Especially glycogen storage disease type IX can be a common cause for ketotic hypoglycemia, with the most common sub-type IXa mainly affecting boys. With glycogen storage disease type XIa, children can usually appear overweight for height, but this is attributed to an enlarged liver (hepatomegaly). Cause There are hundreds of causes of hypoglycemia. Normally, the defensive, physiological response to a falling blood glucose is reduction of insulin secretion to undetectable levels, and release of glucagon, adrenaline, and other counterregulatory hormones. This shift of hormones initiates glycogenolysis and gluconeogenesis in the liver, and lipolysis in adipose tissue. Lipids are metabolized to triglycerides, in turn to fatty acids, which are transformed in the mitochondria of liver and kidney cells to the ketone bodies— acetoacetate, beta-hydroxybutyrate, and acetone. Ketones can be used by the brain as an alternate fuel when glucose is scarce. A high level of ketones in the blood, ketosis, is thus a normal response to hypoglycemia in healthy people of all ages. The presence or absence of ketosis is therefore an important clue to the cause of hypoglycemia in an individual patient. Absence of ketosis ("nonketotic hypoglycemia") most often indicates excessive insulin as the cause of the hypoglycemia. Less commonly, it may indicate a fatty acid oxidation disorder. Natural history Children "outgrow" ketotic hypoglycemia, presumably because fasting tolerance improves as body mass increases. In most the episodes become milder and more infrequent by 4 to 5 years of age and rarely occur after age 9. Onset of hypoglycemia with ketosis after age 5 or persistence after age 7 should elicit referral and an intensive search for a more specific disease. Diagnosis The diagnosis is based on a combination of typical clinical features and exclusion by a pediatric endocrinologist of other causes of "hypoglycemia with ketosis," especially growth hormone deficiency, hypopituitarism, adrenal insufficiency, and identifiable inborn errors of metabolism such as organic acidoses. The most useful diagnostic tests include measurement of insulin, growth hormone, cortisol, and lactic acid at the time of the hypoglycemia. Plasma acylcarnitine levels and urine organic acids exclude some of the important metabolic diseases. When the episodes are recurrent or severe, the definitive test is a hospitalization for a supervised diagnostic fast. This usually demonstrates "accelerated fasting"—a shorter time until the glucose begins to fall, but normal metabolic and counterregulatory responses as the glucose falls. As the glucose reaches hypoglycemic levels, the insulin is undetectable, counterregulatory hormones,