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==Laboratory Findings==
==Laboratory Findings==
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 [[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.
*[[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
*[[Toxicology]] screen: can detect many drugs causing hypoglycemia, especially for [[sulfonylurea]]s
*[[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
*[[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
===Defining Hypoglycemia===
===Defining Hypoglycemia===
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.<ref name=Koh_1988>{{cite journal |author=Koh TH, Eyre JA, Aynsley-Green A |title=Neonatal hypoglycaemia--the controversy regarding definition |journal=Arch. Dis. Child. |volume=63 |issue=11 |pages=1386-8 |year=1988 |pmid=3202648}}</ref><ref name=Cornblath_1990>{{cite journal |author=Cornblath M, Schwartz R, Aynsley-Green A, Lloyd JK |title=Hypoglycemia in infancy: the need for a rational definition. A Ciba Foundation discussion meeting |journal=Pediatrics |volume=85 |issue=5 |pages=834-7 |year=1990 |pmid=2330247}}</ref><ref name=Cornblath_2000>{{cite journal |author=Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz R, Kalhan SC |title=Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds |journal=Pediatrics |volume=105 |issue=5 |pages=1141-5 |year=2000 |pmid=10790476}}</ref>
Hypoglycemia can't be diagnosed only according to blood glucose level because it is misleading maneuver with high false positive results.The measurement should be repeated using a collection tube that contains an inhibitor of glycolysis and processing should not be delayed.
This article expresses glucose in milligrams per deciliter (mg/dL or mg/100 mL) as is customary in the United States, while millimoles per liter (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.
====Measurement Method====
[[Blood glucose]] levels discussed in this article are [[vein|venous]] [[Blood plasma|plasma or serum]] levels measured by standard, automated [[glucose oxidase]] methods used in [[medical laboratory|medical laboratories]]. For clinical purposes, plasma and serum levels are similar enough to be interchangeable. [[Artery|Arterial]] plasma or serum levels are slightly higher than venous levels, and [[capillary]] levels are typically in between.<ref name=Tustison>{{cite journal |author=Tustison WA, Bowen AJ, Crampton JH |title=Clinical interpretation of plasma glucose values |journal=Diabetes |volume=15 |issue=11 |pages=775-7 |year=1966 |pmid=5924610 |doi=}}</ref> 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.<ref>{{cite book |author=[edited by] John Bernard Henry |title=Clinical diagnosis and management by laboratory methods |publisher=Saunders |location=Philadelphia |year=1979 |pages= |isbn=0-7216-4639-5 |oclc= |doi=}}</ref> On the other hand, whole blood glucose levels (e.g., by [[glucose meter|fingerprick meters]]) are about 10%-15% lower than venous plasma levels.<ref name=Tustison>{{cite journal |author=Tustison WA, Bowen AJ, Crampton JH |title=Clinical interpretation of plasma glucose values |journal=Diabetes |volume=15 |issue=11 |pages=775-7 |year=1966 |pmid=5924610 |doi=}}</ref> Furthermore, available finger stick [[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.<ref name=Clarke_1987>{{cite journal |author=Clarke WL, Cox D, Gonder-Frederick LA, Carter W, Pohl SL |title=Evaluating clinical accuracy of systems for self-monitoring of blood glucose |journal=Diabetes Care |volume=10 |issue=5 |pages=622-8 |year=1987 |pmid=3677983}}</ref><ref name=Gama_2000>{{cite journal |author=Gama R, Anderson NR, Marks V |title='Glucose meter hypoglycaemia': often a non-disease |journal=Ann. Clin. Biochem. |volume=37 ( Pt 5) |issue= |pages=731-2 |year=2000 |pmid=11026531}}</ref> 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,<ref>{{cite book |author=[edited by] John Bernard Henry |title=Clinical diagnosis and management by laboratory methods |publisher=Saunders |location=Philadelphia |year=1979 |pages= |isbn=0-7216-4639-5 |oclc= |doi=}}</ref> 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 [[sodium fluoride|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]].<ref name=dePasqua_1984>{{cite journal |author=de Pasqua A, Mattock MB, Phillips R, Keen H |title=Errors in blood glucose determination |journal=Lancet |volume=2 |issue=8412 |pages=1165 |year=1984 |pmid=6150231}}</ref><ref name=Horwitz_1989>{{cite journal |author=Horwitz DL |title=Factitious and artifactual hypoglycemia |journal=Endocrinol. Metab. Clin. North Am. |volume=18 |issue=1 |pages=203-10 |year=1989 |pmid=2645127}}</ref><ref>{{cite book |author=[edited by] John Bernard Henry |title=Clinical diagnosis and management by laboratory methods |publisher=Saunders |location=Philadelphia |year=1979 |pages= |isbn=0-7216-4639-5 |oclc= |doi=}}</ref>
So, Dependence on three characters to diagnose hypoglycemia is the accepted method. It is called Whipple's triad which includes
* Symptoms of hypoglycemia
* A low plasma glucose concentration corellated with symptoms.
* Correction of glucose level relieves symptoms.
Strategy is to seek Whipple's triad under conditions in which hypoglycemia would be expected:
* If the symptoms occur in the fasting state, that evaluation should be performed during fasting.
* If there is a compelling history of postprandial symptoms, it is reasonable to seek Whipple's triad with frequent, timed plasma glucose measurements and recording of any symptoms after a mixed meal.  
* All of the following should be measured:
 
* Glucose: plasma glucose should be <55 mg/dL.
* Insulin
* C-peptide
* Proinsulin
* Sulfonylurea and meglitinide screen
* Beta-hydroxybutyrate
Fasting evaluation:
* If prolonged fasting may result in an episode of symptomatic hypoglycemia, plasma glucose should be measured repeatedly during fasting.
* If symptoms occur and hypoglycemia is documented, the other tests mentioned above should be performed.
* If the results are equivocal so patient needs another confirmatry test such as the 72-hour fast.
Mixed-meal evaluation:
* If symptoms appear within 5 hours after meals, we should suspect postprandial hypoglycemia.[2]  
* Recurrent sampling before and after meals for the following 5 hours will help diagnosis; If severe symptoms occur, the samples for glucose should be analyzed.
* If Whipple's triad is demonstrated, sulfonylureas, meglitinides, and antibodies to insulin should also be measured.
24-hour fasting
* Increased release of glucagon, epinephrine and cortisol is the most important factors that keep blood glucose concentrations from falling during fasting.
* Gluconeogenesis is the most important factor of glucose production after prolonged fast[4].
* If there is high level of insulin, gluconeogenesis will be inhibited causing hypoglycemia during fasting.
The fast is ended when:  [1,2]
* 72 hours have passed
* Plasma glucose concentration is ≤45 mg/dL
* Patient has symptoms or signs of hypoglycemia
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.<ref name="Koh_1988">{{cite journal |author=Koh TH, Eyre JA, Aynsley-Green A |title=Neonatal hypoglycaemia--the controversy regarding definition |journal=Arch. Dis. Child. |volume=63 |issue=11 |pages=1386-8 |year=1988 |pmid=3202648}}</ref><ref name="Cornblath_1990">{{cite journal |author=Cornblath M, Schwartz R, Aynsley-Green A, Lloyd JK |title=Hypoglycemia in infancy: the need for a rational definition. A Ciba Foundation discussion meeting |journal=Pediatrics |volume=85 |issue=5 |pages=834-7 |year=1990 |pmid=2330247}}</ref><ref name="Cornblath_2000">{{cite journal |author=Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz R, Kalhan SC |title=Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds |journal=Pediatrics |volume=105 |issue=5 |pages=1141-5 |year=2000 |pmid=10790476}}</ref>
====Age Differences====
====Age Differences====
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.<ref name="Meites">{{cite book |author=Samuel Meites, editor-in-chief; contributing editors, Gregory J. Buffone... [et al.] |title=Pediatric clinical chemistry: reference (normal) values |publisher=AACC Press |location=Washington, D.C |year=1989 |pages= |isbn=0-915274-47-7 |oclc= |doi=}}</ref> 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.
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.<ref name="Meites">{{cite book |author=Samuel Meites, editor-in-chief; contributing editors, Gregory J. Buffone... [et al.] |title=Pediatric clinical chemistry: reference (normal) values |publisher=AACC Press |location=Washington, D.C |year=1989 |pages= |isbn=0-915274-47-7 |oclc= |doi=}}</ref> 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 after birth. 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 after birth. 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 [[hyperinsulinemic hypoglycemia|hyperinsulinism]] where alternate fuels may be less available.
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 after birth. 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 after birth. 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 [[hyperinsulinemic hypoglycemia|hyperinsulinism]] where alternate fuels may be less available.
====Presence or Absence of Effects====
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. [[hormone|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 A) hypoglycemic symptoms are vague and can be produced by other conditions; B) people with persistently or recurrently low glucose levels can lose their threshold symptoms so that severe neuroglycopenic impairment can occur without much warning; and C) 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.
====Purpose of Definition====
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.


==References==
==References==

Revision as of 20:15, 13 July 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Laboratory Findings

Defining Hypoglycemia

Hypoglycemia can't be diagnosed only according to blood glucose level because it is misleading maneuver with high false positive results.The measurement should be repeated using a collection tube that contains an inhibitor of glycolysis and processing should not be delayed.

So, Dependence on three characters to diagnose hypoglycemia is the accepted method. It is called Whipple's triad which includes

  • Symptoms of hypoglycemia
  • A low plasma glucose concentration corellated with symptoms.
  • Correction of glucose level relieves symptoms.

Strategy is to seek Whipple's triad under conditions in which hypoglycemia would be expected:

  • If the symptoms occur in the fasting state, that evaluation should be performed during fasting.
  • If there is a compelling history of postprandial symptoms, it is reasonable to seek Whipple's triad with frequent, timed plasma glucose measurements and recording of any symptoms after a mixed meal.
  • All of the following should be measured:
  • Glucose: plasma glucose should be <55 mg/dL.
  • Insulin
  • C-peptide
  • Proinsulin
  • Sulfonylurea and meglitinide screen
  • Beta-hydroxybutyrate

Fasting evaluation:

  • If prolonged fasting may result in an episode of symptomatic hypoglycemia, plasma glucose should be measured repeatedly during fasting.
  • If symptoms occur and hypoglycemia is documented, the other tests mentioned above should be performed.
  • If the results are equivocal so patient needs another confirmatry test such as the 72-hour fast.

Mixed-meal evaluation:

  • If symptoms appear within 5 hours after meals, we should suspect postprandial hypoglycemia.[2]
  • Recurrent sampling before and after meals for the following 5 hours will help diagnosis; If severe symptoms occur, the samples for glucose should be analyzed.
  • If Whipple's triad is demonstrated, sulfonylureas, meglitinides, and antibodies to insulin should also be measured.

24-hour fasting

  • Increased release of glucagon, epinephrine and cortisol is the most important factors that keep blood glucose concentrations from falling during fasting.
  • Gluconeogenesis is the most important factor of glucose production after prolonged fast[4].
  • If there is high level of insulin, gluconeogenesis will be inhibited causing hypoglycemia during fasting.

The fast is ended when: [1,2]

  • 72 hours have passed
  • Plasma glucose concentration is ≤45 mg/dL
  • Patient has symptoms or signs of hypoglycemia

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.[1][2][3]

Age Differences

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.[4] 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 after birth. 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 after birth. 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.

References

  1. ↑ Koh TH, Eyre JA, Aynsley-Green A (1988). "Neonatal hypoglycaemia--the controversy regarding definition". Arch. Dis. Child. 63 (11): 1386–8. PMID 3202648.
  2. ↑ Cornblath M, Schwartz R, Aynsley-Green A, Lloyd JK (1990). "Hypoglycemia in infancy: the need for a rational definition. A Ciba Foundation discussion meeting". Pediatrics. 85 (5): 834–7. PMID 2330247.
  3. ↑ Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz R, Kalhan SC (2000). "Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds". Pediatrics. 105 (5): 1141–5. PMID 10790476.
  4. ↑ Samuel Meites, editor-in-chief; contributing editors, Gregory J. Buffone... [et al.] (1989). Pediatric clinical chemistry: reference (normal) values. Washington, D.C: AACC Press. ISBN 0-915274-47-7.


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