A12-month-old girl is brought to the ED after a seizurelike episode. On awakening from a nap, she screamed and then became stiff. Her eyes rolled back, and she began to shake. Both arms and legs were involved symmetrically. The episode lasted 2 minutes, after which she appeared tired. She has been well recently, with no fever or respiratory symptoms.
Her mother reports a history of similar episodes over the last 3 months, with increasing frequency in the last week (up to 10/d), but no medical attention has been sought until now. The child has had no serious illnesses, is receiving no medications, has no allergies, and has not been immunized (by parental choice). She walked at 10 months of age, but in the last week has become unsteady, stumbling when walking. The family history is noncontributory.
The physical examination reveals an alert child who has normal tone, strength, reflexes, and vital signs. All other physical findings also are normal; specifically, no focus of infection is evident.
Blood chemistry levels include: sodium, 137 mEq/L (137 mmol/L); potassium, 5.4 mEq/L (5.4 mmol/L); calcium, 10.4 mg/dL (2.60 mmol/L); and magnesium, 2.43 mg/dL (1.00 mmol/L). The blood glucose level is 37.8 mg/dL (2.1 mmol/L), and liver function test results are normal. The WBC count is 11.5x103/mcL (11.5x109/L), Hgb level is 12.2 g/dL (122 g/L), and platelet count is 347x103/mcL (347 x109/L). A full evaluation for sepsis is negative. CT of the head shows normal findings. Additional testing confirms the diagnosis.
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The girl was admitted to the hospital and started on an intravenous dextrose solution to stabilize her blood glucose. The infusion was interrupted, and repeated blood glucose testing and symptom monitoring were instituted. When hypoglycemia (glucose <50 mg/dL [2.7 mmol/L]) was reached, metabolic studies consisting of measuring serum carnitine, urine organic acids, and plasma amino acids and free fatty acids were carried out to rule out an inborn error of metabolism. All results were normal.
In addition, a critical sample (a measure of various metabolic precursors and hormones involved in glucose regulation taken during an episode of hypoglycemia) was drawn and revealed a glucose value of 1.4 mg/dL (0.8 mmol/L) (asymptomatic). The cortisol concentration was 24.4 mcg/dL (673 nmol/L). The reference range for a morning level is 4.3 to 22.4 mcg/dL (119 to 618 nmol/L); a high value represents a normal response to hypoglycemia. The growth hormone concentration was 12.35 ng/mL (543.4 pmol/L). The reference range for a normal growth hormone value during an episode of hypoglycemia is greater than 8.0 ng/mL (352 pmol/L). The insulin level was 11.4 mcU/mL (82 pmol/L), which was in the normal range (6.0 to 27.0 mcU/mL [43.1 to 193.7 pmol/L]), but during hypoglycemia, insulin should be suppressed (<5.0 mcU/mL [35.9 pmol/L]). Therefore, her value was inappropriately high, given her physiologic state.
MRI of the head and EEG to rule out CNS abnormalities gave normal results. Repeated episodes of asymptomatic hypoglycemia occurred during the first few days in the hospital, then stabilized with initial intravenous dextrose therapy followed by treatment with diazoxide, an inhibitor of insulin release. No additional seizures occurred. The patient was discharged from the hospital on diazoxide (10 mg/kg in three daily doses) and with a glucagon kit and instructions on treating hypoglycemia.
An MRI of the abdomen obtained as an outpatient revealed a discrete mass in the tail of the pancreas, amenable to resection, suggesting the presence of an insulinoma that explained the patient’s hypoglycemia. She underwent a partial pancreatectomy to remove the tumor. Since the surgery, she has been weaned from diazoxide and has had stable blood glucose concentrations.
The Disorder
Insulinomas are extremely rare in children. Although most present as isolated tumors, they may be associated in younger children with the condition known as multiple endocrine neoplasia type I, which is characterized by hyperparathyroidism, pituitary adenomas, and pancreatic adenomas. Symptoms and signs are due primarily to the effects of hypoglycemia on the CNS (tremulousness, poor feeding, irritability, anxiety, dizziness, seizure, coma), may be present for days to years, and may be misdiagnosed as neurologic or psychiatric disease. In 30% to 40% of patients, the hyperinsulinism is caused by a discrete region of adenomatous hyperplasia, but all pancreatic beta cells can be involved (both hyperplasia and hypersecretion), and this determination can affect the treatment plan.
Diagnosis
In general, persistent or recurrent hypoglycemia can result from three mechanisms. Lack of substrate can be due to prolonged fasting, inborn errors of energy metabolism (affecting gluconeogenesis, glycogenolysis, or fatty acid oxidation), and ketotic hypoglycemia. Increased utilization of glucose can result from hyperinsulinemia, either endogenous (infant of a diabetic mother, diffuse or focal hyperinsulinism) or exogenous. The third mechanism involves an inadequate response or deficiency of counterregulatory mechanisms designed to raise blood glucose, causes of which can be endocrinologic (cortisol deficiency, growth hormone deficiency, panhypopituitarism) or toxin-mediated (ethanol, salicylates, propranolol). In a 12-month-old child, the most likely causes are hyperinsulinism, hypopituitarism, adrenal insufficiency, or ketotic hypoglycemia. The critical sample helps to differentiate these diagnoses.
The diagnosis of hyperinsulinemia should be considered in any case of hypoglycemia, particularly if episodes are persistent or recurrent and when other mechanisms have been ruled out. Endogenous hyperinsulinemia is diagnosed by demonstrating inappropriately high insulin and C-peptide levels in the face of hypoglycemia (exogenous administration of insulin causes high insulin, but low C-peptide levels). Indirect measures of hyperinsulinism include lack of ketones in the face of hypoglycemia, an increased glycemic response to glucagon, and an increased glucose requirement (>15 mg/kg per min).
In this case, interpretation of the critical sample showed a normal response of the counterregulatory hormones. The insulin level, although reported as within the normal range, was inappropriately high for the circumstance; insulin should be suppressed completely by hypoglycemia. Additional evidence of hyperinsulinemia was provided by the absence of plasma ketones. Again, although reported as normal, this finding is inappropriate for the circumstance; hypoglycemia should trigger fat oxidation and ketogenesis, but in this case, the presence of insulin inhibited ketogenesis.
Treatment
Once hyperinsulinemia is diagnosed, differentiating between focal (discrete insulinoma) and diffuse disease (infant of a diabetic mother, persistent hyperinsulinemic hypoglycemia of infancy, diffuse hyperinsulinism) has important implications for treatment. Focal disease can be treated pharmacologically, but also may be amenable to partial surgical resection; diffuse disease is less amenable to partial resection. There are two primary pharmacologic options, the first being diazoxide (10 mg/kg per day orally divided into three doses), an inhibitor of insulin release. Major adverse effects include hirsutism, fluid retention, and neutropenia. Octreotide (5 to 20 mcg/kg per day by subcutaneous injection every 6 to 8 h), a somatostatin analogue that inhibits insulin secretion (as well as glucagon and growth hormone), also can be used. Adverse effects include abdominal discomfort, cholelithiasis, and transient growth impairment.
Many approaches have been attempted to localize focal disease. Radiologic studies have not been as successful as hoped, with MRI being the best, correctly localizing up to 45% of insulinomas. A newer, more invasive approach, consisting of selective sampling of pancreatic veins for insulin levels following stimulation with calcium gluconate, has an overall accuracy of up to 94%, but is not yet widely available. Isolated insulinomas localized to the tail of the pancreas are potentially curable with partial resection; diffuse disease, particularly if resistant to pharmacologic treatment, may require subtotal pancreatic resection. Although this procedure cures the hyperinsulinemia, the child ultimately may develop diabetes mellitus from the resulting relative insulin deficiency, once growth exceeds pancreatic function. Unfortunately, the timing of this complication is unpredictable, requiring ongoing monitoring.
Lessons for the Clinician
Investigation of any child presenting with a seizure must include a blood glucose measurement. Hypoglycemia is treated easily, and hypoglycemic seizures may be refractory to anticonvulsant therapy. Hyperinsulinemia, specifically as caused by insulinoma, is a rare condition but one important to diagnose. Obtaining a true hypoglycemic blood sample is vital in making the diagnosis. It is important to remember that results of critical samples must be considered in context. Although the laboratory may report a result as being normal, that level may not be appropriate for the physiologic state. Accurate localization of insulinomas can affect the treatment, allowing the possibility of a cure without sequelae in focal disease.
Marielena DiBartolo, MD
Robert I. Stein, MD
Children’s Hospital of Western Ontario, University of Western Ontario, London, Ontario, Canada
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Хочется подчеркнуть, что у таких больных важно определять КЩС во время эпизода гирогликемии . При отсутствии ацидоза круг диф.диагностики существенно сужается
(практически - до гиперинсулинизма и проблем с обменом жиров).
Кстати, а если бы сахар был нормален, то о каком заболевании при подобной клинике важно было бы подумать?