Differential Diagnosis Of Hypoglycemia Research Articles

Respiratory Chain Defects May Present Only with Hypoglycemia

Hypoglycemia occasionally results from oxidative phosphorylation deficiency, associated with liver failure. Conversely, in some cases of respiratory chain defect, the impairment in glucose metabolism occurs with normal hepatic function. The mechanism for this hypoglycemia remains poorly understood. We report here three unrelated children with hypoglycemia as the presenting symptom associated with oxidative phosphorylation deficiency but without liver dysfunction. Two patients had, respectively, complex III and complex IV deficiency and presented with long fast hypoglycemia. During a fasting test, the first patient showed evidence for impaired gluconeogenesis (progressive increase of plasma lactate and no decrease of alanine levels), whereas the second patient appeared to have impaired fatty acid oxidation (hypoketotic hypoglycemia with increased levels of non esterified fatty acids). The third patient presented with both long and short fast hypoglycemia related to complex IV deficiency. The mechanism of hypoglycemia for this patient may have been partly related to GH insufficiency, whereas impaired glycogen metabolism possibly accounted for short fast hypoglycemia. We suggest that hypoglycemia can be the presenting symptom for respiratory chain defects, through the possible reduction in cofactors resulting from oxidative phosphorylation deficiency, and that respiratory chain defects should therefore be considered in the differential diagnosis of hypoglycemia.

Genetic disorders of mitochondrial fatty acid oxidation

Genetic diseases of mitochondrial fatty acid oxidation have recently emerged as important disorders to consider in the differential diagnosis of hypoglycemia, cardiomyopathy, or skeletal muscle weakness in infants and children. A total of 16 different defects have been identified over the past decade that involve almost all of the possible enzyme steps in the pathway. One of these disorders, medium-chain acyl-coenzyme A dehydrogenase deficiency has a frequency as high as 1 in 10,000 births and is the single most common genetic defect of intermediary metabolism. The disorders are frequently mistaken for Reye syndrome or sudden infant death syndrome. Improved methods have simplified the diagnosis of some of the fatty acid oxidation defects. However, recognition of these disorders remains challenging. Rapid advances have continued to be made over the past year in defining clinical phenotypes, diagnostic methods, and therapeutic strategies. Familiarity with this new group of disorders is becoming increasingly important for general pediatricians as well as subspecialists in metabolism, endocrinology, gastroenterology, cardiology, neurology, and genetics.

Differential diagnosis of hypoglycemia in children by responses to fasting and 2-deoxyglucose

The potential usefulness of the fasting test and the 2-deoxyglucose (2DG) test for differential diagnosis of childhood hypoglycemia was evaluated by comparing responses to these tests in control children and in 28 children with confirmed hypoglycemia from either known or undifferentiated causes. Twelve hypoglycemic subjects with independently established endocrine or metabolic disorders became definitely hypoglycemic within 24 hours of fasting. The diagnosis of hyperinsulinism was confirmed in four by the consistent finding of elevated fasting plasma insulin levels (greater than 4 μU/mL with glucose less than 40 mg/dL); the fasting levels of plasma β-hydroxybutyrate (BOHB) and free fatty acids (FFA) were low relative to glucose, but these abnormalities were variable and not specific to hyperinsulinism. In a single subject with idiopathic adrenal cortical insufficiency cortisol remained unusually low (less than 2 μg/dL) in both tests. Neither test distinguished two children with growth hormone deficiency. In two children with defective gluconeogenesis (glucose-6-phosphatase deficiency), the fasting plasma alanine level was distinctively high relative to glucose. A patient with defective ketogenesis due to carnitine deficiency had an abnormally low plasma BOHB level associated with a high FFA level. Among the 16 subjects with undifferentiated hypoglycemia, only nine became hypoglycemic within 24 hours of fasting; three remained within the control range even after 36 hours. After receiving 2DG (50 mg/kg), 11 of these children responded subnormally with an increase of plasma glucose less than 15 mg/dL, including all of the subjects who failed to become hypoglycemic within 24 hours of fasting. One subject with an undifferentiated cause had a definitely elevated insulin level during fasting hypoglycemia. Epinephrine deficiency was the most common finding among the subjects with undifferentiated causes (five cases). This was established by subnormal urine epinephrine responses to both fasting hypoglycemia and 2DG stimulation (less than 80 ng/mg creatinine) and by a lack of an increase in the levels of plasma glucose, FFA, BOHB, and lactate after 2DG. Three other subjects had diminished epinephrine and metabolic responses to 2DG but the epinephrine responses to fasting and 2DG were inconsistent. No subjects were identified with glucagon deficiency. Plasma alanine and glucose levels were proportionately decreased in all of the undifferentiated subjects. An abnormally low alanine level was not characteristic of any particular subgroup. None of the hypoglycemic children were abnormally ketotic, in that the plasma BOHB level was not unusually high relative to glucose. After these tests seven of the 16 children remained undifferentiated with no specific endocrine or metabolic abnormality identified. It is concluded that fasting is the most useful test for confirming diagnoses of hyperinsulinism and inherited disorders of gluconeogenesis or ketogenesis. The 2DG test is valuable for the detection of epinephrine unresponsiveness, which is the most common abnormality found among children with undifferentiated hypoglycemia. The combined use of these tests makes it unnecessary to extend fasting for more than 24 hours.

Metabolic and hormonal responses of children and adolescents to fasting and 2-deoxyglucose

In order to provide age related reference values that would be useful in the differential diagnosis of hypoglycemia in a pediatric population, substrate and hormonal responses to fasting and to acute hypoglycemia were characterized in a group of children and adolescents who did not have hypoglycemia. The subjects were retrospectively divided into younger children, aged 2 to 8 years, and older subjects, aged 10 to 18 years, on the basis of significant differences in responses to these tests. After fasting for approximately 36 hours, plasma glucose levels were significantly lower in eight younger children than in six older subjects (48 ± 8 v 69 ± 13 mg/dl, ± SD); free fatty acids (FFA) were higher (2.3 ± 0.7 v 1.5 ± 0.4 mmol/L), and β-hydroxybutyrate (BOHB) was higher (3.8 ± 0.4 v 2.1 ± 0.7 mmol/L). These differences are proportionate to correlations between the average concentrations of plasma glucose and FFA ( r = −0.92), BOHB ( r = −0.98), and alanine ( r = 0.85), and between BOHB and FFA ( r = 0.97). In the younger children plasma insulin decreased to a significantly lower level (1.7 ± 0.6 v 4.8 ± 1.3 μU/mL), and two- to three-fold increases were found in levels of urinary epinephine, plasma glucagon, and serum cortisol, which did not occur in the older children. In contrast, following simulation of acute hypoglycemia by administration of 2-deoxyglucose (2DG) (50 mg/kg intravenously), the increase of plasma glucose after one hour was significantly less in nine younger than in six older children (32 ± 12 v 57 ± 25 mg/dL), as was the increase in lactate (0.4 ± 0.3 v 1.0 ± 0.8 mmol/L). In both groups there was an eight-fold increase of urinary epinephrine and a two-fold increase of serum cortisol after 2DG, while insulin increased only slightly and glucagon and growth hormone did not change. It is concluded that there are generally greater metabolic and hormonal responses associated with fasting in younger children than there are in older children, and this is related to lower plasma glucose. The responses of older children are similar to adults. After acute simulated hypoglycemia, however, the increases of glucose and lactate are less in younger children in spite of a similarly large increase of epinephrine. These differences may be related to earlier depletion of available glycogen in younger children. Both tests have potential usefulness in the evaluation of hypoglycemia.

Diagnostic use of glucagon-induced insulin response. Studies in patients with insulinoma or other hypoglycemic conditions.

The intravenous glucagon stimulation test was assessed as a diagnostic tool in the differential diagnosis of hypoglycemia. Six of seven patients with insulinoma had peak insulin values over 130 µU/ml. None of the controls with normal weight or patients with hypoglycemia as a result of other causes had a peak insulin value over 98 µU/ml. In this study and in glucagon tests done by other investigators, the peak insulin responses occurred from 3 to 30 minutes after injection of glucagon. Since this peak is highly transient it may be missed unless sampling is done every 5 minutes for at least 30 minutes. When done properly, this test was positive in over 80% of insulinoma patients. False-negative results occur in patients treated with diazoxide, hydrochlorothiazide, or diphenylhydantoin. False-positive tests may be seen in individuals who are obese or treated with tolbutamide.

Islet Cell Carcinoma of the Pancreas

ISLET cell tumors are not common, but they occur frequently enough to be considered in the differential diagnosis of hypoglycemia and of tumors of the pancreas. Many of these tumors do not cause symptoms and are found only at necropsy. Lopez-Kruger and Dockerty¹reported 44 cases of islet cell tumor which were found in 10,314 consecutive necropsies performed in the routine manner. Eight of these tumors were functioning adenomas. In 500 consecutive examinations of necropsy specimens of the pancreas, Pease²found 8 small nonfunctioning adenomas. About 20 per cent of islet cell tumors are of the functioning type which produce the clinical picture of hyperinsulinism.³This group has received considerable attention since Wilder et al.⁴reported the first case in 1929. About 10 per cent metastasize to the liver, lymph nodes, or surrounding structures.⁵For those patients who have lesions which metastasize, the average period

Hypoglycemia

Summaryo1.In the study of the patient with hypoglycemia, consideration of the physiologic mechanisms which may produce low blood glucose levels is of help in the differential diagnosis of the cause of the hypoglycemia.2.Hypoglycemia is a symptom, not a disease, and the detection of low blood glucose levels is an urgent indication for investigation of the cause of the low blood glucose level.3.The organic hypoglycemias are characterized by prolonged, progressively severe hypoglycemic episodes of slow onset while fasting, with hypoglycemia unresponsiveness.4.The functional hypoglycemias are characterized by brief, nonprogressive hypoglycemia occuring after meals. Hypoglycemia responsiveness is normal.5.Painstaking use of oral and intravenous glucose tolerance tests, the intravenous insulin tolerance test and prolonged fasts aid in the differential diagnosis of hypoglycemia.6.New causes of hypoglycemia continue to be recognized. Careful study of these types of hypoglycemia has yielded information of physiologic, diagnostic and therapeutic importance. Some of these types of hypoglycemia have been described briefly. In the study of the patient with hypoglycemia, consideration of the physiologic mechanisms which may produce low blood glucose levels is of help in the differential diagnosis of the cause of the hypoglycemia. Hypoglycemia is a symptom, not a disease, and the detection of low blood glucose levels is an urgent indication for investigation of the cause of the low blood glucose level. The organic hypoglycemias are characterized by prolonged, progressively severe hypoglycemic episodes of slow onset while fasting, with hypoglycemia unresponsiveness. The functional hypoglycemias are characterized by brief, nonprogressive hypoglycemia occuring after meals. Hypoglycemia responsiveness is normal. Painstaking use of oral and intravenous glucose tolerance tests, the intravenous insulin tolerance test and prolonged fasts aid in the differential diagnosis of hypoglycemia. New causes of hypoglycemia continue to be recognized. Careful study of these types of hypoglycemia has yielded information of physiologic, diagnostic and therapeutic importance. Some of these types of hypoglycemia have been described briefly.

The differential diagnosis of hypoglycemia.

The differential diagnosis of hypoglycemia.