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{{Hypoglycemia}}
{{Hypoglycemia}}
{{CMG}}
{{CMG}} {{AE}} {{MAD}}
==Overview==
Laboratory investigations of hypoglycemia depend on many tests: [[plasma glucose]] is usually <55-70 mg/dL, [[Insulin|insulin,]] [[c-peptide]], [[proinsulin]], [[sulfonylurea]] screen, [[beta-hydroxybutyrate]], and 24-hour fasting [[Glucose levels low|glucose level]] are another tests that are required to establish the etiology.


==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>
The following three characteristics should be present to diagnose hypoglycemia, which is called  [[Whipple's triad]] and include:<ref name="pmid17127144">{{cite journal| author=Guettier JM, Gorden P| title=Hypoglycemia. | journal=Endocrinol Metab Clin North Am | year= 2006 | volume= 35 | issue= 4 | pages= 753-66, viii-ix | pmid=17127144 | doi=10.1016/j.ecl.2006.09.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17127144  }}</ref>
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.
* Symptoms of hypoglycemia
====Measurement Method====
* A low [[plasma glucose]] concentration correlated with symptoms
[[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 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.<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.
* Correction of [[Glucose levels low|glucose level]] relieves symptoms
The strategy is to seek [[Whipple's triad]] under conditions in which hypoglycemia would be expected:
* If symptoms occur in the [[Fasting plasma glucose|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 [[Blood glucose monitoring|glucose measurements]] and recording of any symptoms after a mixed meal.  
* All of the following should be measured:
**[[Glucose]]: plasma glucose is usually <55-70 mg/dL.
**[[Insulin]]
**[[C-peptide]]
**[[Proinsulin]]
**[[Sulfonylurea]] and [[Meglitinide|meglitinide screen]]
**[[Beta-hydroxybutyrate]]<ref name="pmid15886243">{{cite journal| author=Service FJ, O'Brien PC| title=Increasing serum betahydroxybutyrate concentrations during the 72-hour fast: evidence against hyperinsulinemic hypoglycemia. | journal=J Clin Endocrinol Metab | year= 2005 | volume= 90 | issue= 8 | pages= 4555-8 | pmid=15886243 | doi=10.1210/jc.2005-0033 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15886243  }}</ref>
{| class="wikitable"
!Fasting evaluation<ref name="pmid19088155">{{cite journal| author=Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER et al.| title=Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2009 | volume= 94 | issue= 3 | pages= 709-28 | pmid=19088155 | doi=10.1210/jc.2008-1410 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19088155  }}</ref><ref name="pmid11095416">{{cite journal| author=Service FJ, Natt N| title=The prolonged fast. | journal=J Clin Endocrinol Metab | year= 2000 | volume= 85 | issue= 11 | pages= 3973-4 | pmid=11095416 | doi=10.1210/jcem.85.11.6934 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11095416  }}</ref>
!Mixed-meal evaluation<ref name="pmid235895422">{{cite journal| author=Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L et al.| title=Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. | journal=Diabetes Care | year= 2013 | volume= 36 | issue= 5 | pages= 1384-95 | pmid=23589542 | doi=10.2337/dc12-2480 | pmc=3631867 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23589542  }}</ref>
|-
|
* If prolonged fasting results in an episode of symptomatic hypoglycemia, [[plasma glucose]] should be measured repeatedly during fasting.
* If symptoms occur and hypoglycemia is documented, other tests mentioned above should be performed.
* If results are equivocal, patient needs another confirmatory test, such as 72-hour fast.
|
* If symptoms appear within 5 hours after meals, we should suspect postprandial hypoglycemia.<ref name="pmid105009292">{{cite journal| author=Service FJ| title=Diagnostic approach to adults with hypoglycemic disorders. | journal=Endocrinol Metab Clin North Am | year= 1999 | volume= 28 | issue= 3 | pages= 519-32, vi | pmid=10500929 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10500929  }}</ref>  
* Recurrent sampling before and after meals for the following 5 hours will help diagnosis; If severe symptoms occur, blood glucose must be measured.
* If [[Whipple's triad]] is demonstrated, [[sulfonylureas]], [[Meglitinide|meglitinides]], and antibodies to insulin should also be measured.
|}


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>
=== [[24-hour|24-hour fasting]] ===
====Age Differences====
* Increased release of [[glucagon]], [[epinephrine]], and [[cortisol]] are the most important factors that keep [[Blood sugar|blood glucose]] concentrations from falling during fasting.
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.
* [[Gluconeogenesis]] is the most important factor of [[glucose]] production after a prolonged fast.<ref name="pmid8755648">{{cite journal| author=Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC| title=Contributions of gluconeogenesis to glucose production in the fasted state. | journal=J Clin Invest | year= 1996 | volume= 98 | issue= 2 | pages= 378-85 | pmid=8755648 | doi=10.1172/JCI118803 | pmc=507441 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8755648  }}</ref>  
* If insulin level is high, [[gluconeogenesis]] will be inhibited causing hypoglycemia during fasting.<ref name="pmid6876881">{{cite journal| author=Hogan MJ, Service FJ, Sharbrough FW, Gerich JE| title=Oral glucose tolerance test compared with a mixed meal in the diagnosis of reactive hypoglycemia. A caveat on stimulation. | journal=Mayo Clin Proc | year= 1983 | volume= 58 | issue= 8 | pages= 491-6 | pmid=6876881 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6876881  }}</ref>


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 fasting should be stopped in any of the following conditions: <ref name="pmid10500929">{{cite journal| author=Service FJ| title=Diagnostic approach to adults with hypoglycemic disorders. | journal=Endocrinol Metab Clin North Am | year= 1999 | volume= 28 | issue= 3 | pages= 519-32, vi | pmid=10500929 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10500929  }}</ref>
**Seventy-two 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:<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>
**Measurement method
**Age


====Presence or Absence of Effects====
=== Identifying the cause ===
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.
The following table describes the possible causes of hypoglycemia.
{| class="wikitable"
!
!Plasma insulin<ref name="pmid17609405">{{cite journal| author=Vezzosi D, Bennet A, Fauvel J, Caron P| title=Insulin, C-peptide and proinsulin for the biochemical diagnosis of hypoglycaemia related to endogenous hyperinsulinism. | journal=Eur J Endocrinol | year= 2007 | volume= 157 | issue= 1 | pages= 75-83 | pmid=17609405 | doi=10.1530/EJE-07-0109 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17609405  }}</ref>
!C-peptide<ref name="pmid17609405" />
!proinsulin
!Sulfonylurea in plasma
!insulin or insulin receptor antibodies
!Postprandial symptoms
!Fasting symptoms
|-
|[[Insulinoma]]
|High
|High
|High
| -
| -
| -
| +
|-
|[[Oral hypoglycemics]]<ref name="pmid9056803">{{cite journal| author=Perros P, Henderson AK, Carter DC, Toft AD| title=Lesson of the week. Are spontaneous hypoglycaemia, raised plasma insulin and C peptide concentrations, and abnormal pancreatic images enough to diagnose insulinoma? | journal=BMJ | year= 1997 | volume= 314 | issue= 7079 | pages= 496-7 | pmid=9056803 | doi= | pmc=2125998 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9056803  }}</ref>
|High
|High
|High
| +
| -
| -
| -
|-
|[[Autoimmune]] hypoglycemia<ref name="pmid19440117">{{cite journal| author=Lupsa BC, Chong AY, Cochran EK, Soos MA, Semple RK, Gorden P| title=Autoimmune forms of hypoglycemia. | journal=Medicine (Baltimore) | year= 2009 | volume= 88 | issue= 3 | pages= 141-53 | pmid=19440117 | doi=10.1097/MD.0b013e3181a5b42e | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19440117  }}</ref>
|High
|High
|High
| -
| +
| -
| -
|-
|[[NIPHS]]*
|High
|High
|High
| -
| -
| +
| -
|-
|Exogenous [[insulin]]
|High
|Low
|Low
| -
| -
| -
| -
|-
|[[Non-islet|Non-islet cell tumors]]
|Low
|Low
|Low
| -
| -
| -
| -
|}
<nowiki>*</nowiki>(NIPHS) non-insulinoma pancreatogenous hypoglycemia syndrome


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.
=== Neonatal hypoglycemia: ===
Most of the neonatal hypoglycemias are transient but suspected cases as following should be investigated for metabolic diseases: 
* Hypoglycemia that requires prolonged high rates of [[dextrose]] infusion
* Persistent hypoglycemia
* [[Neurological|Neurologic]] symptoms
* History or physical findings suggestive of metabolic disease


[[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.
==== '''What to measure?''' ====
 
* Measure plasma insulin, plasma [[C-peptide]] and [[beta-hydroxybutyrate]]
====Purpose of Definition====
* [[PH|Blood pH,]] [[bicarbonate]], and [[lactate]]
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.
* [[Free fatty acids]], [[Acylcarnitine hydrolase|acylcarnitine profile]], plasma free and total [[Carnitine|carnitine levels]]


* [[Growth hormone]] and [[Cortisol]]
* [[Urine organic acids]] and [[Amino acids|serum amino acids]]
==References==
==References==
{{Reflist|2}}
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Latest revision as of 14:37, 16 November 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Overview

Laboratory investigations of hypoglycemia depend on many tests: plasma glucose is usually <55-70 mg/dL, insulin, c-peptide, proinsulin, sulfonylurea screen, beta-hydroxybutyrate, and 24-hour fasting glucose level are another tests that are required to establish the etiology.

Laboratory Findings

Defining Hypoglycemia

The following three characteristics should be present to diagnose hypoglycemia, which is called Whipple's triad and include:[1]

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

Fasting evaluation[3][4] Mixed-meal evaluation[5]
  • If prolonged fasting results in an episode of symptomatic hypoglycemia, plasma glucose should be measured repeatedly during fasting.
  • If symptoms occur and hypoglycemia is documented, other tests mentioned above should be performed.
  • If results are equivocal, patient needs another confirmatory test, such as 72-hour fast.
  • If symptoms appear within 5 hours after meals, we should suspect postprandial hypoglycemia.[6]
  • Recurrent sampling before and after meals for the following 5 hours will help diagnosis; If severe symptoms occur, blood glucose must be measured.
  • If Whipple's triad is demonstrated, sulfonylureas, meglitinides, and antibodies to insulin should also be measured.

24-hour fasting

  • The fasting should be stopped in any of the following conditions: [9]
    • Seventy-two 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:[10][11]
    • Measurement method
    • Age

Identifying the cause

The following table describes the possible causes of hypoglycemia.

Plasma insulin[12] C-peptide[12] proinsulin Sulfonylurea in plasma insulin or insulin receptor antibodies Postprandial symptoms Fasting symptoms
Insulinoma High High High - - - +
Oral hypoglycemics[13] High High High + - - -
Autoimmune hypoglycemia[14] High High High - + - -
NIPHS* High High High - - + -
Exogenous insulin High Low Low - - - -
Non-islet cell tumors Low Low Low - - - -

*(NIPHS) non-insulinoma pancreatogenous hypoglycemia syndrome

Neonatal hypoglycemia:

Most of the neonatal hypoglycemias are transient but suspected cases as following should be investigated for metabolic diseases:

  • Hypoglycemia that requires prolonged high rates of dextrose infusion
  • Persistent hypoglycemia
  • Neurologic symptoms
  • History or physical findings suggestive of metabolic disease

What to measure?

References

  1. ↑ Guettier JM, Gorden P (2006). "Hypoglycemia". Endocrinol Metab Clin North Am. 35 (4): 753–66, viii–ix. doi:10.1016/j.ecl.2006.09.005. PMID 17127144.
  2. ↑ Service FJ, O'Brien PC (2005). "Increasing serum betahydroxybutyrate concentrations during the 72-hour fast: evidence against hyperinsulinemic hypoglycemia". J Clin Endocrinol Metab. 90 (8): 4555–8. doi:10.1210/jc.2005-0033. PMID 15886243.
  3. ↑ Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER; et al. (2009). "Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 94 (3): 709–28. doi:10.1210/jc.2008-1410. PMID 19088155.
  4. ↑ Service FJ, Natt N (2000). "The prolonged fast". J Clin Endocrinol Metab. 85 (11): 3973–4. doi:10.1210/jcem.85.11.6934. PMID 11095416.
  5. ↑ Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L; et al. (2013). "Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society". Diabetes Care. 36 (5): 1384–95. doi:10.2337/dc12-2480. PMC 3631867. PMID 23589542.
  6. ↑ Service FJ (1999). "Diagnostic approach to adults with hypoglycemic disorders". Endocrinol Metab Clin North Am. 28 (3): 519–32, vi. PMID 10500929.
  7. ↑ Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC (1996). "Contributions of gluconeogenesis to glucose production in the fasted state". J Clin Invest. 98 (2): 378–85. doi:10.1172/JCI118803. PMC 507441. PMID 8755648.
  8. ↑ Hogan MJ, Service FJ, Sharbrough FW, Gerich JE (1983). "Oral glucose tolerance test compared with a mixed meal in the diagnosis of reactive hypoglycemia. A caveat on stimulation". Mayo Clin Proc. 58 (8): 491–6. PMID 6876881.
  9. ↑ Service FJ (1999). "Diagnostic approach to adults with hypoglycemic disorders". Endocrinol Metab Clin North Am. 28 (3): 519–32, vi. PMID 10500929.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 12.0 12.1 Vezzosi D, Bennet A, Fauvel J, Caron P (2007). "Insulin, C-peptide and proinsulin for the biochemical diagnosis of hypoglycaemia related to endogenous hyperinsulinism". Eur J Endocrinol. 157 (1): 75–83. doi:10.1530/EJE-07-0109. PMID 17609405.
  13. ↑ Perros P, Henderson AK, Carter DC, Toft AD (1997). "Lesson of the week. Are spontaneous hypoglycaemia, raised plasma insulin and C peptide concentrations, and abnormal pancreatic images enough to diagnose insulinoma?". BMJ. 314 (7079): 496–7. PMC 2125998. PMID 9056803.
  14. ↑ Lupsa BC, Chong AY, Cochran EK, Soos MA, Semple RK, Gorden P (2009). "Autoimmune forms of hypoglycemia". Medicine (Baltimore). 88 (3): 141–53. doi:10.1097/MD.0b013e3181a5b42e. PMID 19440117.
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