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('''hypoglycaemia''' in
British English ) is a medical term referring to a
Pathologic state produced by a lower than normal level of
Glucose (
Sugar ) in the blood. The term ''hypoglycemia'' literally means "under-sweet blood" (
Gr. ''hypo-'', ''glykys'', ''haima''). Hypoglycemia can produce a variety of symptoms and effects but the principal problems arise from an inadequate supply of glucose as fuel to the
Brain , resulting in impairment of function (
Neuroglycopenia ). Derangements of function can range from vaguely "feeling bad" to
Coma and (rarely) permanent brain damage or death. Hypoglycemia can arise from many causes and can occur at any age. The most common forms of moderate and severe hypoglycemia occur as a complication of treatment of
Diabetes Mellitus with
Insulin or
Oral Medications . Hypoglycemia is usually treated by the ingestion or administration of glucose, or foods digestible to glucose.
Endocrinologist s (specialists in disorders of glucose
Metabolism ) typically consider the following criteria (referred to as
Whipple's Triad ) as proving that an individual's
Symptom s can be attributed to hypoglycemia:
#Symptoms known to be caused by hypoglycemia
#Low glucose at the time the symptoms occur
#Reversal or improvement of symptoms or problems when the glucose is restored to normal
However, not everyone has accepted these suggested diagnostic criteria, and even the level of glucose low enough to define hypoglycemia has been a source of controversy in several contexts. For many purposes,
Plasma glucose levels below 70 mg/dl or 3.9 mmol/L are considered hypoglycemic, but these issues are elaborated in more detail below.
No single glucose value alone serves to define the medical condition termed hypoglycemia for all people and purposes. Throughout the 24 hour cycles of eating, digestion, and fasting,
Blood Plasma glucose levels are generally maintained within a range of 70-140 mg/dL (3.9-7.8 mmol/L) for healthy humans.
1 Although 60 or 70 mg/dL (3.3 or 3.9 mmol/L) is commonly cited as the lower limit of normal glucose, different values (typically below 40, 50, 60, or 70 mg/dL) have been defined as low for different populations, clinical purposes, or circumstances.
The precise level of glucose considered low enough to define hypoglycemia is dependent on (1) the measurement method, (2) the age of the person, (3) presence or absence of effects, and (4) the purpose of the definition. While there is no disagreement as to the normal range of blood sugar, debate continues as to what degree of hypoglycemia warrants medical evaluation or treatment, or can cause harm.
234
This article expresses glucose in milligrams per deciliter (mg/dL or mg/100 mL) as is customary in the United States, while millimoles per
Litre (mmol/L or mM) are the
SI (International System) units used in most of the rest of the world. Glucose concentrations expressed as mg/dL can be converted to mmol/L by dividing by 18. For example, a glucose concentration of 90 mg/dL is 5 mmol/L or 5 mM.
Blood Glucose levels discussed in this article are
Venous Plasma Or Serum levels measured by standard, automated
Glucose Oxidase methods used in
Medical Laboratories . For clinical purposes, plasma and serum levels are similar enough to be interchangeable.
Arterial plasma or serum levels are slightly higher than venous levels, and
Capillary levels are typically in between.
5 This difference between arterial and venous levels is small in the fasting state but is amplified and can be greater than 10% in the postprandial state.
6 On the other hand, whole blood glucose levels (e.g., by
Fingerprick Meters ) are about 10%-15% lower than venous plasma levels.
7 Furthermore, available
Fingerstick Glucose Meter s are only warranted to be accurate to within 15% of a simultaneous laboratory value under optimal conditions, and home use in the investigation of hypoglycemia is fraught with misleading low numbers.
89 In other words, a meter glucose reading of 39 mg/dL could be properly obtained from a person whose laboratory serum glucose was 53 mg/dL; even wider variations can occur with "real world" home use.
Two other factors significantly affect glucose measurement: hematocrit and delay after phlebotomy. The disparity between venous and whole blood concentrations is greater when the
Hematocrit is high,
10 as in newborn infants, or adults with
Polycythemia . High neonatal hematocrits are particularly likely to confound glucose measurement by meter. Second, unless the specimen is drawn into a
Fluoride tube or processed immediately to separate the serum or plasma from the cells, the measurable glucose will be gradually lowered by ''in vitro'' metabolism of the glucose at a rate of approximately 7 mg/dL/hr, or even more in the presence of
Leukocytosis .
111213
Surveys of healthy children and adults show that plasma glucoses below 60 mg/dL (3.3 mM) or above 100 mg/dL (5.6 mM) are found in less than 5% of samples after an overnight fast.
14 In infants and young children up to 10% have been found to be below 60 mg/dL after an overnight fast. As the duration of fasting is extended, plasma glucose levels can fall further, even in healthy people. In other words, many healthy people can occasionally have glucose levels in the hypoglycemic range without symptoms or disease.
The normal range of newborn blood sugars continues to be debated. Surveys and experience have revealed blood sugars often below 40 mg/dL (2.2 mM), rarely below 30 mg/dL (1.7 mM), in apparently healthy full-term infants on the first day of life. It has been proposed that newborn brains are able to use alternate fuels when glucose levels are low more readily than adults. Experts continue to debate the significance and risk of such levels, though the trend has been to recommend maintenance of glucose levels above 60-70 mg/dL after the first day of life. In ill,
Undersized , or
Premature newborns, low blood sugars are even more common, but there is a consensus that sugars should be maintained at least above 50 mg/dL (2.8 mM) in such circumstances. Some experts advocate 70 mg/dL as a therapeutic target, especially in circumstances such as
Hyperinsulinism where alternate fuels may be less available.
Research in healthy adults shows that mental efficiency declines slightly but measurably as blood glucose falls below 65 mg/dL (3.6 mM) in many people.
Hormonal defense mechanisms (
Adrenaline and
Glucagon ) are activated as it drops below a threshold level (about 55 mg/dL for most people), producing the typical
Symptom s of shakiness and
Dysphoria . On the other hand, obvious impairment does not often occur until the glucose falls below 40 mg/dL, and up to 10% of the population may occasionally have glucose levels below 65 in the morning without apparent effects. Brain effects of hypoglycemia, termed
Neuroglycopenia , determine whether a given low glucose is a "problem" for that person, and hence some people tend to use the term ''hypoglycemia'' only when a moderately low glucose is accompanied by symptoms.
Even this criterion is complicated by the facts that hypoglycemic symptoms are vague and can be produced by other conditions, that people with persistently or recurrently low glucose levels can lose their threshold symptoms so that severe neuroglycopenic impairment can occur without much warning, and that many of our measurement methods (especially
Glucose Meter s) are imprecise at low levels.
Diabetic Hypoglycemia represents a special case with respect to the relationship of measured glucose and hypoglycemic symptoms for several reasons. Although home
Glucose Meter readings are sometimes misleading, the probability that a low reading accompanied by symptoms represents real hypoglycemia is higher in a person who takes insulin. Second, the hypoglycemia has a greater chance of progressing to more serious impairment if not treated, compared to most other forms of hypoglycemia that occur in adults. Third, because glucose levels are above normal most of the time in people with diabetes, hypoglycemic symptoms may occur at higher thresholds than in people who are normoglycemic most of the time. For all of these reasons, people with diabetes usually use higher meter glucose thresholds to determine hypoglycemia.
For all of the reasons explained in the above paragraphs, deciding whether a blood glucose in the borderline range of 45-75 mg/dL (2.5-4.2 mM) represents clinically problematic hypoglycemia is not always simple. This leads people to use different "cutoff levels" of glucose in different contexts and for different purposes.
Like most animal tissues,
Brain Metabolism depends primarily on glucose for fuel in most circumstances. A limited amount of glucose can be derived from
Glycogen stored in
Astrocyte s, but it is consumed within minutes. For most practical purposes, the brain is dependent on a continual supply of glucose diffusing from the blood into the interstitial tissue within the
Central Nervous System and into the
Neuron s themselves.
Therefore, if the amount of glucose supplied by the blood falls, the brain is one of the first organs affected. In most people, subtle reduction of mental efficiency can be observed when the glucose falls below 65 mg/dl (3.6 mM). Impairment of action and judgement usually becomes obvious below 40 mg/dl (2.2 mM).
Seizure s may occur as the glucose falls further. As blood glucose levels fall below 10 mg/dl (0.55 mM), most neurons become electrically silent and nonfunctional, resulting in
Coma . These brain effects are collectively referred to as
Neuroglycopenia .
The importance of an adequate supply of glucose to the brain is apparent from the number of
Nervous ,
Hormonal and metabolic responses to a falling glucose. Most of these are defensive or adaptive, tending to raise the blood sugar via
Glycogenolysis and
Gluconeogenesis or provide alternative fuels.
Brief or mild hypoglycemia produces no lasting effects on the brain, though it can temporarily alter brain responses to additional hypoglycemia. Prolonged, severe hypoglycemia can produce lasting damage of a wide range. This can include impairment of cognitive function, motor control, or even consciousness. The likelihood of permanent brain damage from any given instance of severe hypoglycemia is difficult to estimate, and depends on a multitude of factors such as age, recent blood and brain glucose experience, concurrent problems such as hypoxia, and availability of alternative fuels. The vast majority of symptomatic hypoglycemic episodes result in no detectable permanent harm.
15
Hypoglycemic symptoms and manifestations can be divided into those produced by the counterregulatory hormones (
Adrenaline and
Glucagon ) triggered by the falling glucose, and the neuroglycopenic effects produced by the reduced brain sugar.
- Abnormal mentation, impaired judgement
- Nonspecific Dysphoria , Anxiety , moodiness, depression, crying
- Negativism, irritability, belligerence, combativeness, Rage
- change, emotional lability
- Fatigue , weakness, apathy, Lethargy , daydreaming, Sleep
- Confusion, Amnesia , dizziness, Delirium
- Staring, "glassy" look, blurred vision, Double Vision
- Automatic behavior, also known as Automatism
- Difficulty speaking, slurred speech
- Ataxia , incoordination, sometimes mistaken for " Drunkenness "
- Focal or general motor deficit, Paralysis , Hemiparesis
- Paresthesia s, Headache
- Stupor, Coma , abnormal breathing
- Generalized or focal Seizure s
Not all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by severity of the hypoglycemia. In young children vomiting often accompanies morning hypoglycemia with
Ketosis . In older children and adults, moderately severe hypoglycemia can resemble
Mania , mental illness,
Drug Intoxication , or
Drunkenness . In the elderly, hypoglycemia can produce focal
Stroke -like effects or a hard-to-define malaise. The symptoms of a single person do tend to be similar from episode to episode.
In newborns, hypoglycemia can produce irritability, jitters,
Myoclonic Jerk s,
Cyanosis , respiratory distress,
Apneic episodes, sweating,
Hypothermia , somnolence,
Hypotonia , refusal to feed, and seizures or "spells". Hypoglycemia can resemble
Asphyxia ,
Hypocalcemia ,
Sepsis , or
Heart Failure .
In both young and old patients, the brain may habituate to low glucose levels, with a reduction of noticeable symptoms despite neuroglycopenic impairment. In insulin-dependent diabetic patients this phenomenon is termed ''hypoglycemia unawareness'' and is a significant clinical problem when improved
Glycemic Control is attempted. Another aspect of this phenomenon occurs in
Type I Glycogenosis , when chronic hypoglycemia before diagnosis may be better tolerated than acute hypoglycemia after treatment is underway.
Nearly always, hypoglycemia severe enough to cause seizures or unconsciousness can be reversed without obvious harm to the brain. Cases of death or permanent neurological damage occurring with a single episode have usually involved prolonged, untreated unconsciousness, interference with breathing, severe concurrent disease, or some other type of vulnerability. Nevertheless, brain damage or death has occasionally resulted from severe hypoglycemia.
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
# a of blood obtained at the time of hypoglycemia, before it is reversed.
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.
Hospital ized patients, especially in
Intensive Care Unit s 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
Syndrome s and
Metabolic Diseases may be recognizable by clues such as
Hepatomegaly or
Micropenis .
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. 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 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 is obtained ''at the time of hypoglycemia, before it is reversed'', it can provide information that would otherwise require a several-thousand-dollar
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,
Hormone s 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
- Electrolyte s 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
- Ketone s: 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 undetectable; if elevated suggests hyperinsulinism; low c-peptide with high insulin suggests exogenous (injected) insulin
- Proinsulin : detectable levels suggest hyperinsulinism; levels disproportionate to a detectabe insulin level suggest insulinoma
- Ethanol : suggests alcohol intoxication
- s
- Insulin Antibodies : if positive suggests repeated insulin injection or antibody-mediated hypoglycemia
- 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
- 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 Acid s: abnormal patterns may suggest certain inborn errors of amino acid metabolism or gluconeogenesis
When suspected hypoglycemia recurs and a critical specimen has not been obtained, the diagnostic evaluation may take several paths.
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.
There are several ways to classify hypoglycemia. The following is a list of the more common causes and factors which may contribute to hypoglycemia grouped by age, followed by some causes that are relatively age-independent. See
Causes Of Hypoglycemia for a more complete list grouped by etiology.
Hypoglycemia is a common problem in critically ill or extremely low birthweight infants. If not due to maternal hyperglycemia, in most cases it is multifactorial, transient and easily supported. In a minority of cases hypoglycemia turns out to be due to significant hyperinsulinism, hypopituitarism or an inborn error of metabolism and presents more of a management challenge.
Single episodes of hypoglycemia due to gastroenteritis or fasting, but recurrent episodes nearly always indicate either an
Inborn Error Of Metabolism , congenital hypopituitarism, or congenital hyperinsulinism
By far the most common cause of severe hypoglycemia in this age range is insulin injected for
Type 1 Diabetes . Circumstances should provide clues fairly quickly for the new diseases causing severe hypoglycemia. All of the congenital metabolic defects, congenital forms of hyperinsulinism, and congenital hypopituitarism are likely to have already been diagnosed or are unlikely to start causing new hypoglycemia at this age. Body mass is large enough to make starvation hypoglycemia and idiopathic
Ketotic Hypoglycemia quite uncommon. Recurrent mild hypoglycemia may fit a
Reactive Hypoglycemia pattern, but this is also the peak age for
Idiopathic Postprandial Syndrome , and recurrent "spells" in this age group can be traced to
Orthostatic Hypotension or
Hyperventilation as often as demonstrable hypoglycemia.
The incidence of hypoglycemia due to complex drug interactions, especially involving
Oral Hypoglycemic Agent s and insulin for diabetes rises with age. Though much rarer, the incidence of insulin-producing tumors also rises with advancing age. Most tumors causing hypoglycemia by mechanisms other than insulin excess occur in adults.
