually sick and may have positive examination findings like postural hypotension, dark pigmentations, and electrolyte abnormalities like hyperkalemia and hyponatremia. All such findings were absent

 

  1. Alcohol use (Alcohol metabolism decreases gluconeogenesis): No history of alcohol addiction

Interpretation of 72 hours of fasting study

 

Features Normal Fast Exogenous insulin Oral hypoglycemic drugs Insulinoma
Glucose

   

     ↓

      ↓

    ↓

Insulin level

   ↓

   

      ↑

     ↑

C-peptide level

   ↓

    ↓

      ↑

    ↑

 

Clinical Diagnosis

Insulinoma:

Further, work up

  1. Localization of insulinoma: In our patient, we localized with USG and CT scan
    1. Transabdominal ultrasonography
    2. CT scan or MRI
  2. If the tumor is not visualized then further studies should be done
    1. Non-invasive: PET scan
    2. Invasive:
      1. Endoscopic ultrasound
      2. Arteriography: (SACT = selective arterial calcium stimulation)
    3. Work up for MEN-1:
      1. Hyperprolactinemia (due to pituitary adenoma)
      2. Hyperparathyroidism (due to parathyroid hyperplasia)
      3. Hypergastrinemia (due to gastrinoma)

 

Treatment

  1. Surgical resection: Preferred treatment
  2. Medical treatment: Following medications can be used temporarily to prevent hypoglycemia in patients with insulinoma
    • Diazoxide
    • Octreotide
    • Everolimus
    • Verapamil:

Questions 

  1. How does insulinoma behave? Indolent or metastatic?

Usually, it remains indolent or benign however it has the potential to metastasize. In one study 5 of 65 patients showed metastasis

 

  1. How to perform 72 hours fast test?

Restrict food intake by the patient. However, drinking water is allowed. Monitor blood sugar level every 1-2 hours. Fasting should be continued until glucose level drops below 55 mg/dl and the patient develops symptoms. If symptoms are not present below 55 mg/dl then continue fasting till the appearance of symptoms. Sample should be sent for blood sugar level, serum insulin, C-peptide levels

 

  1. What is Whipple’s triad?
    • Symptoms of hypoglycemia:
    • Documented hypoglycemia
    • Resolution of symptoms after correction of hypoglycemia

 

  1. Should the patient be screened for MEN-1? And what are indications to screen.

Insulinoma itself is an indication for screening of MEN-1, Although more than 90% of insulinomas are single and benign tumors. 6% are associated with MEN-1

  1. Why the patients with insulinoma have Hypoglycemia unawareness as compared to other hypoglycemic patients?

Hypoglycemia normally causes the release of counter-regulatory hormones including epinephrine, cortisol, and glucagon. Epinephrine causes sympathoadrenal symptoms (palpitations, sweating) of hypoglycemia. While neuroglycopenic symptoms (confusion, blurry vision, garbled speech, abnormal movement) are due to lack of glucose delivery to the brain. Recurrent hypoglycemia leads to a decrease in the release of counter-regulatory hormone especially epinephrine and produces unawareness of hypoglycemia

 

  1. Name some other neuroendocrine tumors?

This patient has a pancreatic neuroendocrine tumor. While other neuroendocrine tumors are

  • Carcinoid tumor in lungs, GI tract, or thymus
  • Gastrinoma
  • Glucagonoma
  • Medullary thyroid carcinoma
  • Merkel cell carcinoma (neuroendocrine tumor of skin)
  • Pheochromocytoma of the adrenal gland
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