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Journal Scan

November 2018

Rare cause of hypoglycemia highlighted in case study report

Summarized from Wexler D, Macias-Konstantopoulos W, Forcione D. Case 23-2018: A 36 year old man with episodes of confusion and hypoglycemia. New Eng J Med 2018; 379: 376-85
Blood glucose concentration is normally maintained within the approximate reference range of 3.5-8.5 mmol/L (63-153 mg/dL) largely by the synergistic opposing action of two pancreatic hormones: insulin and glucagon. Insulin secretion, induced by rising blood glucose concentration, causes it to fall; whilst glucagon secretion, induced by falling blood glucose concentration, causes it to rise. 

Hypoglycemia (reduced blood glucose concentration) is usually defined as blood glucose <2.2 mmol/L (<40 mg/dL), although hypoglycemic symptoms may occur at higher concentration (up to 3.0 mmol/L (54 mg/dL)). Symptoms of hypoglycemia reflect two consequences of reduced blood glucose. The first is an adrenergic physiological response to hypoglycemia aimed at increasing blood glucose by increased secretion of adrenal counterregulatory hormones such as norepinephrine that, like glucagon, oppose the blood-glucose-lowering action of insulin.

The second consequence is reduced glucose within the brain (neuroglycopenia). Signs and symptoms of the protective adrenergic response, though uncomfortable, have no serious consequence; they include: hand tremor, feeling of hunger and anxiety, palpitations, increased heart rate (tachycardia) and excessive sweating (diaphoresis). Neuroglycopenia by comparison is more serious; symptoms include: confusion, inability to concentrate, blurred vision, speech impairment and fatigue.

Seizures and coma may ensue. Rarely, neuroglycopenia can result in permanent brain damage and brain death. Emergency iv administration of glucose (dextrose) or equivalent is necessary to alleviate the discomfort of the adrenergic response and avoid the potentially catastrophic consequences of neuroglycopenia. 

The most common cause of hypoglycemia is “excessive” diabetic drug treatment (exogenous insulin or other blood-glucose-lowering agents) so that the vast majority of patients presenting with hypoglycemia have a history of diabetes.

There are many other causes of hypoglycemia unrelated to diabetes and its treatment including insulinoma, a rare usually benign tumor of pancreatic β cells (where insulin is normally produced). Insulinoma is the subject of a recent detailed case study report published under the renowned banner of Case Records Of Massachusetts General Hospital, a celebrated teaching feature of every issue of the New England Journal of Medicine for the past 95 years. 

The case concerns a married 36-year-old firefighter and father of two who was admitted to hospital because of episodes of altered mental status over a period of years. His wife reported that the first episode occurred 6 years prior to admission and lasted for just 30 minutes. He was wandering around at home unsure of where he was, making nonsensical speech and complaining of blurred vision.

Normal mental status was soon restored and no further reported episodes occurred during the following 4 years. Two years prior to admission similar episodes began to recur once or twice a year, and became increasingly more frequent (once or twice a month) at 4 months prior to admission. The patient attributed the episodes to stress and did not seek medical help. 

Things came to a head when, on the day of admission, the patient vomited early in the morning, was sweating excessively and remained intermittently confused throughout the morning. During a telephone call to a friend in the afternoon he was speaking nonsensically; this and other continuing familiar elements of previous episodes persuaded his worried friend that he needed urgent medical help. The friend assisted him to the hospital emergency room.

On admission, the patient was confused and agitated. Attention, concentration, abstract reasoning and memory were all judged to be poor. Two abnormal neurological signs, asterixis (hand tremor) and vertical nystagmus (involuntary vertical movement of the eyes) were present. Vital signs were normal, save a slightly increased heart rate (103 bpm).

Extensive hematological, biochemical and toxicological blood testing revealed no abnormalities except a slight increase in serum CRP/ESR and marked decrease in blood glucose (1.1 mmol/L, 20 mg/dL), allowing a diagnosis of hypoglycemia. The diagnosis prompted iv administration of 20 % dextrose in water, which resulted in blood glucose concentration to rise to 14.3 mmol/L (257 mg/dL). With this treatment, symptoms rapidly resolved. The patient was now no longer confused or agitated; normal neurological and mental status had been restored. 

The patient had satisfied the three elements of Whipple’s triad: symptoms of adrenergic response/neuroglycopenia; confirmed low blood glucose at the time of the symptoms; and rapid resolution of symptoms after correction of hypoglycemia. This allowed attending physicians to exclude many possible neurological disorders and drug effects that might explain the symptomatic episodes the patient had suffered. Instead, the well-justified assumption was that they were caused by episodes of hypoglycemia. The cause of the hypoglycemic episodes remained to be established. 

Much of this case study report is devoted to discussion of the many causes of hypoglycemia and outlines the aspects of this case that suggested insulinoma was the most likely cause of hypoglycemia. There follows a general discussion of the pathophysiology of insulinoma and its clinical presentation from which we learn, for example, that insulinomas secrete insulin autonomously, i.e. without the feedback control of reducing blood glucose concentration which would normally diminish insulin secretion. Inappropriately high concentration of insulin and its precursor C-peptide, when blood glucose is reduced, is thus a diagnostic feature of insulinoma that proved useful in this case.

Final confirmatory diagnosis of insulinoma is made by pancreatic imaging and histopathological examination of tissue biopsied from the pancreatic tumor site identified by imaging. These aspects of the case are well detailed in the report. 

Following histopathological diagnosis of insulinoma and identification of its precise location in the pancreas, the patient was referred for surgical resection of the insulinoma. Atypical location of the tumor allowed less radical surgical treatment than is usual in insulinoma. The authors report that within 24 hours of the operation the patient was able to maintain normal blood glucose concentration and that he was discharged 7 days after admission. At outpatient follow-up, he reported no further symptoms of hypoglycemia. 
 
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Chris Higgins

has a master's degree in medical biochemistry and he has twenty years experience of work in clinical laboratories.

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