The circumstances of hypoglycemia provide most of the clues to diagnosis. Circumstances include the age of the patient, time of day, time since last meal, previous episodes, nutritional status, physical and mental development, drugs or toxins (especially insulin or other diabetes drugs), diseases of other organ systems, family history, and response to treatment. When hypoglycemia occurs repeatedly, a record or "diary" of the spells over several months, noting the circumstances of each spell (time of day, relation to last meal, nature of last meal, response to carbohydrate, and so forth) may be useful in recognizing the nature and cause of the hypoglycemia.
An especially important aspect is whether the patient is seriously ill with another problem. Severe disease of nearly all major organ systems can cause hypoglycemia as a secondary problem. Hospitalized patients, especially in intensive care units or those prevented from eating, can suffer hypoglycemia from a variety of circumstances related to the care of their primary disease. Hypoglycemia in these circumstances is often multifactorial or even iatrogenic. Once identified, these types of hypoglycemia are readily reversed and prevented, and the underlying disease becomes the primary problem.
Apart from determining nutritional status and identifying whether there is likely to be an underlying disease more serious than hypoglycemia, the physical examination of the patient is only occasionally helpful. Macrosomia in infancy usually indicates hyperinsulinism. A few syndromes and metabolic diseases may be recognizable by clues such as hepatomegaly or micropenis.
It may take longer to recover from severe hypoglycemia with unconsciousness or seizure even after restoration of normal blood glucose. When a person has not been unconscious, failure of carbohydrate to reverse the symptoms in 10–15 minutes increases the likelihood that hypoglycemia was not the cause of the symptoms. When severe hypoglycemia has persisted in a hospitalized patient, the amount of glucose required to maintain satisfactory blood glucose levels becomes an important clue to the underlying etiology. Glucose requirements above 10 mg/kg/minute in infants, or 6 mg/kg/minute in children and adults are strong evidence for hyperinsulinism. In this context this is referred to as the ''glucose infusion rate'' (GIR). Finally, the blood glucose response to glucagon given when the glucose is low can also help distinguish among various types of hypoglycemia. A rise of blood glucose by more than 30 mg/dl (1.70 mmol/l) suggests insulin excess as the probable cause of the hypoglycemia.
In less obvious cases, a "critical sample" may provide the diagnosis. In the majority of children and adults with recurrent, unexplained hypoglycemia, the diagnosis may be determined by obtaining a sample of blood during hypoglycemia. If this critical sample is obtained ''at the time of hypoglycemia, before it is reversed'', it can provide information that would otherwise require a hospital admission and unpleasant starvation testing. Perhaps the most common inadequacy of emergency department care in cases of unexplained hypoglycemia is the failure to obtain at least a basic sample before giving glucose to reverse it.
Part of the value of the critical sample may simply be the proof that the symptoms are indeed due to hypoglycemia. More often, measurement of certain hormones and metabolites at the time of hypoglycemia indicates which organs and body systems are responding appropriately and which are functioning abnormally. For example, when the blood glucose is low, hormones which raise the glucose should be rising and insulin secretion should be completely suppressed.
The following is a brief list of hormones and metabolites which may be measured in a critical sample. Not all tests are checked on every patient. A "basic version" would include insulin, cortisol, and electrolytes, with C-peptide and drug screen for adults and growth hormone in children. The value of additional specific tests depends on the most likely diagnoses for an individual patient, based on the circumstances described above. Many of these levels change within minutes, especially if glucose is given, and there is no value in measuring them after the hypoglycemia is reversed. Others, especially those lower in the list, remain abnormal even after hypoglycemia is reversed, and can be usefully measured even if a critical specimen is missed. Although interpretation in difficult cases is beyond the scope of this article, for most of the tests, the primary significance is briefly noted.
- Glucose: needed to document actual hypoglycemia
- Insulin: any detectable amount is abnormal during hypoglycemia, but physician must know assay characteristics
- Cortisol: should be high during hypoglycemia if pituitary and adrenals are functioning normally
- Growth hormone: should rise after hypoglycemia if pituitary is functioning normally
- Electrolytes and total carbon dioxide: electrolyte abnormalities may suggest renal or adrenal disease; mild acidosis is normal with starvation hypoglycemia; usually no acidosis with hyperinsulinism
- Liver enzymes: elevation suggests liver disease
- Ketones: should be high during fasting and hypoglycemia; low levels suggest hyperinsulinism or fatty acid oxidation disorder
- Beta-hydroxybutyrate: should be high during fasting and hypoglycemia; low levels suggest hyperinsulinism or fatty acid oxidation disorder
- Free fatty acids: should be high during fasting and hypoglycemia; low levels suggest hyperinsulinism; high with low ketones suggests fatty acid oxidation disorder
- Lactic acid: high levels suggest sepsis or an inborn error of gluconeogenesis such as glycogen storage disease
- Ammonia: if elevated suggests hyperinsulinism due to glutamate dehydrogenase deficiency, Reye syndrome, or certain types of liver failure
- C-peptide: should be low or undetectable; if elevated suggests hyperinsulinism; low c-peptide with high insulin suggests exogenous (injected) insulin
- Proinsulin: detectable levels suggest hyperinsulinism; levels disproportionate to a detectable insulin level suggest insulinoma
- Ethanol: suggests alcohol intoxication
- Toxicology screen: can detect many drugs causing hypoglycemia, especially for sulfonylureas
- Insulin antibodies: if positive suggests repeated insulin injection or antibody-mediated hypoglycemia
- Urine organic acids: elevated in various characteristic patterns in several types of organic aciduria
- Carnitine, free and total: low in certain disorders of fatty acid metabolism and certain types of drug toxicity and pancreatic disease
- Thyroxine and TSH: low T4 without elevated TSH suggests hypopituitarism or malnutrition
- Acylglycine: elevation suggests a disorder of fatty acid oxidation
- Epinephrine: should be elevated during hypoglycemia
- Glucagon: should be elevated during hypoglycemia, except in the case of type 1 diabetes mellitus where irreparable damage is done to the cells which produce this counterregulatory hormone.
- IGF-1: low levels suggest hypopituitarism or chronic malnutrition
- IGF-2: low levels suggest hypopituitarism; high levels suggest non-pancreatic tumor hypoglycemia
- ACTH: should be elevated during hypoglycemia; unusually high ACTH with low cortisol suggests Addison's disease
- Alanine or other plasma amino acids: abnormal patterns may suggest certain inborn errors of amino acid metabolism or gluconeogenesis
- Somatostatin should be elevated during hypoglycemia as it acts to inhibit insulin production and increase blood glucose level
Further diagnostic steps
When suspected hypoglycemia recurs and a critical specimen has not been obtained, the diagnostic evaluation may take several paths. However good nutrition and prompt intake is essential.
When general health is good, the symptoms are not severe, and the person can fast normally through the night, experimentation with diet (extra snacks with fat or protein, reduced sugar) may be enough to solve the problem. If it is uncertain whether "spells" are indeed due to hypoglycemia, some physicians will recommend use of a home glucose meter to test at the time of the spells to confirm that glucoses are low. This approach may be most useful when spells are fairly frequent or the patient is confident that he or she can provoke a spell. The principal drawback of this approach is the high rate of false positive or equivocal levels due to the imprecision of the currently available meters: both physician and patient need an accurate understanding of what a meter can and cannot do to avoid frustrating and inconclusive results.
In cases of recurrent hypoglycemia with severe symptoms, the best method of excluding dangerous conditions is often a ''diagnostic fast''. This is usually conducted in the hospital, and the duration depends on the age of the patient and response to the fast. A healthy adult can usually maintain a glucose level above 50 mg/dl (2.8 mM) for 72 hours, a child for 36 hours, and an infant for 24 hours. The purpose of the fast is to determine whether the person can maintain his or her blood glucose as long as normal, and can respond to fasting with the appropriate metabolic changes. At the end of the fast the insulin should be nearly undetectable and ketosis should be fully established. The patient's blood glucose levels are monitored and a critical specimen is obtained if the glucose falls. Despite its unpleasantness and expense, a diagnostic fast may be the only effective way to confirm or refute a number of serious forms of hypoglycemia, especially those involving excessive insulin.
A traditional method for investigating suspected hypoglycemia is the oral glucose tolerance test, especially when prolonged to 3, 4, or 5 hours. Although quite popular in the United States in the 1960s, repeated research studies have demonstrated that many healthy people will have glucose levels below 70 or 60 during a prolonged test, and that many types of significant hypoglycemia may go undetected with it. This combination of poor sensitivity and specificity has resulted in its abandonment for this purpose by physicians experienced in disorders of glucose metabolism.
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