Determining the cause Hundreds of conditions can cause hypoglycemia. Common causes by age are
listed below. While many aspects of the
medical history and
physical examination may be informative, the two best guides to the cause of
unexplained hypoglycemia are usually
- the circumstances
- a critical sample of blood obtained at the time of hypoglycemia,
before it is reversed.
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.
ospitalized
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
yndromes
and
metabolic diseases may be recognizable by clues such as
hepatomegaly or
icropenis.
Response to treatment, especially the amount of carbohydrate needed to
reverse or prevent recurrence of hypoglycemia, may provide important clues as
well. When 15-30 grams of sugar or starch are given by mouth, a low blood
glucose will usually rise by 18-36 mg/dl (1-2 mmol/l) within 5-10 minutes,
relieving hypoglycemic symptoms within 10 minutes[itation
needed]. 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 several-thousand-dollar
ospital
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.
- lucose:
needed to document actual hypoglycemia
- nsulin:
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
cidosis
is normal with starvation hypoglycemia; usually no acidosis with
hyperinsulinism
-
Liver enzymes: elevation suggests liver disease
- etones:
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
- mmonia:
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
- thanol:
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 SH:
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
- lanine
or other plasma
mino
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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