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Harrison's Internal Medicine > Chapter Hypoglycemia" Introd#ction

Hypoglycemia is most commonly ca#sed $y dr#gs #sed to treat dia$etes mellit#s or $y e%pos#re to other dr#gs& incl#ding alcohol. However& a n#m$er o' other disorders& incl#ding ins#linoma& critical organ 'ail#re& sepsis and inanition& hormone de'iciencies& non-cell t#mors& inherited meta$olic disorders& and prior gastric s#rgery& may ca#se hypoglycemia (Ta$le !-)*. Hypoglycemia is most convincingly doc#mented $y Whipple's triad: ()* symptoms consistent with hypoglycemia& (+* a low plasma gl#cose concentration meas#red with a precise method (not a gl#cose monitor*& and ( * relie' o' those symptoms a'ter the plasma gl#cose level is raised. The lower limit o' the 'asting plasma gl#cose concentration is normally appro%imately ,- mg.d/ ( .! mmol./*& $#t s#$stantially lower veno#s gl#cose levels occ#r normally& late a'ter a meal. Gl#cose levels 011 mg.d/ ( .mmol./* with symptoms that are relieved promptly a'ter the gl#cose level is raised doc#ment hypoglycemia. Hypoglycemia can ca#se serio#s mor$idity2 i' severe and prolonged& it can $e 'atal. It sho#ld $e considered in any patient with episodes o' con'#sion& an altered level o' conscio#sness& or a sei3#re. Ta$le !-) Ca#ses o' Hypoglycemia

Fasting (Postabsorptive) Hypoglycemia 4r#gs 5specially ins#lin& s#l'onyl#reas& ethanol 6ometimes 7#inine& pentamidine 8arely salicylates& s#l'onamides& others Critical illnesses Hepatic& renal& or cardiac 'ail#re 6epsis

Inanition Hormone de'iciencies Cortisol& growth hormone& or $oth Gl#cagon and epinephrine (in ins#lin-de'icient dia$etes* 9on-cell t#mors

5ndogeno#s hyperins#linism Ins#linoma :ther cell disorders

Ins#lin secretagog#e (s#l'onyl#rea& other* A#toimm#ne (a#toanti$odies to ins#lin or the ins#lin receptor* 5ctopic ins#lin secretion 4isorders o' in'ancy or childhood Transient intolerance o' 'asting Congenital hyperins#linism Inherited en3yme de'iciencies Reactive (Postprandial) Hypoglycemia Alimentary (postgastrectomy* 9onins#linoma pancreatogeno#s hypoglycemia syndrome In the a$sence o' prior s#rgery ;ollowing 8o#%-en-<-gastric $ypass :ther ca#ses o' endogeno#s hyperins#linism

Hereditary 'r#ctose intolerance& galactosemia Idiopathic

6ystemic Gl#cose =alance and Gl#cose Co#nterreg#lation Gl#cose is an o$ligate meta$olic '#el 'or the $rain #nder physiologic conditions. The $rain cannot synthesi3e gl#cose or store more than a 'ew min#tes' s#pply as glycogen and there'ore re7#ires a contin#o#s s#pply o' gl#cose 'rom the arterial circ#lation. As the arterial plasma gl#cose concentration 'alls $elow the physiologic range& $lood-to-$rain gl#cose transport $ecomes ins#''icient to s#pport $rain energy meta$olism and '#nction. However& red#ndant gl#cose co#nterreg#latory mechanisms normally prevent or rapidly correct hypoglycemia. >lasma gl#cose concentrations are normally maintained within a relatively narrow range& ro#ghly ,-?))- mg.d/ ( .!?@.) mmol./* in the 'asting state with transient higher e%c#rsions a'ter a meal& despite wide variations in e%ogeno#s gl#cose delivery 'rom meals and in endogeno#s gl#cose #tili3ation $y& 'or e%ample& e%ercising m#scle. =etween meals and d#ring 'asting& plasma gl#cose levels are maintained $y endogeno#s gl#cose prod#ction& hepatic glycogenolysis& and hepatic (and renal* gl#coneogenesis (;ig. !-)*. Altho#gh hepatic glycogen stores are #s#ally s#''icient to maintain plasma gl#cose levels 'or appro%imately A h& this time period can $e shorter i' gl#cose demand is increased $y e%ercise or i' glycogen stores are depleted $y illness or starvation. ;ig#re !-)

Physiology of glucose counterregulationthe mechanisms that normally prevent or rapidly correct hypoglycemia. In ins#lin-de'icient dia$etes& the Bey co#nterreg#latory responsesCs#ppression o' ins#lin and increases o' gl#cagonC are lost& and the stim#lation o' sympathoadrenal o#t'low is atten#ated.

Gl#coneogenesis re7#ires a coordinated s#pply o' prec#rsors 'rom m#scle and adipose tiss#e to the liver (and Bidneys*. M#scle provides lactate& pyr#vate& alanine& gl#tamine& and other amino acids. Triglycerides in adipose tiss#e are $roBen down

into 'atty acids and glycerol& which is a gl#coneogenic prec#rsor. ;atty acids provide an alternative o%idative '#el to tiss#es other than the $rain (which re7#ires gl#cose*. 6ystemic gl#cose $alanceCmaintenance o' the normal plasma gl#cose concentrationCis accomplished $y a networB o' hormones& ne#ral signals& and s#$strate e''ects that reg#late endogeno#s gl#cose prod#ction and gl#cose #tili3ation $y tiss#es other than the $rain (Chap. A*. Among the reg#latory 'actors& ins#lin plays a dominant role (Ta$le !-+2 ;ig. !-)*. As plasma gl#cose levels decline within the physiologic range in the 'asting state& pancreatic cell ins#lin secretion decreases& there$y increasing hepatic glycogenolysis and hepatic (and renal* gl#coneogenesis. /ow ins#lin levels also red#ce gl#cose #tili3ation in peripheral tiss#es& ind#cing lipolysis and proteolysis& there$y releasing gl#coneogenic prec#rsors. Th#s& a decrease in ins#lin secretion is the 'irst de'ense against hypoglycemia. Ta$le !-+ >hysiologic 8esponses to 4ecreasing >lasma Gl#cose Concentrations

Response

Glycemic Threshold mmol!" (mg!d") D.D?D., (A-?A1*

Physiologic #ffects

Role in the Prevention or $orrection of Hypoglycemia (Glucose $ounterregulation) >rimary gl#cose reg#latory 'actor.'irst de'ense against hypoglycemia >rimary gl#cose co#nterreg#latory 'actor.second de'ense against hypoglycemia Third de'ense against 8c hypoglycemia& critical when gl#cagon is de'icient Involved in de'ense against 8c prolonged hypoglycemia& not critical

Ins#lin

8a 8d*

Gl#cagon

.@? .! (@1?,-*

8a

5pinephri ne Cortisol and growth hormone 6ymptoms

.@? .! (@1?,-*

8a&

.@? .! (@1?,-*

8a&

+.A? .) (1-?11* 8ecognition o' >rompt $ehavioral de'ense hypoglycemia against hypoglycemia ('ood

Response

Glycemic Threshold mmol!" (mg!d") 0+.A (01-*

Physiologic #ffects

Role in the Prevention or $orrection of Hypoglycemia (Glucose $ounterregulation) ingestion*

Cognition

(Compromises $ehavioral de'ense against hypoglycemia*

Note" 8a& rate o' gl#cose appearance& gl#cose prod#ction $y the liver and Bidneys2 8c& rate o' gl#cose clearance& gl#cose #tili3ation relative to the am$ient plasma gl#cose concentration2 8d& rate o' gl#cose disappearance& gl#cose #tili3ation $y the $rain (which is #naltered $y the gl#coreg#latory hormones* and $y ins#lin-sensitive tiss#es s#ch as sBeletal m#scle (which is reg#lated $y ins#lin& epinephrine& cortisol& and growth hormone*. As plasma gl#cose levels decline E#st $elow the physiologic range& gl#cose co#nterreg#latory (plasma gl#cose?raising* hormones are released (Ta$le !-+2 ;ig. !-)*. Among these& pancreatic cell gl#cagon& which stim#lates hepatic glycogenolysis& plays a primary role. Gl#cagon is the second de'ense against hypoglycemia. Adrenomed#llary epinephrine& which stim#lates hepatic glycogenolysis and gl#coneogenesis (and renal gl#coneogenesis*& is not normally critical. However& it $ecomes critical when gl#cagon is de'icient. 5pinephrine is the third de'ense against hypoglycemia. Fhen hypoglycemia is prolonged& cortisol and growth hormone also s#pport gl#cose prod#ction and limit gl#cose #tili3ation. As plasma gl#cose levels 'all to lower levels& symptoms prompt the $ehavioral de'ense against hypoglycemia& incl#ding the ingestion o' 'ood (Ta$le !-+2 ;ig. !-)*. The normal glycemic thresholds 'or these responses to decreasing plasma gl#cose concentrations are shown in Ta$le !-+. However& these thresholds are dynamic. They shi't to higher-than-normal gl#cose levels in people with poorly controlled dia$etes who can e%perience symptoms o' hypoglycemia when their gl#cose levels decline into the normal range. :n the other hand& they shi't to lower-than-normal gl#cose levels in people with rec#rrent hypoglycemia& e.g.& those with aggressively treated dia$etes or an ins#linoma. 6#ch patients have symptoms at gl#cose levels lower than those that ca#se symptoms in healthy individ#als. Clinical Mani'estations 9e#roglycopenic symptoms o' hypoglycemia are the direct res#lt o' central nervo#s system (C96* gl#cose deprivation. They incl#de $ehavioral changes& con'#sion&

'atig#e& sei3#re& loss o' conscio#sness& and& i' hypoglycemia is severe and prolonged& death. 9e#rogenic (or a#tonomic* symptoms o' hypoglycemia are the res#lt o' the perception o' physiologic changes ca#sed $y the C96-mediated sympathoadrenal discharge triggered $y hypoglycemia. They incl#de adrenergic symptoms (mediated largely $y norepinephrine released 'rom sympathetic postganglionic ne#rons $#t perhaps also $y epinephrine released 'rom the adrenal med#llae* s#ch as palpitations& tremor& and an%iety. They also incl#de cholinergic symptoms (mediated $y acetylcholine released 'rom sympathetic postganglionic ne#rons* s#ch as sweating& h#nger& and paresthesias. Clearly& these are nonspeci'ic symptoms. Their attri$#tion to hypoglycemia re7#ires a corresponding low plasma gl#cose concentration and their resol#tion a'ter the gl#cose level is raised (Fhipple's triad*. Common signs o' hypoglycemia incl#de diaphoresis and pallor. Heart rate and systolic $lood press#re are typically raised& $#t these 'indings may not $e prominent. 9e#roglycopenic mani'estations are o'ten o$serva$le. Transient 'ocal ne#rologic de'icits occ#r occasionally. >ermanent ne#rologic de'icits are rare. 5tiology and >athophysiology Hypoglycemia is most commonly a res#lt o' the treatment o' dia$etes. This topic is there'ore addressed $e'ore considering other ca#ses o' hypoglycemia.

Hypoglycemia in %iabetes
Impact and ;re7#ency Hypoglycemia is the limiting 'actor in the glycemic management o' dia$etes. ;irst& it ca#ses rec#rrent mor$idity in most people with type ) dia$etes (T)4M* and many with type + dia$etes (T+4M* and is sometimes 'atal. 6econd& it precl#des maintenance o' e#glycemia over a li'etime o' dia$etes and th#s '#ll reali3ation o' the well-esta$lished $ene'its o' glycemic control. Third& it ca#ses a vicio#s cycle o' rec#rrent hypoglycemia $y prod#cing hypoglycemia-associated a#tonomic 'ail#re Cthe clinical syndromes o' de'ective gl#cose co#nterreg#lation and o' hypoglycemia #nawareness. Hypoglycemia is a 'act o' li'e 'or people with T)4M. They s#''er an average o' two episodes o' symptomatic hypoglycemia per weeB and at least one episode o' severe& at least temporarily disa$ling& hypoglycemia each year. An estimated +?DG o' people with T)4M die as a res#lt o' hypoglycemia. :verall& hypoglycemia is less 're7#ent in T+4M. Met'ormin& thia3olidinediones& -gl#cosidase inhi$itors& gl#cagon-liBe peptide-) (G/>-)* receptor agonists or analog#es& and dipeptidyl peptidase-IH (4>>-IH* inhi$itors sho#ld not ca#se hypoglycemia. However& they

increase the risB when com$ined with an ins#lin secretagog#e& s#ch as one o' the s#l'onyl#reas& or with ins#lin. 9ota$ly& the 're7#ency o' hypoglycemia approaches that in T)4M as persons with T+4M develop ins#lin de'iciency and re7#ire treatment with ins#lin. Conventional 8isB ;actors The conventional risB 'actors 'or hypoglycemia in dia$etes are $ased on the premise that relative or a$sol#te ins#lin e%cess is the sole determinant o' risB. 8elative or a$sol#te ins#lin e%cess occ#rs when ()* ins#lin (or ins#lin secretagog#e* doses are e%cessive& ill-timed& or o' the wrong type2 (+* the in'l#% o' e%ogeno#s gl#cose is red#ced (e.g.& d#ring an overnight 'ast or 'ollowing missed meals or snacBs*2 ( * ins#lin-independent gl#cose #tili3ation is increased (e.g.& d#ring e%ercise*2 (D* sensitivity to ins#lin is increased (e.g.& with improved glycemic control& in the middle o' the night& late a'ter e%ercise& or with increased 'itness or weight loss*2 (1* endogeno#s gl#cose prod#ction is red#ced (e.g.& 'ollowing alcohol ingestion*2 and (@* ins#lin clearance is red#ced (e.g.& in renal 'ail#re*. However& these conventional risB 'actors alone e%plain a minority o' episodes2 other 'actors are typically involved. Hypoglycemia-Associated A#tonomic ;ail#re Fhile marBed ins#lin e%cess alone can ca#se hypoglycemia& iatrogenic hypoglycemia in dia$etes is typically the res#lt o' the interplay o' relative or a$sol#te ins#lin e%cess and compromised physiologic and $ehavioral de'enses against 'alling plasma gl#cose concentrations (Ta$le !-+2 ;ig. !-+*. 4e'ective gl#cose co#nterreg#lation compromises physiologic de'ense& and hypoglycemia #nawareness compromises $ehavioral de'ense. ;ig#re !-+

Hypoglycemia&associated autonomic failure in insulin&deficient diabetes. (Adapted 'rom Cryer >5" 9 5ngl I Med 1-"++,+& +--D. Copyright Massach#setts Medical 6ociety& +--D.*

4e'ective Gl#cose Co#nterreg#lation In the setting o' endogeno#s ins#lin de'iciency& ins#lin levels do not decrease as

plasma gl#cose levels 'all2 the 'irst de'ense against hypoglycemia is lost. ;#rthermore& $eca#se the decrement in intraislet ins#lin is normally a signal to stim#late gl#cagon secretion& gl#cagon levels do not increase as plasma gl#cose levels 'all '#rther2 the second de'ense against hypoglycemia is lost. ;inally& the increase in epinephrine levels& the third de'ense against hypoglycemia& in response to a given level o' hypoglycemia is typically atten#ated. The glycemic threshold 'or the sympathoadrenal (adrenomed#llary epinephrine and sympathetic ne#ral norepinephrine* response is shi'ted to lower plasma gl#cose concentrations. That is typically the res#lt o' recent antecedent iatrogenic hypoglycemia. In the setting o' a$sent decrements in ins#lin and o' a$sent increments in gl#cagon& the atten#ated increment in epinephrine ca#ses the clinical syndrome o' de'ective gl#cose co#nterreg#lation. A''ected patients are at +1-'old or greater increased risB o' severe iatrogenic hypoglycemia d#ring aggressive glycemic therapy o' their dia$etes compared with those with normal epinephrine responses. Hypoglycemia Jnawareness The atten#ated sympathoadrenal response (largely the red#ced sympathetic ne#ral response* to hypoglycemia ca#ses the clinical syndrome o' hypoglycemia #nawareness& i.e.& loss o' the warning adrenergic and cholinergic symptoms that previo#sly allowed the patient to recogni3e developing hypoglycemia and there'ore a$ort the episode $y ingesting car$ohydrates. A''ected patients are at a si%'old increased risB o' severe iatrogenic hypoglycemia d#ring aggressive glycemic therapy o' their dia$etes. Hypoglycemia-Associated A#tonomic ;ail#re The concept o' hypoglycemia-associated a#tonomic 'ail#re (HAA;* in dia$etes posits that recent antecedent iatrogenic hypoglycemia (or sleep or prior e%ercise* ca#ses $oth de'ective gl#cose co#nterreg#lation ($y red#cing the epinephrine response to a given level o' s#$se7#ent hypoglycemia in the setting o' a$sent ins#lin and gl#cagon responses* and hypoglycemia #nawareness ($y red#cing the sympathoadrenal response to a given level o' s#$se7#ent hypoglycemia*. These impaired responses create a vicio#s cycle o' rec#rrent iatrogenic hypoglycemia (;ig. !-+*. Hypoglycemia #nawareness& and to some e%tent the red#ced epinephrine component o' de'ective gl#cose co#nterreg#lation& is reversi$le $y as little as +? weeBs o' scr#p#lo#s avoidance o' hypoglycemia in most a''ected patients. =ased on this pathophysiology& additional risB 'actors 'or hypoglycemia in dia$etes incl#de ()* ins#lin de'iciency that indicates that ins#lin levels will not decrease and gl#cagon levels will not increase as plasma gl#cose levels 'all2 (+* a history o' severe hypoglycemia or o' hypoglycemia #nawareness& implying recent antecedent hypoglycemia& that indicates that the sympathoadrenal response will $e atten#ated2

and ( * lower H$A)C levels or lower glycemic goals that& all other 'actors $eing e7#al& increase the pro$a$ility o' recent antecedent hypoglycemia. Hypoglycemia 8isB ;actor 8ed#ction It is possi$le to red#ce the risB o' hypoglycemia while maintaining a degree o' glycemic control in patients with dia$etes. This involves application o' the principles o' aggressive glycemic therapy (Chap. A*Cpatient ed#cation and empowerment& 're7#ent sel'-monitoring o' $lood gl#cose& 'le%i$le ins#lin (and other dr#g* regimens incl#ding the #se o' ins#lin analog#es& individ#ali3ed glycemic goals& and ongoing pro'essional g#idance and s#pportCand consideration o' $oth the conventional risB 'actors and those indicative o' compromised gl#cose co#nterreg#lation. Given a history o' hypoglycemia #nawareness& a +- to -weeB period o' scr#p#lo#s avoidance o' hypoglycemia is indicated. ;asting Hypoglycemia There are many ca#ses o' 'asting (posta$sorptive* hypoglycemia (Ta$le !-)*. However& dr#gs are the most common ca#se $y 'ar. Those #sed to treat dia$etes mellit#s (see a$ove* are 're7#ent o''enders& as is alcohol. :' the critical illnesses that ca#se hypoglycemia& sepsis is the most common. 8elevant hormone de'iciencies& non-cell t#mors& and endogeno#s hyperins#linism& as well as hypoglycemic disorders with their onset in in'ancy and childhood& are rare. 4r#gs Ins#lin and ins#lin secretagog#es s#ppress gl#cose prod#ction and stim#late gl#cose #tili3ation. 5thanol $locBs gl#coneogenesis $#t not glycogenolysis. Th#s& alcohol-ind#ced hypoglycemia typically occ#rs a'ter a several-day ethanol $inge d#ring which the person eats little 'ood& there$y ca#sing glycogen depletion. 5thanol is #s#ally meas#ra$le in $lood at the time o' presentation& $#t its levels correlate poorly with plasma gl#cose concentrations. =eca#se gl#coneogenesis $ecomes the predominant ro#te o' gl#cose prod#ction d#ring prolonged hypoglycemia& alcohol can contri$#te to the progression o' hypoglycemia in patients with ins#lin-treated dia$etes. 6alicylates in large doses can ca#se hypoglycemia $y inhi$iting gl#cose prod#ction. 6#l'onamides also rarely ca#se hypoglycemia $y stim#lating ins#lin secretion. >entamidine is to%ic to pancreatic cells. It ca#ses ins#lin release initially& with hypoglycemia in a$o#t )-G o' treated patients& and can ca#se dia$etes later. K#inine also stim#lates ins#lin secretion. However& the relative contri$#tion o' hyperins#linemia to the pathogenesis o' hypoglycemia in critically ill patients with

malaria treated with 7#inine is de$ated. K#inolone anti$iotics& partic#larly gati'lo%acin& have $een reported to ca#se hypoglycemia& o'ten in the setting o' dr#g-treated dia$etes. Among the antiarrhythmic dr#gs& 7#inidine& disopyramide& and ci$en3oline have $een reported to ca#se hypoglycemia. Hypoglycemia has $een attri$#ted to many other dr#gs& incl#ding the nonselective -adrenergic antagonist propanolol. 6ince the glycemic actions o' epinephrine and the adrenergic symptoms o' hypoglycemia ($#t not the cholinergic symptoms s#ch as sweating* are mediated $y
+

-adrenergic receptors& it is reasona$le to

#se a relatively selective )-adrenergic antagonist (e.g.& atenolol or metoprolol* in a setting in which hypoglycemia might occ#r. Critical Illness Among hospitali3ed patients& serio#s illnesses s#ch as renal& hepatic& or cardiac 'ail#re& sepsis& and inanition are second only to dr#gs as ca#ses o' hypoglycemia. 8apid and e%tensive hepatic destr#ction (e.g.& to%ic hepatitis* ca#ses 'asting hypoglycemia $eca#se the liver is the maEor site o' endogeno#s gl#cose prod#ction. The mechanism o' hypoglycemia in patients with cardiac 'ail#re is #nBnown. It may involve hepatic congestion and hypo%ia. Altho#gh the Bidneys are a so#rce o' gl#cose prod#ction& hypoglycemia in patients with renal 'ail#re is also ca#sed $y the red#ced clearance o' ins#lin and red#ced mo$ili3ation o' gl#coneogenic prec#rsors in renal 'ail#re. 6epsis is a relatively common ca#se o' hypoglycemia. Increased gl#cose #tili3ation is ind#ced $y cytoBine prod#ction in macrophage-rich tiss#es s#ch as the liver& spleen& and l#ng. Hypoglycemia develops i' gl#cose prod#ction 'ails to Beep pace. CytoBine-ind#ced inhi$ition o' gl#coneogenesis in the setting o' n#tritional glycogen depletion& in com$ination with hepatic and renal hypoper'#sion& may also contri$#te to hypoglycemia. Hypoglycemia can $e seen with starvation& perhaps $eca#se o' loss o' whole-$ody 'at stores and s#$se7#ent depletion o' gl#coneogenic prec#rsors (e.g.& amino acids*& necessitating increased gl#cose #tili3ation. Hormone 4e'iciencies 9either cortisol nor growth hormone is critical to the prevention o' hypoglycemia& at least in ad#lts. 9onetheless& hypoglycemia can occ#r with prolonged 'asting in patients with primary adrenocortical 'ail#re (Addison's disease* or hypopit#itarism. Anore%ia and weight loss are typical 'eat#res o' chronic cortisol de'iciency and

liBely res#lt in glycogen depletion. Cortisol de'iciency is associated with impaired gl#coneogenesis and low levels o' gl#coneogenic prec#rsors& s#ggesting that s#$strate-limited gl#coneogenesis& in the setting o' glycogen depletion& is the ca#se o' hypoglycemia. Growth hormone de'iciency can ca#se hypoglycemia in yo#ng children. In addition to e%tended 'asting& high rates o' gl#cose #tili3ation (e.g.& d#ring e%ercise or in pregnancy* or low rates o' gl#cose prod#ction (e.g.& 'ollowing alcohol ingestion* can precipitate hypoglycemia in ad#lts with previo#sly #nrecogni3ed hypopit#itarism. Hypoglycemia is not a 'eat#re o' the epinephrine-de'icient state that res#lts 'rom $ilateral adrenalectomy& when gl#cocorticoid replacement is ade7#ate& nor does it occ#r d#ring pharmacologic adrenergic $locBade when other gl#coreg#latory systems are intact. Com$ined de'iciencies o' gl#cagon and epinephrine play a Bey role in the pathogenesis o' iatrogenic hypoglycemia in people with ins#lin-de'icient dia$etes. :therwise& de'iciencies o' these hormones are not #s#ally considered in the di''erential diagnosis o' a hypoglycemic disorder. 9on-Cell T#mors

;asting hypoglycemia& o'ten termed non-islet cell t#mor hypoglycemia& occ#rs occasionally in patients with large mesenchymal or epithelial t#mors (e.g.& hepatomas& adrenocortical carcinomas& carcinoids*. The gl#cose Binetic patterns resem$le those o' hyperins#linism (see $elow*& $#t ins#lin secretion is s#ppressed appropriately d#ring hypoglycemia. In most instances& hypoglycemia is d#e to overprod#ction o' an incompletely processed 'orm o' ins#lin-liBe growth 'actor II (L$ig IG;-IIL* that does not comple% normally with circ#lating $inding proteins and th#s more readily gains access to target tiss#es. The t#mors are #s#ally apparent clinically& and 'ree IG;-II levels Mand levels o' pro-IG;-II (5)-+)*N are elevated. C#rative s#rgery is seldom possi$le& $#t red#ction o' t#mor $#lB may ameliorate hypoglycemia. Therapy with a gl#cocorticoid& growth hormone& or $oth has also $een reported to alleviate hypoglycemia. 5ndogeno#s Hyperins#linism Hypoglycemia d#e to endogeno#s hyperins#linism can $e ca#sed $y ()* a primary cell disorder& typically a cell t#mor (ins#linoma*& sometimes m#ltiple cell

ins#linomas& or& especially in in'ants and yo#ng children& a '#nctional

disorder with cell hypertrophy or hyperplasia2 (+* a cell secretagog#e s#ch as a s#l'onyl#rea2 ( * an a#toanti$ody to ins#lin2 or (D* rarely& ectopic ins#lin secretion. 9one o' these ca#ses is common. 5ndogeno#s hyperins#linism is more liBely in an overtly healthy individ#al witho#t cl#es to other potential ca#ses o'

hypoglycemia. Accidental& s#rreptitio#s& or even malicio#s administration o' an ins#lin secretagog#e or ins#lin also sho#ld $e considered in s#ch an individ#al. The '#ndamental pathophysiologic 'eat#re o' endogeno#s hyperins#linism ca#sed $y a primary cell disorder or an ins#lin secretagog#e is the 'ail#re o' ins#lin secretion to 'all to very low levels d#ring hypoglycemia. This is assessed $y meas#ring plasma ins#lin& C-peptide (the connecting peptide that is cleaved 'rom proins#lin to prod#ce ins#lin*& and gl#cose concentrations d#ring hypoglycemia2 proins#lin levels also can $e meas#red. Ins#lin& C-peptide& and proins#lin levels need not $e high relative to normal& e#glycemic val#es2 they are o'ten inappropriately high in the setting o' a low plasma gl#cose concentration. Critical diagnostic 'indings are a plasma ins#lin concentration pmol./* and a plasma C-peptide concentration -.@ ng.m/ ( J.m/ ( )A

-.+ nmol./*

(with a plasma proins#lin concentration 1.- pmol./* when the plasma gl#cose concentration is 011 mg.d/ (0 .- mmol./* with symptoms o' hypoglycemia. Most primary cell disorders& s#ch as an ins#linoma& ca#se 'asting hypoglycemia. The diagnostic strategy is to maBe the a$ove meas#rements d#ring spontaneo#s& symptomatic hypoglycemia& i.e.& a'ter an overnight 'ast& an e%tended o#tpatient 'ast& or& i' necessary& an inpatient prolonged (DA- or ,+-h* 'ast. It is necessary to screen the plasma 'or s#l'onyl#reas and other ins#lin secretagog#es (repaglinide& nateglinide* at the time o' hypoglycemia since these prod#ce an ins#lin& C-peptide& proins#lin& and gl#cose pattern indisting#isha$le 'rom that prod#ced $y an ins#linoma. A#toanti$odies to ins#lin also sho#ld $e so#ght $#t need not $e meas#red at the time o' hypoglycemia. The nonins#linoma pancreatogeno#s hypoglycemia syndrome& which also ca#ses postprandial hyperins#linemic hypoglycemia& is disc#ssed later. The rare a#toanti$odies to the ins#lin receptor are sometimes agonists2 ins#lin secretion is s#ppressed d#ring hypoglycemia $#t ins#lin levels tend to $e inappropriately high& perhaps $eca#se o' decreased clearance o' ins#lin via the receptor. 5ctopic ins#lin secretion has $een reported& $#t it m#st $e 7#ite rare and is #s#ally not considered in the di''erential diagnosis o' a hypoglycemic disorder. ;inally& the 'inding o' inappropriately high ins#lin levels $#t low C-peptide levels d#ring hypoglycemia indicates e%ogeno#s ins#lin administration. A diagnostic algorithm 'or a patient with s#spected endogeno#s hyperins#linism is shown in ;ig. !- . ;ig#re !-

%iagnostic approach to a patient 'ith documented hypoglycemia or s#spected hypoglycemia $ased on a history o' s#ggestive symptoms& a low plasma gl#cose concentration& or $oth. A$O& positive 'or anti$ody to ins#lin2 6JO& positive 'or s#l'onyl#rea (or other secretagog#e*.

Ins#linomas are #ncommonCthe yearly incidence is estimated to $e ) in +1-&---C $#t $eca#se more than !-G are $enign& they are a treata$le ca#se o' potentially 'atal hypoglycemia. The median age at presentation is 1- years in sporadic cases& $#t it #s#ally presents in the third decade when it is a component o' m#ltiple endocrine neoplasia type ) (Chap. D1*. More than !!G o' ins#linomas are within the s#$stance o' the pancreas and they are #s#ally small (!-G 0+.- cm*. There'ore& they come to clinical attention $eca#se o' hypoglycemia rather than mass e''ects. Comp#ted tomography detects appro%imately ,-?A-G o' ins#linomas& and magnetic resonance imaging detects a$o#t A1G. These methods detect metastases in the ro#ghly )-G o' patients with a malignant ins#linoma. Transa$dominal #ltraso#nd will o'ten identi'y ins#linomas& and endoscopic #ltraso#nd has a sensitivity o' a$o#t !-G. 6omatostatin receptor scintigraphy is tho#ght to detect ins#linomas in a$o#t hal' o' patients. 6elective pancreatic arterial calci#m inEections& with the endpoint o' a sharp increase in hepatic veno#s ins#lin levels& regionali3es ins#linomas with high sensitivity& $#t this invasive proced#re is seldom necessary. The same is tr#e o' transhepatic portal veno#s sampling. Intraoperative pancreatic #ltrasonography almost invaria$ly locali3es ins#linomas that are not readily palpa$le $y the s#rgeon. 6#rgical resection o' a solitary ins#linoma is generally c#rative. 4ia3o%ide& which inhi$its ins#lin secretion& or the somatostatin analog#e octreotide can $e #sed to treat hypoglycemia in patients with #nresecta$le t#mors. 4isorders o' In'ancy and Childhood 4isc#ssion o' the vario#s disorders that ca#se hypoglycemia in in'ancy and childhood& incl#ding m#ltiple ca#ses o' transient intolerance o' 'asting& congenital hyperins#linism& and inherited en3yme de'iciencies& is $eyond the scope o' this chapter. 8eactive Hypoglycemia 8eactive (postprandial* hypoglycemia occ#rs e%cl#sively a'ter meals. Its diagnosis re7#ires doc#mentation o' Fhipple's triad a'ter a mi%ed meal. The diagnosis sho#ld not $e made on the $asis o' seemingly low veno#s plasma gl#cose concentrations a'ter an oral gl#cose load. It can occ#r 'ollowing gastrectomy. Termed alimentary

hypoglycemia& this is tho#ght to $e the res#lt o' early hyperins#linemia ca#sed $y rapid increments in plasma gl#cose and enhanced secretion o' the g#t incretin G/>) co#pled with s#ppression o' gl#cagon secretion $y G/>-). Administration o' an -gl#cosidase inhi$itor (e.g.& acar$ose or miglitol* is a concept#ally attractive treatment& altho#gh controlled clinical trials doc#menting its e''icacy are lacBing. 8eactive hypoglycemia also occ#rs in patients with a#toanti$odies to ins#lin and in the nonins#linoma pancreatogeno#s hypoglycemia syndrome. A''ected patients have symptomatic hyperins#linemic postprandial hypoglycemia ($#t negative ,+-h 'asts* that remits 'ollowing partial pancreatectomy. Histologic 'indings incl#de cell hypertrophy with or witho#t hyperplasia. A similar syndrome 'ollowing 8o#%-en-< gastric $ypass s#rgery 'or o$esity has $een descri$ed. The e%istence o' a clinically relevant idiopathic reactive hypoglycemia syndrome is de$ated. The iss#e is whether symptoms are ca#sed $y hypoglycemia& an e%aggerated sympathoadrenal response to declining gl#cose levels late a'ter a meal& or some gl#cose-independent mechanism. In any event& ca#tion sho#ld $e e%ercised $e'ore la$eling a person with a diagnosis o' hypoglycemia. ;re7#ent 'eedings& avoidance o' simple s#gars& and high-protein diets are commonly recommended to patients tho#ght to have idiopathic reactive hypoglycemia. The e''icacy o' these approaches has not $een esta$lished $y controlled clinical trials. ;actitio#s and Arti'act#al Hypoglycemia ;actitio#s hypoglycemia& ca#sed $y s#rreptitio#s or even malicio#s administration o' ins#lin or an ins#lin secretagog#e& shares many clinical and la$oratory 'eat#res with ins#linoma. It is most common among health care worBers& patients with dia$etes or their relatives& and people with a history o' other 'actitio#s illnesses. However& it sho#ld $e considered in all patients $eing eval#ated 'or hypoglycemia o' o$sc#re ca#se. Accidental ingestion o' an ins#lin secretagog#e (e.g.& the res#lt o' a pharmacy error* also occ#rs. Analytical error in the meas#rement o' plasma gl#cose concentrations is rare. :n the other hand& gl#cose monitors #sed to g#ide treatment o' dia$etes are not 7#antitative instr#ments& partic#larly at low gl#cose levels& and these sho#ld not $e #sed 'or the de'initive diagnosis o' hypoglycemia. 5ven with a 7#antitative method& low meas#red gl#cose concentrations can $e arti'act#al& e.g.& the res#lt o' contin#ed gl#cose meta$olism $y the 'ormed elements o' the $lood e% vivo& partic#larly in the presence o' le#Bocytosis& erythrocytosis& or throm$ocytosis& or i' separation o' the ser#m 'rom the 'ormed elements is delayed (pse#dohypoglycemia*.

(pproach to the Patient) Hypoglycemia

In addition to recognition and doc#mentation o' hypoglycemia& and o'ten #rgent treatment& diagnosis o' the hypoglycemic mechanism is critical 'or choosing a treatment that prevents& or at least minimi3es& rec#rrent hypoglycemia. A diagnostic algorithm is shown in ;ig. !- . ). 8ecognition and 4oc#mentation Hypoglycemia is s#spected in patients with typical symptoms2 in the presence o' con'#sion& an altered level o' conscio#sness& or a sei3#re2 or in a clinical setting in which hypoglycemia is Bnown to occ#r. Jrgent treatment is o'ten necessary in patients with s#spected hypoglycemia. =lood sho#ld $e drawn& whenever possi$le& $e'ore the administration o' gl#cose to allow doc#mentation o' a low plasma gl#cose concentration. Convincing doc#mentation o' hypoglycemia re7#ires the '#l'illment o' Fhipple's triad. Th#s& the ideal time to meas#re the plasma gl#cose level is d#ring a symptomatic episode. A normal gl#cose level e%cl#des hypoglycemia as the ca#se o' the symptoms. A low gl#cose level con'irms that hypoglycemia is the ca#se o' the symptoms& provided the latter resolve a'ter the gl#cose level is raised. Fhen the ca#se o' the hypoglycemic episode is o$sc#re& additional meas#rements& while the gl#cose level is low and $e'ore treatment& sho#ld incl#de plasma ins#lin& C-peptide& and ethanol concentrations& as well as levels o' ins#lin secretagog#es. Fhen the history s#ggests prior hypoglycemia& and a potential mechanism is not apparent& the diagnostic strategy is to meas#re the plasma gl#cose& ins#lin& and Cpeptide levels #nder conditions when hypoglycemia wo#ld $e e%pected& typically d#ring 'asting. :n the other hand& while it cannot $e ignored& a distinctly low plasma gl#cose concentration meas#red in a patient witho#t corresponding symptoms raises the possi$ility o' an arti'act (pse#dohypoglycemia*. +. 4iagnosis o' the Hypoglycemic Mechanism In a patient with doc#mented hypoglycemia& a pla#si$le hypoglycemic mechanism can o'ten $e ded#ced 'rom the history& physical e%amination& and availa$le la$oratory data (Ta$le !-)2 ;ig. !- *. 4r#gs& partic#larly those #sed to treat dia$etes or alcohol& sho#ld $e the 'irst consideration& even in the a$sence o' Bnown #se o' a relevant dr#g& given the possi$ility o' s#rreptitio#s& accidental& or malicio#s dr#g administration. :ther considerations incl#de evidence o' a relevant critical illness& less commonly hormone de'iciencies& and rarely a non? -cell t#mor that can $e p#rs#ed diagnostically. A$sent one o' these mechanisms& in an otherwise overtly well individ#al& one sho#ld consider endogeno#s hyperins#linism and proceed with meas#rements and assessment o' symptoms #nder 'asting conditions o' s#''icient d#ration to elicit or e%cl#de 'asting hypoglycemia.

. Jrgent Treatment :ral treatment with gl#cose ta$lets or gl#cose-containing 'l#ids& candy& or 'ood is appropriate i' the patient is a$le and willing to taBe these. A reasona$le initial dose is +- g o' gl#cose. I' the patient is #na$le or #nwilling& $eca#se o' ne#roglycopenia& to taBe car$ohydrates orally& parenteral therapy is necessary. Intraveno#s gl#cose (+1 g* sho#ld $e given and 'ollowed $y a gl#cose in'#sion g#ided $y serial plasma gl#cose meas#rements. I' intraveno#s therapy is not practical& s#$c#taneo#s or intram#sc#lar gl#cagon ().- mg in ad#lts* can $e #sed& partic#larly in patients with T)4M. =eca#se it acts $y stim#lating glycogenolysis& gl#cagon is ine''ective in glycogen-depleted individ#als (e.g.& those with alcohol-ind#ced hypoglycemia*. It also stim#lates ins#lin secretion and is there'ore less #se'#l in T+4M. These treatments raise plasma gl#cose concentrations only transiently& and patients sho#ld there'ore $e #rged to eat as soon as is practical to replete glycogen stores. D. >revention o' 8ec#rrent Hypoglycemia >revention o' rec#rrent hypoglycemia re7#ires an #nderstanding o' the hypoglycemic mechanism. :''ending dr#gs can $e discontin#ed or their doses red#ced. Hypoglycemia ca#sed $y a s#l'onyl#rea can persist 'or ho#rs& or even days. Jnderlying critical illnesses can o'ten $e treated. Cortisol and growth hormone can $e replaced i' they are de'icient. 6#rgical& radiotherape#tic& or chemotherape#tic red#ction o' a non? -cell t#mor can alleviate hypoglycemia even i' the t#mor cannot $e c#red2 gl#cocorticoid or growth hormone administration also may red#ce hypoglycemic episodes in s#ch patients. 6#rgical resection o' an ins#linoma is c#rative2 medical therapy with dia3o%ide or octreotide can $e #sed i' resection is not possi$le and in patients with a nont#mor cell disorder. >artial pancreatectomy may $e necessary in the latter patients. The treatment o' a#toimm#ne hypoglycemia (e.g.& with a gl#cocorticoid or imm#nos#ppressive dr#gs* is pro$lematic& $#t the disorders are o'ten sel'-limited. ;ailing these treatments& 're7#ent 'eedings and avoidance o' 'asting may $e re7#ired. Administration o' #ncooBed cornstarch at $edtime or even an overnight intragastric in'#sion o' gl#cose may $e necessary in some patients. ;#rther 8eadings =oyle >I& Pre$iec I" Management o' dia$etes-related hypoglycemia. 6o#th Med I )--(+*")A & +--, M>MI4" ), -@A!N Cryer >5" Gl#cose homeostasis and hypoglycemia& in Williams Textbook of Endocrinology& ))th ed. Qronen$erg HM et al (eds*. >hiladelphia& 6a#nders& an imprint o' 5lsevier& Inc +--A& pp )1- ?)1 " 4iverse ca#ses o' hypoglycemia-associated a#tonomic 'ail#re in dia$etes.

9 5ngl I Med 1-"++,+& +--D 6ervice ;I" Hypoglycemic disorders. 5ndocrinol Meta$ Clin 9orth Am +A"D@,& )!!!

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