hypoglycemia william

8/13/2019 Hypoglycemia William

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RISIKO HIPOGLIKEMIA PADA PEMAKAIAN INSULIN

Alwi Shahab

Subbagian Endokrinologi Metaboli!e

"agian Il!u Pen#akit Dala!

$K Unri% RSMH Pale!bang

Pendahuluan

Hipoglikemia adalah suatu keadaan klinis yang terjadi akibat penurunan

k ad ar g lu ko sa d arah d ib aw ah r en tang b at as n orma l. H ip og li kemi a d ap at

disebabkan oleh berbagai kelainan dan berat r ingannya di tentukan pula oleh

lamanya terjadi penurunan kadar glukosa darah serta berat ringan gejala yang

t imbul. Pada pasien d iabe tes mel i tus , h ipog likemia t e ru tama t e rj adi ak iba t

pemb erian obat-obat golongan sulfonyl urea dan pemakaian insulin. Pengaruhburuk hipoglikemia terutama akan me nye babkan gangguan fungsi sya raf otak

yang b il a berl angsung l ama akan meningkatkan morb id i tas dan mor tal i tas .

Kekawat i ran akan t e rj adinya h ipogl ikemia da lam penatalaksanaan d iabetes

mel i tus , terutama pada pas ien us ia lanjut menimbulkan permasalahan dalam

kendal i g lukosa darah yang akan meningkatkan r is iko komplikas i makro dan

mikrovasku lar ak iba t h ipergl ikemia . T injauan pus taka in i akan membahas

patofisiologi dan penatalaksanaan hipoglikemi a pada pemakaian insulin terutama

pada pasien D usia lanjut .

Regulai kadar glukoa darah &Ho!eotai Glukoa'

!is tem syaraf pusat sangat tergantung dengan oksidas i g lukosa sebagai

s umber ene rg i u tamany a. " an gg uan s up la i g lu ko sa akan men gaki ba tk an

gangguan fungsi o tak #neurog l ikopen ia$ , dan b i la berl angsung l ama akan

menyebabkan kerusakan syaraf otak yang irreversibel dan kematian. Pada orang

dewasa sehat dengan %% &' kg, kebutuhan glukosa otak diperkirakan sebanyak

( mg)kg)menit$ atau sebanyak ('' g)hari . *mbilan glukosa otak difasil i tasi oleh

+ t ransporter g lukosa yaitu "T ( dan "T yang t idak tergantung dengan

insulin. Dalam keadaan hipoglikemia, sistem tranportasi glukosa ini mengalami

g an gg uan. !ed an gk an p ad a h ip og li kemi a k ro ni k akan t er jadi u p r eg ul as i

t ransporter g lukosa, suatu fenomena penting yang berperan dalam ter jadinya

hypoglycemia unawareness .

(


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Dalam keadaan puasa, otak dapat menggunakan benda+ keton # -hydroksi-butirat

dan aseto asetat$ sebagai sumber energi al ternative. *mbilan benda+ keton oleh

otak proporsional dengan kadarnya didalam darah. /ksidasi benda+ keton dapat

menjadi sumber energ i hanya b il a kadarnya d ida lam s i rkulasi mengalami

peningkatan, seperti ter jadi dalam keadaan puasa ya ng lama. 0adi bila kadar

glukosa darah rendah, sedangkan kadar keton sangat t inggi, maka otak sebagian

ter l indung dari efek buruk hipogl ikemia. 1amun bi la kadar glukosa dan keton

rendah, sepert i terjadi pada hipoglikemi akibat pemberian insulin dan gangguan

oksidas i asam lemak, o tak akan sangat rentan terhadap gangguan metabol ik .

Kadar glukosa didalam s i rkulasi d i tentukan oleh keseimbangan antara asupan

g lukosa #absorps i 2 p roduks i $ dan u t il i sas i) penggunaannya o leh berbagai

jaringan. Da lam keadaan puasa, produksi glukosa tergantung pada ketersediaan

subs t ra t+ yang d iper lukan bagi p roses g l ikogenol i si s dan g lukoneogenes i s.

!ementara ut i l i sas i g lukosa di tentukan oleh ambi lan glukosa dan ketersediaan

sumber energi al ternat ive terutama bagi jar ingan otot . ekanisme utama yang

berperan dalam pen3egahan hipoglikemi a ditunjukkan dalam gamb ar dibawah

ini 4

Dalam keadaan puasa (post absorptive state) , kadar insulin menurun, sehingga

menurunkan ambilan glukosa oleh hepar, otot dan lemak. "likogenolisis didalam

hati merupakan proses paling penting untuk memenuhi kebutuhan glukosa dalam

keadaan puasa selama (+ sampai +5 jam.

+


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%ila puasa berlangsung lebih lama, setelah s impanan gl ikogen hat i berkurang,

akan terjadi l ipolisis dan peme3ahan protein untuk mempertahankan kadar asam

lemak , g l i se rol dan asam amino d ida lam a l i ran darah. *sam lemak akan

digunakan oleh otot sebagai sumber energi dan oleh hat i untuk memproduksi

benda+ keton ya ng akan digunakan sebagai sumb er energi al ternative bagi

jaringan+ tubuh lain. "liserol dan asam amino akan diamb il oleh hati dan ginjal

y an g akan d ig un ak an s eb ag ai b ah an u tama b ag i p ro ses g lu ko neog en es is .

Peneli t ian terbaru menunjukkan bahwa produksi g lukosa pada laki- laki sehat

sekitar (,6 mg)kg)menit selama dalam keadaan puasa sampai 5' jam. Kontribusi

proses glukoneogenesis terhadap produksi glukosa basal meningkat dari 5(7

setelah (+ jam sampai 8+7 setelah 5' jam puasa. Dalam keadaan puasa yang

lama, g injal memproduksi +97 atau lebih dari to tal kebutuhan akan glukosa,

terutama melalui proses glukoneogenesis dari g lutamine, laktat dan gl iserol.

Pada insuf is i ens i g in jal k ron ik yang bera t akan t e rj adi gangguan p roduks i

g lukosa rena l sehingga akan menimbulkan h ipogl ikemi puasa. %i la kadar

g lukosa p lasma berada d ibawah n i la i ambang h ipog l ikemi , akan t e rj adi

pelepasan hormo n+ kontra regulasi , sebagai usaha untuk meningkatkan produksi

g lu ko sa . 1 il ai a mb an g i ni d ip er ki ra ka n p ad a k ad ar : & m g) dl . % ag ia n

vent romedial hypo tha lamus merupakan o rgan u tama yang berperan da lam

respons kontra regulasi .

Hormon+ kontra regulasi terbagi dalam + kelompok 4

- Hormon+ ker ja 3epat yai tu ka teko lamin dan g lukagon .

- Hormon+ ker ja l ambat yai tu g rowth hormone dan kor ti sol .

Katekolamin #epinefr in dan norepinefr in$ bekerja menghambat sekres i insul in

dan se3ara langsung merangsang proses glukoneogenesis d i hepar dan ginjal ,

menghambat u t il i sas i g lukosa d i j a ringan peri fer dan merangsang p roses

l ipo l is i s. !e lan ju tnya p roses l ipo l is is akan menghas ilkan subs t ra t+ yang

diperlukan untuk glikoneogenesis #yaitu gliserol$ dan sumber energi al ternative

bagi otot #ya itu asam lema k dan benda+ keton$. "lukagon terutama bekerja

merangsang p roduks i g lukosa ha ti , namun sangat sedik it a t au bahkan t idak

mempunyai e fek t e rhadap u t il i sas i g lukosa peri fer a t au s t imulasi p roduks i

glukosa ginjal . ;alaupun glukagon merangsang l ipolisis dan ketogenesis, namun

hanya mempunyai efek minimal terhadap mobilisasi prekursor glukoneogenesis

dari lemak.


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plasma be3ause glu3ose is me tabol i=ed by the gly3 olyt i3 pathway in red blood

3e ll s and l euko3y tes , resu lt ing in une?ual d i st r ibut ion o f g lu3ose be tween

intra3ellular and e@tra3ellular fluid. ;hole-blood glu3ose measurements may be

s pu ri ou sl y h ig h i n s ev ere anemi a and l ow i n p ol y3yt hemi a v era o r i n t he

presen3e of e@3essive leuko3yt osis. !puriously low glu3ose me asureme nts due to

gly3olys is in blood 3el ls in vi t ro #pseudohypogly3emia$ should be avoided by

t ransferr ing p lasma rapidly to the l aborato ry fo r 3ent r ifuga t ion . > f de lay i s

ant i3 ip at ed , 3hi ll in g o n i 3e w il l d e3 reas e t he r at e o f in v i tro gly3olysis.

*l ternat ively , th is ar t i fa3t 3an be minimi=ed by 3ol le3t ing the blood in a tube

3ontaining inhibitors of gly3olysis, su3h as o@alate and fluoride.

" lu 3o se v al ues f re?u en tl y a re measu red i n 3ap il la ry b lo od o bt ai ned b y a

fingerst i3k and applied to a reagent strip for analysis by visual inspe3tion or by

a glu3ose meter . Aisual inspe3t ion of a reagent s t r ip to whi3h blood has been

appl ied is not a rel iable way to dis t inguish normal from low glu3ose values .

"lu3ose-meter measurements may be subje3t to ar t i fa3ts resul t ing from poor

t e3hn i? ue o f t he p at ient o r t he med i3al s ta ff p er fo rmin g t he t es t o r f ro m

te3hni3al problems wi th the glu3ose meter . oreover , most g lu3ose meters are

3al ibrated to measure high glu3ose values and thus may be ina33urate in the

hypogly3emi3 range. Therefore, al though glu3ose meters may be very useful for

s 3r eeni ng p at ient s t o d et ermi ne i f s ympt oms 3or re la te w it h l ow g lu 3o se

measurements, thus e@3luding hypogly3emia when levels are high, the definit ive

diagnosis of hypogly3emia must always be based on an appropriately 3alibrated,

standard 3hemi3al test in the laboratory.

DE$INISI HIPOGLIKEMI

Diagnosis hipoglikemi ditegakkan berdasarkan trias ;hipple, yaitu 4

- * da nya g ej al a+ h ip og li ke mi

- K ad ar gl uk os a p la sma yang rend ah

- Terjadi pemul ihan ge jala se telah kadar g lukosa p lasma kembali normal

melalui pemberian glukosa eksogen.

1amun, nilai cutoff dari kadar glukosa plasma untuk menetapkan hipoglikemi

masih simpang siur. %erbagai kepustakaan menggunakan rentang nilai antara 59

s ampa i & 9 mg) dl #+,9 B 5 ,+ mmo l) l$ . D al am p rakt ek s eh ar i-ha ri , d ef in is i

hipoglikemi disesuaikan dengan keadaan klinis. ;alaupun t idak ada ketentuan

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pasti tentang seberapa rendah kadar glukosa darah sebagai patokan

mendefinisikan hipoglikemi, namun terdapat kesepakatan bahwa kadar glukosa

plasma vena antara 59 sampai :' mg)dl #+,9 B , mm ol)l$ jelas mendukung

adanya hipogl ikemi , dan bi la d ibawah 59 mg)dl #+ ,9 mmol) l $ b iasanya sudah

menimbulkan gejala k l inis yang berat. %i la kadar glukosa darah yang rendah

disertai dengan gejala+ neurologik, ke3urigaan terhadap hipoglikemi lebih t inggi

dan perlu segera di3ari faktor penyebabnya. Pada pasien diabetes yang diterapi

dengan insul in , kadar g lukosa darah hendaklah dipertahankan diatas &9 mg)dl

#5 ,+ mmol) l $ untuk men3egah kemungkinan ter jadinya hipogl ikemi s imtomatis

dan hypoglycemia unawareness .

(anda+tanda dan ge,ala+ge,ala hi-oglike!i

Tanda- tanda dan ge ja la-geja la h ipog likemi d ibag i da lam + ka tegor i , yai tu 4

otonomik dan neuroglikopenik. Tanda-tanda dan gejala-gejala otonomik terjadi

akibat akt ivas i s is tem syaraf o tonom melalui pelepasan epinefr in dari medul la

adren al k ed al am s irku la si d an n orepi ne fr in d ar i u ju ng + s ya ra f s imfa ti s

postganglioni3 kedalam jaringan+ target .

Dalam keadaan normal, ambang g likemik bagi pe lepasan kateko lamin l ebih

tinggi daripada ambangnya bagi induksi gejala-gejala neuroglikopenik. !ehingga

gejala-gejala otonomik mengawali t imbulnya gejala-gejala neuroglikopenik.

"ejala-gejala dan tanda-tanda yang berhubungan dengan pelepasan katekolamin

dapat berupa t remor , muka pu3a t , pa lp it asi , t akh ikardia , t ekanan nadi yang

melebar dan rasa 3emas #ansietas$ . %erkeringat , rasa lapar dan pares tes ia juga

umum ditemukan, yang biasanya dimediasi oleh adanya pelepasan aseti lkholin.

Pada orang dewasa, pengeluaran keringat lebih men3olok, hal ini diduga akibat

st imulasi oleh syaraf+ simfatis kolinergik post ganglionik.

(abel ./ (anda+tanda dan ge,ala+ge,ala hi-oglike!i -ada orang dewaa

:


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Otono!ik Neurogliko-enik

Ge,ala+

ge,ala

(anda+tanda Ge,ala+ge,ala (anda+tanda

Casa lapar uka pu3at %adan lemas, rasa

3apek

orti3al blindness

%erkeringat Takhikardia Di==iness Hypothermia

Casa 3emas Tekanan nadi

melebar

!akit kepala !ei=ures

Parestesia %ingung oma

Palpitasi Perubahan tingkah

laku

Tremor "angguan fungsi

kognitif

P en gl ih at an k ab ur ,

diplopia.

"ejala+ neuroglikopenik terjadi akibat kekurangan glukosa didalam otak. Karena

glukosa merupakan sumber energi utama untuk metabolisme jaringan otak, maka

penurunan kadar glukosa darah t idak 3ukup untuk me menuhi kebutuhan energi

bagi otak. 0adi, gejala+ neuroglikopenia tidak dapat dibedakan dengan gejala+

akibat terjadinya hipoksia jaringan otak. "ejala+ tersebut antara lain berupa rasa

lemas, kelelahan, pusing, sakit kepala, perubahan peri laku dan bingung.

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Pasien dapat mengalami letargi , mudah tersinggung dan bahkan dapat bersikap

agresi f . Dapat pula ter jadi gangguan fungsi kogni t i f, gangguan berfik i r dan

berkonsentrasi , aphasia dan bi3ara ka3au. Disamp ing itu, hipoglikemia dapat

menyebabkan pandangan kabur, kebutaan, paresthesia, hemiplegi, hipotermi, dan

bahkan koma, kejang dan berakhir dengan kema tian.

!ymptoms are less spe3ifi3 in the neonate than in the older 3hild and adult and

may in3lude i r ri t ab i li ty, j i tt e riness, 3hanges in tone , 3yanos i s, t a3hypnea ,

lethargy, and frank 3oma or sei=ures #see se3tion on neonatal hypogly3emia$.

The g ly3emi3 thresho ld for the appearan3e o f 3oun ter regula to ry hormone

response and fo r neurogly3open i3 symptoms i s dynami3 . > t sh if t s to h igher

g lu3ose 3on3ent rat ions fo llowing susta ined hypergly3emia in pat i en t s wi th

poorly 3ontrolled diabetes #(5$ and to lower glu3ose 3on3entrations in patients

w it h r e3ur rent epi so des o f h yp og ly3emi a #( 9$ . < ven a s in gl e epi so de o f

hypogly3emia 3an blunt 3ate3holamine response to subse?uent hypogly3emia

#(:$. The shift in gly3emi3 thresholds following re3urrent hypogly3emia results

from an adapt ive in3rease in uptake of g lu3ose by the brain , probably due to

in3reased 3erebral blood flow #(&$ and enhan3ed e@tra3tion of glu3ose indu3ed

by upregulation of the brain glu3ose transporters "T( and "T # (6$. >n

addi t ion to depending on the previous gly3emi3 environment , the response to

hypogly3emia depends on the availabil i ty of al ternative fuels for the brain, su3h

as ketone bodies and la3tate #(8$.

erebral energy re?uirements , the adapt ive 3hanges in glu3ose e@tra3t ion, and

the abi l i ty to ut i l i=e al ternat ive fuels are not uniform in al l the regions of the

brain. Thus, enhan3ed uptake of glu3ose in response to re3urrent hyp ogly3 emi a

3an main ta in normal metabol i sm and fun3 t ion in some regions o f the b rain ,

w hi le o th er r eg io ns m ay r ema in s us 3e pt ib le t o h yp og ly3 emi a- in du 3e d

dysfun3tion. Erom the 3lini3al standpoint , a patient with re3urrent hypogly3emia

may fail to develop warning symptoms of hypogly3emia and may not be able to

rea3 t ?ui3kly enough to aver t severe neurogly3open ia and 3oma when the

glu3ose 3on3entration rea3hes a 3ri t i3al threshold. Therefore, enhan3ed uptake

o f g lu 3o se b y t he b ra in fol lo wi ng r e3ur rent h yp og ly3emi a i s p ot en ti al l y

dangerous and should be 3onsidered maladaptive #(6$.

!evere and prolonged hypogly3emi3 episodes may 3ause neuronal 3el l death ,

r es ul ti ng i n p er ma ne nt i mp ai rme nt o f b ra in f un 3t io n. H ow ev er , i f t he

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hypogly3emia is treated effe3tively, apparent full re3overy is the rule even after

s ev er e e pi so de s o f h yp og ly3 em ia . T he re a re 3 on 3e rn s t ha t r e3 ur re nt

hypogly3emia may result in permanent damage to intelle3tual 3apa3ity, al though

in adul ts there i s no 3on3lus ive eviden3e to support th is not ion. Prospe3t ive

studies of patients with diabetes at risk for re3urrent severe hypogly3emia show

no effe3t on long-term 3ognit ive fun3tion #+',+($. >n 3ontrast , 3hildren younger

than 9 years of age do show a permanent impairment in >F after re3urrent events

of hypogly3emia #++$ . Thus , hypogly3emia is harmful to the developing brain

during the first years of l ife.

)LASSI$I)A(ION O$ H0POGL0)EMI) DISORDERS

The di fferential d iagnosis of hypogly3emia is broad #Eig . :8.$. The various

hypogly3emi3 d i so rders 3an be 3 lass if i ed on the basi s o f g lu3ose k ine t i3s

# in 3reased g lu 3o se u ti li =a ti on v s. d ef i3 ient g lu 3o se p ro du 3t io n$ , i ns ul in

mediat ion #hyperinsul inemi3 vs . hypoinsul inemi3$ , e t iology #endogenous vs .

e@ogenous 3auses$ , age #adu l ts vs. in fan ts and 3hi ldren$ , and the 3 l in i3a l

3hara3terist i3s of the patient #appears healthy or i l l$ # +$.

$igure 12/3/ T he maj or 3au ses o f h yp og ly 3emi a i n t he adu lt a re g ro up ed

a33ording to me3hanism. 1>PH!, noninsulinoma pan3reatogenous hypogly3emiaG

PP*C-, pero@ isome prol i fe rato r-a3t iva ted re3ep to r - *n th is 3hapter , we refer to hypogly3emi3 disorders based on the age group of

the patients. >n adults , hypogly3emia may be 3aused by drugs, systemi3 disease,

abnormalit ies in 3ounterregulatory hormones, or tumors. Hypogly3emia arising

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as a 3onse?uen3e of the therapeuti3 use of insulin or oral hypogly3emi3 agents

in patients with diabetes, the most 3ommon e@ogenous 3ause of hypogly3emia, is

3onsidered elsewhere in th is volume #see hapters 5' and 5($ . >n infants and

nondiabeti3 3hildren, hypogly3emia often results from inborn geneti3 defe3ts in

proteins imp ortant for regulating insulin se3retion or substrate me tabolism. >n

re3ent years, there has been an e@plosion of information on the human genome,

leading to bet ter 3 lassi f i3at ion and 3hara3ter i=at ion of d i fferent hypogly3emi3

disorders. Thus, the et iologies of hypogly3emia in this age group are dis3ussed

separately.

E4OGENOUS )AUSES O$ H0POGL0)EMIA

Drug-Induced Hypoglycemia

%eberapa obat dapat menyebabkan hipogl ikemi , namun beberapa diantaranya

masih belum jelas hubungan sebab akibatnya. Eaktor predisposis i ter jadinya

drug-indu3ed hypogly3emia antara lain faktor usia, gangguan fungsi ginjal dan

hati dan gi=i buruk.

/bat-obatan dapat menyebabkan hipoglikemi melalui beberapa mekanisme, yaitu

melalui 4

a . Peningkatan sekresi insu lin

b. Peningkatan amb ilan dan uti lisasi glukosa dijaringan perifer

3 . Penurunan produksi g lukosa d i hat i .

Disamping i tu , beberapa jenis obat dapat pula mengadakan interaksi dengan

golongan sul foni lurea dan insul in , sehingga memperkuat efek hipogl ikemik

kedua jenis obat ini .

(A"LE 12/5/ H#-ogl#6e!ia+)auing Drug

('


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In6reaed

inul in

In6reaed

inulin

eni t i7 i t#a

De6reaed

he-ati6

g lu6oe out-ut

Autoi!!une

!e6hani!

M i 6e ll an eo u a nd

unknown

!e6hani! b

>nsulin

#3ommon$

I-adrenergi3

b lo3kers

*l3ohol

#3ommon$

Hydra la=ine !ulfonamides

!ulfonylureas

#3ommon$

* < in hi bi to rs n rip e a kee

frui t

Pro3ainamide !ali3ylates

Disopyramide %iguanides J >sonia= id *nti3oagulan ts

#di3umarol , warfar in$

Fuinine PP*C agonis ts J >nterferon- *nalgesi3 and

anti inflammatory

drugs # i ndome t ha3 i n ,

3ol3hi3ine,

para3etamol

phenylbuta=one$

Pentamid ine J J !ulfhydryl -

3 on ta in in g d ru gs

#methima=ole,

peni3i l l amine,

3ap to pr il , go ld

thioglu3ose$

* n ti p sy 3h o ti 3 d r u gs

#haloperidol ,

3hlorproma=ine,

l i thium$

Ci todr ine J J J Keto3ona=ole

>sonia= idc J J J !elegi l ine

#antiparkinsonian

agent$

hloro?uine c J J J /3treo tide

Phenytoin

((


12/59

* n

addit ion to ?uinine-indu3ed hyperinsulinemia, a3utely i l l patients with malaria

are prone to development of hypogly3emia be3ause of 3onsumption of g lu3ose

by the ma larial parasites. >n patients with ma laria fal3iparum

P.((9

who are t reated wi th ?uinine, hypogly3emia may be overlooked be3ause the

neurologi3 symptoms may be at t ributed to 3erebral malar ia . Therefore, b lood

glu3ose should be 3arefully monitored and a glu3ose supplement administered to

prevent dangerous hyp ogly3 emia #+&,+6$.

Disopyramide

(+


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Disopyramide, used 3l in i3al ly as an ant iarrhythmi3 agent , has been shown to

in3rease insulin se3retion from pan3reati3 I-3ells , result ing in hyperinsulinemi3

hypogly3emia. The drug 3auses 3losure of the I-3ell K*T P 3hannel, binding to the

3hannel at a si te dist in3t from the sulfonylurea binding si te #+8$. Disopyramide

of ten i s used in e lder ly pa ti ent s , who may a l so su ffe r f rom impai red rena l

fun3tion and who appear to be part i3ularly sus3eptible to the glu3ose-lowering

effe3t of the drug #'$ . * re3ent s tudy found that the use of d isopyramide did

no t a f fe3 t the r i sk o f hypogly3emia in an ambula tory pa ti ent popu lat ion ,

suggesting that this side effe3t may be minor in the general population and may

be of 3lini3al imp ortan3e only in sele3ted patients at part i3ular risk # ($. >t has

been 3laime d that, al though rare in absolute terms, disopyr amide is one of the

most 3ommon 3auses of drug-indu3ed hypogly3emia in nondiabeti3 patients # +$.

-!drenoreceptor !gonists

Citodrine therapy to delay premature del ivery during pregnan3y 3an s t imulate

insu l in se3re tion and 3ause hypogly3emia in the newborn and ra re ly in the

mother #$ . Therapeut i3 doses of I +-adrenore3eptor agonists administered to

patients with bron3hial asthma we re not reported to indu3e hyp ogly3 emiaG

however, a lbuterol overdose was reported to 3ause hypogly3emia in a young

3hild #5$.

"entamidine

Pentamid ine i s used fo r the t reatment o f Pneumo cystis carinii pneumonia in

patients with *>D! and for parasiti3 infe3tions, in3luding tryp anosomi asis and

leishmaniasis. The drug is to@i3 to pan3reati3 I-3ells , result ing in unregulated

re lease o f insu lin f rom the damaged I-3e l ls and l ead ing to hypogly3emia

followed by hypergly3emia and even permanent diabetes mell i tus. The to@i3ity

to the I-3ells is more 3ommon and severe following systemi3 administrat ion and

is related to the 3umulative dose of the drug #9,:$.

DRUGS (HA( IN)REASE INSULIN SENSI(I*I(0

#iguanides and "ero$isome "roliferator-!ctivated Recepto-% !gonists

etformin and the gl i ta=ones do not usual ly 3ause hypogly3emia when taken

alone. /ver (' years of fol low-up among pat ients wi th type + diabetes taking

metformin in the K Prospe3t ive Diabetes !tudy #KPD!$, the proport ion of

patients per ye ar who had one or mo re episodes of hyp ogly3 emia was 5.+7, none

of whom developed severe hypogly3emia #&$ . The biguanides and gl i ta=ones

(


14/59

may augment hypogly3emia 3aused by sul fonylureas and insul in by in3reas ing

the uptake and ut i l i=at ion of g lu3ose #6$ . etformin also de3reases hepat i3

produ3tion of glu3ose and de3reases intestinal absorption of glu3ose.

!ngiotensin-&onverting 'nyme Inhibitors

The asso3iat ion between angiotensin-3onvert ing en=yme #*


15/59

ra ther than hypogly3emia . ! imi lar to *< inhibi tors , I-blo3kers were not

asso3iated with a higher fre?uen3y of hypogly3emi3 episodes in large series of

patients with typ e + diabetes, in3luding the KPD! # 5$. I-%lo3kers may blo3k

the adrenergi3 response to hypogly3emia, leading to hypogly3emia unawareness

and a predominan3e of the neurogly3openi3 symptoms. oreover , I-blo3kers

m ay d el ay t he r e3 ov er y f ro m h yp og ly3 emi a b e3 au se o f i nh ib it io n o f

3ate3holamine-mediated glu3ose 3ounterregulation. ate3holamines are not

re?uired for prompt re3overy from hypogly3emia in patients with inta3t islet-3ell

fun3 t ion G however , I-blo3kade may be3ome 3r it i 3a l in g lu3agon-defi3 ien t

patients with typ e ( diabetes. The risk for severe hyp ogly3 emi a in insulin-

t rea ted pa t i en t s wi th d iabe tes 3an be redu3ed by us ing one o f the re la t ive ly

sele3tive I (-adrenergi3 antagonists #5&$.

DRUGS (HA( DE)REASE HEPA(I) GLU)OSE PRODU)(ION

Hypogly3emia resul t ing from suppressed hepat i3 produ3t ion of g lu3ose may

o33ur in the set t ing of a3ute drug in to@i3at ion, whi3h may resul t in metabol i3

inhibi t ion of g lu3oneogenesis , su3h as wi th al3ohol or in hepat i3 ne3rosis , as

may o33ur af ter para3etamol poisoning. Hypogly3emia may be e@a3erbated i f

a3ute renal fai lure o33urs 3on3omitantly with hepati3 to@i3ity.

!lcohol-Induced Hypoglycemia

The most 3ommon 3ause of drug-indu3ed hypogly3emia se3ondary to suppressed

glu3oneogenesis is al3ohol overdose. *l3ohol-indu3ed hypogly3emia may o33ur

in persons of al l ages and in al l 3 lasses of so3iety . > t i s more 3ommon in men

than in women and in malnour i shed persons on a low-3alo ri e d ie t . Loung

3h ild ren a re espe3 ia l ly sus3ept ible to the hypogly3emi3 e f fe3 ts o f a l 3ohol .

Therefore , a33iden tal 3onsumpt ion o f even modest amounts o f a l 3ohol may

resul t in hypogly3emia in infants and young 3hi ldren #56$ . Eewer than (7 of

patients with

P.((95

al3ohol in to@i3at ion present ing to the emergen3y room have hypogly3emia.

However, be3ause of the very high in3iden3e of al3ohol into@i3ation relat ive to

the in3iden3e of al l other 3auses of hypogly3emia, al3ohol 3an be impli3ated in

(67 to 9+7 of pa ti ent s admi t ted to the emergen3y depar tment be3ause o f

sustained hypogly3emia #+:$. This variat ion in the in3iden3e of al3ohol-indu3ed

(9


16/59

hypogly3emia in di fferent ser ies probably ref le3ts so3ial , e thni3, and 3ul tural

differen3es in al3ohol 3onsumption among the populations studied. !ymptoms of

al3ohol in to@i3at ion may be very s imi lar to those of neurogly3openia, making

3lini3al differentiat ion diffi3ult . Thus, immediate routine determination of blood

glu3ose is re3ommended for al l into@i3ated patients in the emergen3y department

to guarantee rapid identifi3ation of those with signifi3ant hypogly3emia. * delay

in the diagnosis may result in permanent brain damage and death. The mortali ty

rate among hospital i=ed patients with al3ohol-indu3ed hypogly3emia may be as

high as ('7 #+:$.

n

addit ion, plasma ketone bodies are often high and 3an be used as an alternative

fuel for brain metabol ism. !ome pat ients present wi th al3ohol i3 ketoa3idosis ,

whi3h may o33ur several days fo llowing a l3ohol ingest ion and resembles

diabeti3 ketoa3idosis. >n these patients, plasma glu3ose levels are usually normal

or highG however, some patients may present with severe hypogly3emia. %oth the

pathogenesis of this 3ondit ion and the reason 3ertain patients develop

hypogly3emia whi le o thers be3ome hypergly3emi3 are unknown. This medi3al

emergen3y should be t reated wi th in t ravenous glu3ose in je3t ion pre3eded by

thiamine inje3tion to prevent the development of ;erni3ke en3ephalopathy.

* l3oh ol 3au ses h yp og ly3emi a b y i nh ib it in g g lu 3o neog en es is . < th an ol i s

metaboli=ed in the l iver by al3ohol dehydrogenase to a3etaldehyde and then to

(:


17/59

a3et i3 a3id by aldehyde dehydrogenase. The en=ymat i3 rea3tions generate free

hydrogen ions, with subse?uent redu3tion of ni3otinamide dinu3leotide #1*D$ to

1*DH. The depletion of hepati3 1*D stores inhibits the me tabolism of

pre3ursors in the glu3oneogeni3 pathwa y, in3luding the 3onversion of la3tate to

pyr uvate, several steps in the tri3arbo@yl i3 a3id 3y3 le, and the 3onversion of

gly3erol to glu3ose #58$ .


18/59

Hypogly3emia may o33ur af ter the ingest ion of the unripe akee frui t . The akee

frui t i s 3ommonly 3onsumed in 0amai3a, and i f eaten unripe may 3ause severe

weakness, vomiting, 3onvulsions, 3oma, and eventually death. The symptoms are

asso3iated wi th severe hypogly3emia resul t ing from the to@in hypogly3in *,

whi3h inhibits fat ty a3id o@idation and thus 3auses a metaboli3 syndrome very

similar to that 3aused by inborn errors of fat ty a3id metabolism #see se3tion on

h yp ogl y3 emi a in th e n eo nat e$ # 99 $. %o th ke tog ene sis a nd he pa ti 3

glu3oneogenesis are inhibited, 3ausing both hypogly3emia and lowered ketone

bodies, a 3omb ination that may be parti3ularly neuroto@i3.

O(HER DRUGS

any drugs 3ause hypogly3emia by various me3hanisms, some of whi3h have

not yet been 3ompletely defined. !ome drugs, su3h as sulfonamide, di3umarol,

and phenylbuta=one, intera3t with sulfonylureas to enhan3e their hypogly3emi3

a3tivity. /ther drugs, in3luding isonia=id and syntheti3 antimalarial drugs su3h

as 3hloro?uine, may rarely indu3e hypogly3emia in pat ients wi th diabetes by

redu3ing the 3learan3e of insulin from the blood. * large dose of sali3ylates may

indu3e hypogly3emia in young 3hildren, but rarely in adults . The me3hanism of

sal i3ylate- indu3ed hypogly3emia is unknown but may be related to in3reased

peripheral utili=ation of glu3ose, suppression of hepati3 glu3oneogenesis, or

augmentation of insulin release # +:$. Ce3ent studies have shown that sali3ylates

3an enhan3e insulin sensit ivity by inhibit ing the >M% kinase # 9:$.

*actit ious Hypoglycemia

ost 3a se s of fa 3t it io us h yp og ly3 emi a a re 3 aus ed b y t he d elib er at e

adminis t rat ion of insul in or oral hypogly3emi3 agents by the pat ient , a l though

a33idental adminis t rat ion or adminis t rat ion by a 3aregiver may o33ur as wel l .

The prevalen3e of fa3ti t ious hypogly3emia is unknown. >t was suggested that i t

i s more 3ommon in women than in men, al though this has not been 3onfi rmed

#9&$. The typi3al patient is young, aged (9 to 5' years, and has a33ess to insulin

or oral hypogly3emi3 agents su3h as sulfonylureas. The patient may be a medi3al

or paramedi3al

P.((99

w orke r o r a f amil y member o f a p er so n w it h d iabe te s t reat ed w it h o ra l

h yp og ly3emi 3 agent s o r i ns ul in and may k no w t he e ff e3 ts o f t he abu sed

(6


19/59

medi3at ion and the symptoms of hypogly3emia . ost pa ti ent s seem to be

Nmentally healthyO and provide detailed des3ription of their Ni l lness,O obviously

o mi tt in g t he f a3 t t ha t h yp og ly3emi 3 d ru gs w ere abu sed. ! imil ar t o o th er

f a3t it io us d is ea se s, u se o f h yp og ly3emi 3 d ru gs i s u su al ly d en ied. ; hen

3onfron ted wi th th is poss ibi l ity, the pa ti ent may respond in an aggress ive

manner, blaming the physi3ian for not trusting him or her. These patients may be

very sophist i3ated in 3on3ealing self-administrat ion of hypogly3emi3 drugs, and

ep isodes o f hypogly3emia may o33ur even during 3 lose supervi s ion in the

hospi tal. The his tory of episodes of hypogly3emia may e@tend over periods of

many years, somet imes wi th inte rva ls o f remission e@pla ined by i r regular

ad mi ni st ra ti on o f t he d ru gs . T he h is to ry may s ug gest t he p re sen3e o f an

insulinoma, and failure to diagnose the 3ause of hyperinsulinism may result in

an unne3essary laparotomy and even pan3reate3tomy.

*33idental administrat ion of insulin or oral hypogly3emi3 agents may produ3e

Nfa3t i t iousO hypogly3emia. >nadvertent adminis t rat ion of insul in to the wrong

patient in a hospital is a rare 3ause of hyp ogly3 emi a. nintended use of oral

hypogly3emi3 agents may resul t f rom a pres3ribing error by a physi3ian or a

pharma 3ist or by substi tution of an oral hyp ogly3 emi 3 for another medi3ation by

t he p at ient o r b y a f amil y member . > ns ul in and d ru g- in du 3ed f a3 ti ti ou s

hypogly3emia may also be the result of at tempted sui3ide or homi3ide.

The diagnosis of fa3t i t ious hypogly3emia should be 3onsidered in al l pat ients

wi th hyperinsul inemi3 hypogly3emia. The in i tia l h is tory may provide 3lues

suggest ing the presen3e or absen3e of fa3t it ious hypogly3emiaG however , ea3h

patient mu st be fully evaluated regardless of initial imp ression. ;e re3ently

evaluated a young soldier wi th a h ighly suggest ive his tory of insul inoma, no

apparent a33ess to insul in or drugs , and no suggestion of se3ondary gain , who

was subse?uently proven to have ingested gliben3lamide. *nother patient , with a

3lini3al history highly suspi3ious of fa3ti t ious hypogly3emia and easy a33ess to

medi3al personnel and medi3at ion, was subse?uent ly proven to have a benign

insulinoma.

The b io3hemi3a l d iagnosi s o f insu lin -indu3ed fa3t i tious hypogly3emia i s

relat ively s imple i f b lood is 3ol le3ted during an episode of hypogly3emia for

g lu3ose , insu lin , and -pep tide measurement . P lasma insu l in i s h igh , with

dis3ordant low levels of -pept ide, ref le3t ing the suppress ion of endogenous

(8


20/59

insulin se3retion by low glu3ose levels. >f insulin and -peptide measurements

are dis3ordant, the presen3e of antibodies to insulin should be e@3luded. >nsulin

antibodies may 3ause spuriously high or low insulin measurements, depending

on the method used in the insulin assay. The presen3e of 3ir3ulating antibodies

should also be e@3luded by di re3t measurement us ing spe3i fi3 assays and by

measuring insu lin l eve l s on seri a l d ilu tions o f p lasma samples . 1onl inear

3orrelation between measured insulin and plasma dilution indi3ates the presen3e

of a substan3e that interferes with the insulin assay. >n the past , the presen3e of

insulin antibodies was thought to be prima facie eviden3e of e@ogenous insulin

administrat ion. However, modern, highly purified, re3ombinant human insulin

rarely 3auses 3l ini3ally signifi3ant antibody produ3tion, and i t is now 3lear that

antibodies may also o33ur in rare patients with autoimmune hypogly3emia and

prior to the 3lini3al onset of typ e ( diabetes. Therefore, dete3tion of insulin

an tibod ies shou ld no t be regarded as a spe3 if i 3 and sens it ive assay fo r the

diagnosis of fa3t it ious hypogly3emia. >n the pas t , a l l 3ommer3ially available

insu l in was ob ta ined f rom beef o r por3 ine pan3reas . Thus , spe3 ies -spe3i f i3

assays 3ould be developed to prove the e@ogenous origin of 3ir3ulating insulin.

Today, mos t 3ommer3 ial insu l in i s o f human or ig in, making these assays

obsoleteG however, the in3reasing use of insulin analogues may 3ause a revival

of this approa3h.

>n 3ontras t to surrept i tious administ rat ion of insul in , se3retagogue-indu3ed

hypogly3emia is asso3iated with elevation of both insulin and -peptide levels.

P lasma l eve l s o f -pep tide fa il to be suppressed in response to the insu lin

hypogly3emia test , and the response to different st imuli , su3h as glu3agon and

glu3ose, may be e@3essive, similar to the findings in patients with insulinoma.

Therefore, the diagnosis of fa3ti t ious hypogly3emia due to insulin se3retagogues

is usually a diffi3ult 3hallenge. Eor 3onfirmation or e@3lusion of the diagnosis,

blood levels of some of the relevant drugs should be me asured during

hypogly3emia in an e@perien3ed to@i3ology laboratory. The in3reasing number

o f d ru gs ava il ab le t ha t s ti mu la te i ns ul in s e3 re ti on i s mak in g t hi s t as k

progressively mo re diffi3ult.

/n 3ert a in o33as ions, when there i s s t rong 3 l in i3a l susp i3 ion o f fa3t i tious

hypogly3emia, i t may be ne3essary to sear3h the hospi tal room of a pat ient to

find insulin vials, syringes, needles, or drug tablets to 3onfirm the diagnosis of

+'


21/59

fa3t it ious hypogly3emia. * room sear3h is 3onsidered by some to be unethi3al

and should be performed only af ter 3areful 3onsiderat ion and approval of the

appropriate hospital a uthorit ies.

The treatment of fa3ti t ious hypogly3emia is the same whether i t is mediated by

insu l in o r sul fonylurea and in3 ludes immedia te re li e f o f hypogly3emia by

int ravenous glu3ose fol lowed by psy3hiat r i3 in tervent ion to prevent re3urrent

episodes of hypogly3emia. anagement involves a support ive 3onfrontat ion

fol lowed by long-term psy3hiat r i3 3are. Ea3t it ious hypogly3emia is a ser ious

psy3 hiatri3 disturban3e. *lthough some patients admi t that the motive is to gain

at tent ion, sympathy, or some other se3ondary gain , in the majori ty ins ight i s

l imited and the long-term prognosis is poor. Hypogly3emia may re3ur or may be

fol lowed by other psy3hosomat i3 symptoms or drug abuse. !ome pat ients may

later 3ommit sui3ide #96$.

ENDOGENOUS )AUSES O$ H0POGL0)EMIA

Hypoglycemia Due to &rit ical-+r gan *ailure

!eps i s and d i seases that 3ause severe hepa t i3 , 3ard ia3 , o r rena l fa ilu re a re

3ommon 3auses of hypogly3emia among hospi tali=ed pat ients . Pat ients wi th

malnutri t ion or with fai lure of more than one 3ri t i3al organ are more sus3eptible

to severe hypogly3emia.

HEPA(I) DISEASES

H ep at i3 g ly3og en ol ys is and g lu 3o neog en es is p lay 3 ri ti 3a l r ol es i n t he

maintenan3e of postabsorptive blood glu3ose. !in3e the normal l iver has a very

large 3apa3ity for glu3ose produ3tion, hypogly3emia will o33ur only in the fa3e

of massive destru3tion of the l iver paren3hyma or in the presen3e of a33elerated

ut i l i=at ion of g lu3ose. *33elerated ut i li=at ion of g lu3ose may be present in

several 3l ini3al 3ondit ions, in3luding treatment with insulin or oral medi3ations

and during sepsis. Hypogly3emia has been reported in patients with severe l iver

failure due to to@i3 hepati t is , fulminant viral hepati t is , fat ty l iver, or hepati t is

asso3iated wi th al3ohol adminis trat ion and 3holangit i s . >n the lat ter , sepsis

3o mp li 3a ti ng b il ia ry o bs tru3 ti on may 3on tr ib ut e t o t he d ev el op ment o f

hypogly3emia. Hypogly3emia is un3ommon in pat ients wi th 3i rrhosis . Plasma

leve l s o f insu lin may be re la t ive ly h igh be3ause o f the p resen3e o f por tal -

systemi3 shunts and redu3ed hepati3 insulin e@tra3tion #98$.

P.((9:

+(


22/59

)ARDIA) $AILURE

/33asionally, hypogly3emia may o33ur in patients with severe 3ongestive heart

fai lure. The primary me3hanism 3ausing hypogly3emia in these pat ients i s not

known but may be the 3ombination of 3a3he@ia, la3k of glu3oneogeni3 substrate,

and l iver dysfun3tion due to hepati3 hypo@ia and 3ongestion. Patients admitted

to intensive 3are units may develop is3hemi3 hepati t is result ing from episodes of

a3ute hear t fa ilure and hypo tension. * re trospe3t ive s tudy o f pa ti ent s with

is3hemi3 hepati t is showed that hypogly3emia is 3ommon, o33urring in one third

of the patients #:'$.

RENAL $AILURE

Cenal insuf fi 3 ien3y may be asso3 ia ted with hypogly3emia , part i 3u lar ly in

patients with end-stage renal disease # :($. >n one retrospe3tive study, .:7 of

patients with end-stage renal failure admi tted to the hospital had hyp ogly3 emia

#:+$. The most 3ommon asso3iated pathologies were drug-indu3ed hypogly3emia

and seps is . !evere malnut r it ion was asso3 ia ted with &7 of hypogly3emi3

ep isodes in these pa ti ent s . Hypogly3emia asso3 ia ted with e i ther seps i s o r

malnutri t ion was asso3iated with a part i3ularly high mortali ty.

Diabeti3 and nondiabeti3 patients undergoing either hemodialysis or peri toneal

dialys is 3an develop spontaneous hypogly3emia during or immediately af ter

dialysis #:$. This is thought to be 3aused by in3reased insulin se3retion indu3ed

by a high glu3ose 3on3entration in the dialys is fluid 3ombined with redu3ed

renal insulin 3learan3e. >n addit ion, hypogly3emia may o33ur when the patients

are dialy=ed wi th a g lu3ose-free dialys is f lu id . Pat ients wi th an in i t ia l ly low

plasma glu3ose level and those who do not eat during dialys is are part i3ularly at

risk for hypogly3emia. The hormonal response to hypogly3emia is blunted, and

hypogly3emia unawareness is 3ommon # :5$.

T he p at ho ge ne si s o f h yp og ly3 emi a i n r en al f ai lu re i nv ol ve s mu lt ip le

me3hani sms , in3 lud ing redu3ed supp ly o f subs t ra te fo r g lu3oneogenes i s,

e sp e3 ia ll y i n p at ient s w it h s ev ere 3a3he@i a, mal nu tr it io n w it h d e3 reas ed

3arbohydrate in take, res is tan3e to the hypergly3emi3 effe3t of g lu3agon, and

i nh ib it io n o f g lu 3o neog en es is #: 9$ . > n h ea lt hy v ol un teer s, r en al g lu 3o se

produ3tion a33ounts for +97 of sys temi 3 glu3ose appearan3e in the

postabsorptive state. Eurthermore, epinephrine infusion, whi3h in3reased plasma

epinephrine to levels observed during hypogly3emia, in3reased the renal release

++


23/59

of g lu3ose near ly twofo ld so that , a t the end o f the in fusion, rena l g lu3ose

release a33ounted for 5'7 of systemi3 glu3ose produ3tion and essential ly al l of

the in3rease due to adrenergi3 st imulation #::$. Thus, renal glu3ose produ3tion

may have an important ro le in glu3ose homeostas is in the postabsorptive s tate

and d ur in g h yp og ly 3emi a. Pat ient s w it h r en al f ai lu re a re t he re fo re more

sus3eptible to hypogly3emia #:&$. * 3onsiderable number of patients with end-

stage renal fai lure have diabetes. These patients may develop hypogly3emia as a

result of de3reased 3learan3e of hypogly3emi3 drugs or insulin.

,epsis

!epsis fre?uent ly i s asso3iated wi th hypogly3emia in hospi tal i=ed pat ients . >n

e@perimental animals , there are several metabol i3al ly dis t in3t phases . >n the

early phase of sepsis , g lu3ose produ3tion and ut i li=at ion are in3reased and the

animals may be hypergly3emi3. Hypergly3emia is fo l lowed by a hypogly3emi3

phase in whi3h hepati3 glu3ose produ3tion is de3reased. This phase is

3hara3te ri =ed by a rapid deple tion o f hepa t i3 g ly3ogen 3ontent , impaired

g ly3o genesi s, and d ep re ss ed g lu 3o neog en es is , 3ombi ned w it h i n3 reas ed

peripheral uti li=ation of glu3ose #:6$. Cegulation of glu3ose metabolism by the

liver is a 3ompli3ated pro3ess that in3ludes several hormonal regulatory fa3tors,

s u3 h a s i ns ul in , g lu 3a go n, a nd 3 at e3 ho la mi ne s. T ra ns 3r ip ti on al a nd

posttrans3riptional regulation of I +-adrenergi3 re3eptor gene e@pression may be

responsible for the al tered hepati3 glu3ose metabolism during the progression of

seps i s #:8$ . >n3reased u t il i =a t ion o f g lu3ose during seps i s i s e@pla ined by

in3reased use of g lu3ose by ma3rophage-r i3h t i ssues su3h as l iver, spleen, and

lung #&'$. The mus3le and fat 3ells make only a only modest 3ontribution to the

in3rease in glu3ose uti l i=ation. ytokines su3h as interleukin-(, interleukin-:,

and tumor ne3rosis fa3tor- released during sepsis 3an in3rease insulin se3retion

and s ti mu la te g lu 3o se t rans po rt , l eadi ng t o i mb al an 3e b et ween g lu 3o se

produ3tion and uti li=ation #&(,&+$. !ome of these fa3tors have also been

impli3ated in indu3tion of insulin resistan3e in states of sepsis.

'ndocrine Deficiency Disorders and Hypoglycemia

D e3reas ed s e3 re ti on o f mul ti pl e g lu 3o regu la to ry h ormo nes s e3on da ry t o

re3ur rent hypogly3emia in pa ti ent s wi th insu linoma or type ( d iabe tes may

e@a3erba te hypogly3emia and p revent p rompt re3overy o f g lu3ose l eve l s.

However, in the adult , hormone defi3ien3ies alone are rarely dire3tly responsible

+


24/59

for spontaneous hypogly3emia, sin3e insulin se3retion is suppressed in response

to hypogly3emia and the 3ounterregulatory me3hanisms are part ial ly redundant.

lucagon and &atecholamine Deficiency

"lu3agon and epinephrine are important in the 3ounterregulatory response to

short-term hypogly3emia. "lu3agon in3reases endogenous glu3ose produ3tion by

stimulating hepati3 gly3ogenolysis and glu3oneogenesis. >n 3ontrast to glu3agon,

whi3h e@3lus ively affe3ts g lu3ose produ3t ion, 3ate3holamines have mul tip le

effe3ts on glu3ose homeostasis , in3luding suppress ion of endogenous insul in

se3retion, st imulation of glu3oneogenesis and gly3ogenolysis, and inhibit ion of

g lu 3o se u ti li =a ti on . T he r el at iv e i mp or tan3e o f g lu 3ago n 3ompared w it h

3ate3holamines in the physiologi3 response to hypogly3emia is 3ontrovers ialG

however, defi3ien3y of both glu3agon and epinephrine in the presen3e of insulin

may result in severe hypogly3emia #&$. >n 3l ini3al pra3ti3e, isolated defi3ien3y

of glu3agon and)or epinephrine in pat ients wi thout d iabetes i s e@t remely rare.

T he re a re v ery f ew 3as e r ep or ts o f 3hi ld ren w it h h yp og ly 3emi a t ha t w as

presume d to be due to sele3tive defi3ien3y of epinephrine or glu3agon # &5,&9$.

>n some patients with presumed glu3agon or epinephrine defi3ien3y, other 3auses

of hypogly3emia, su3h as hyperinsulinism, were not e@3luded and the se3retion

of other g lu3oregulatory hormones was not s tudied. Hypogly3emia does not

o33ur in pat ients re3eiving glu3o3ort i3oid and mineralo3ort i3oid repla3ement

therapy after bilateral adrenale3tomy and in patients treated with adrenore3eptor

blo3kers #&$. Thus, isolated defi3ien3ies of epinephrine or glu3agon rarely, if

ever, 3ause spontaneous hypogly3emia in the absen3e of hyperinsulinism or an

addit ional fa3tor that de3reases glu3ose levels.

GRO8(H+HORMONE AND )OR(ISOL DE$I)IEN)IES

>n 3ont ras t to the rapid -a3 ting hormones g lu3agon and ep inephr ine , g rowth

hormone and 3ortisol are more important in the late response to hypogly3emia.

The 3ounterregulatory effe3ts of these hormones are evident af ter more than

hours of hypogly3emia. "rowth hormone and 3ortisol in3rease plasma levels of

free fat ty a3ids and gly3erol , result ing in suppression of glu3ose uti l i=ation and

an in3rease in glu3oneogenesis. >n addit ion, 3ort isol in3reases glu3oneogenesis

by indu3tion of

P.((9&

+5


25/59

hepati3 glu3oneogeni3 en=ymes #($. The major glu3oregulatory effe3ts of growth

hormone and 3ort i so l a re on hepa t i3 g lu3oneogenes is . Therefore , defi 3 ien t

growth hormone and)or 3orti sol may 3ause hypogly3emia, espe3ially af ter a

prolonged fast when hepati3 gly3 ogen stores are depleted. The problem ma y be

3o mp ou nd ed w hen b ot h h ormo nes a re d ef i3 ient , a s s een i n p at ient s w it h

hypopituitarism.

>n 3lini3al pra3ti3e, however, most adults with growth-hormone and)or 3ort isol

defi3ien3y do not develop spontaneous hypogly3emia. Eas t ing plasma glu3ose

3on3entrations of patients with primary adrenal insuffi3ien3y and patients with

3ort i3ot ropin defi3ien3y are s imi lar to those in normal 3ontrols # &:$ . Plasma

glu3ose 3on3entrations af ter prolonged insul in infus ion were lower in pat ients

with panhypopituitarismG however, the re3overy from hypogly3emia was inta3t

#&&$, and the risk of hypogly3emia is not higher 3ompared with that in patients

with isolated defi3ien3y of growth hormone or 3ort i3otropin. ;hen present, the

tenden3y to develop hypogly3emia following prolonged fasting 3an be 3orre3ted

by glu3o3orti3oid repla3eme nt, whereas growth-hormo ne repla3ement has

minimal effe3t on fasting glu3ose # &&$. *dults with hypopituitarism may develop

hypogly3emia when glu3ose produ3tion is de3reased, as during al3ohol ingestion

or sepsis , or when glu3ose ut i li=at ion is in3reased, su3h as during vigorous

e@er3ise or pregnan3y. 1ewborns and young 3hildren with hypopituitarism are

more sus3ept ible to hypogly3emia . Thus , 3o rt i so l and g rowth hormone are

probably mo re imp ortant in glu3ose 3ounterregulation in early life. This

hypo thesi s i s suppor ted by e@per imental da ta showing that g lu3o3ort i 3o id-

defi3ient newborn mi3e develop hypogly3emia more fre?uent ly during fas ting

than do adult mi3e #&6$.

Immune Hypoglycemia

Hypogly3emia may rarely result from autoantibodies dire3ted against insulin or

the insulin re3eptor. The antibodies disrupt the syn3hronous 3oupling between

3hanges in blood glu3ose and insulin a3tion, thus leading to hypogly3emia.

H0POGL0)EMIA )AUSED " 0 AN(I"ODIES (O INSULIN

The most 3ommon 3ause for the presen3e of 3ir3ulating insulin antibodies is the

adminis t rat ion of insul in to pat ients wi th diabetes . The ant ibodies may redu3e

the levels of free insulin postinje3tion, result ing in higher postprandial levels of

+9


26/59

glu3ose, but may also in3rease the hal f- l i fe of insul in # &8$ . Theoreti3al ly , a

prolonged half- life of insulin 3auses late hyp ogly3 emia after a bolus inje3tion of

insu l in . >n p ra3 t i3e , however , the an tibod ies do no t have a major e f fe3 t on

gly3emi3 3ontrol and the in3iden3e of severe hypogly3emia #6'$. *ntibodies to

insul in also may develop in pat ients wi th re3ent-onset type ( diabetes before

insulin treatment, relat ives of patients with type ( diabetes or other autoimmune

disorders, and o33asionally in otherwise healthy subje3ts # 6($.

>n rare patients, insulin antibodies may be a primary 3ause of hypogly3emia. The

majori ty of pat ients wi th hypogly3emia indu3ed by ant ibodies to insul in are

0apanese. The higher prevalen3e of autoimmune hypogly3emia in the 0apanese

population is probably e@plained by the higher prevalen3e of spe3ifi3 H* 3lass

+ al leles that are s t rongly asso3iated wi th the disease in th is populat ion #6+$ .

Hypogly3emia is of ten postprandial, a l though fas ting hypogly3emia may also

o33ur. Patients often develop hypergly3emia immediately after a meal or glu3ose

load followed by hypogly3emia + to hours later. The severity of hypogly3emia

varies, and the presentation may be of severe neurogly3openia with symptoms of

3onfusion, 3ogn it ive dys fun3tion, and even 3oma. Pa ti ent s may have o ther

autoimmune diseases, su3h as "raves disease, systemi3 lupus erythematosus, or

rheumatoid a r th r it i s #6'$. nterferon- and medi3ations that 3ause drug-indu3ed lupus, su3h as hydrala=ine,

pro3ainami de, and isonia=id, also ma y 3ause the development of insulin

antibodies and hypogly3emia. !everal patients with plasma-3ell dys3rasias were

reported to have hypogly3emia due to mono3lonal insul in-binding ant ibodies

with a low affinity for insulin and a high binding 3apa3ity # 6'$. >nsulin levels in

patients with insulin antibodies 3ausing hyp ogly3 emi a usually are high #(''

Q)m$. The endogenous insulin antibodies may interfere with the insulin assay,

leading to spurious high or low results , depending on the insulin assay used. -

peptide levels are not fully suppressed be3ause insulin is endogenously se3reted.

>n 3ontras t , surrept i t ious insul in in je3t ion leads to high plasma insul in levels

together wi th 3omplete suppression of -pept ide se3ret ion. The presen3e of

insul in ant ibodies 3an be 3onfi rmed by high binding of radioa3t ively labeled

insulin to polyethylene gly3ol-pre3ipitated serum samples or by en=yme-linked

immunosorbent assay #6($. >nsulin autoantibodies asso3iated with hypogly3emia

+:


27/59

3annot be d i st ingui shed f rom those found in insu lin -t rea ted pa ti ent s wi th

diabetes.

The pathogenesis of hypogly3emia 3aused by insul in ant ibodies ref le3ts the

e?uil ibrium between bound and free insulin, leading to inappropriate release of

f ree insu l in that d i sso3ia tes f rom the ant ibod ies whi le the b lood g lu3ose

3on3ent rat ion i s a l ready de3reased. /ther poss ible me3hani sms , in3luding

enhan3ement of insul in binding to i t s re3eptor resul t ing from 3ross- l inking by

the insu l in an tibod ies o r d i re3 t s t imula tion o f insu lin se3re tion by insu lin

antibodies, may be operative in some patients #6'$.

os t p at ient s w it h aut oi mmun e h yp og ly3emi a d ue t o i ns ul in ant ib od ie s

e@p er ien3e s po nt an eo us r emis si on #6 +$ . > f aut oi mmun e h yp og ly3emi a i s

pre3ipitated by a me di3at ion, it should be dis3ontinued and the problem of

hypogly3emia will resolve. Patients with re3urrent nonremitt ing hypogly3emia

may benef it f rom f re?uen t low-3arbohydrate meal s to redu3e postprand ial

hypergly3emia and insulin se3retion. edi3ations that redu3e glu3ose absorption

or insulin se3retion, su3h as a3arbose, dia=o@ide, and o3treotide, have also been

usedG however, the results are not 3onsistent . Einally, glu3o3orti3oid therapy and

plasmapheresis have also been tried, with the goal of lowering the titer of

insulin antibodies #6'$.

H0POGL0)EMIA )AUSED " 0 AN(I"ODIES (O INSULIN RE)EP(OR

ost patients with hypogly3emia 3aused by antibodies to the insulin re3eptor are

women. * his tory of 3on3omitant autoimmune disease is 3ommon, and several

patients with Hodgkin disease have been reported. The hyp ogly3 emi a ma y be

f as ti ng o r p os tp ra nd ia l a nd o ft en p re se nt s w it h s ev er e s ym pt om s o f

neurogly3openia. Hypogly3emia may be pre3eded by a phase of severe insul in

resi s tan3e asso3 ia ted wi th a3an thos is n igr i 3ans and hyperg ly3emia in some

patients, whereas others present only with hyp ogly3 emia. The reason for the

versati l i ty in the biologi3 fun3tion of the insulin re3eptor antibodies, even in the

same pa ti ent a t d if ferent t ime po in t s, i s not 3 l ear . > t may be re la ted to the

possibility that the poly3 lonal antibodies to insulin re3eptor are 3omp osed of

d i ffe rent subpopula t ions o f immunoglobu l ins , some a3 tivat ing the insu l in

re3eptor and others inhibi t ing insul in a3t ion. Thus , variat ion in the t i ter of

di fferent ant ibody populations over t ime may determine whether the pat ient

+&


28/59

presents with insulin resistan3e or hyp ogly3 emi a. The t iter of the insulin-

re3eptor antibodies also may affe3t the

P.((96

3lini3al presentation. ow antibody t i ter with part ial o33upation of the insulin

re3eptor may indu3e ma@imal s t imulat ion of the insul in re3eptor , leading to

hypogly3emia. However, a h igh t i ter of insul in ant ibodies may in3rease the

degradation of the insulin re3eptor and de3rease the number and fun3tion of the

re3eptors, leading to insulin resistan3e and hypergly3emia. >t also was suggested

that the appearan3e of low-aff in i ty insul in re3eptors that are res is tant to the

inhibi tory effe3ts of insul in-re3eptor ant ibodies may 3ontr ibute to the swi t3h

from insul in res istan3e and hypergly3emia to hypogly3emia in some pat ients

with insulin-re3eptor antibodies #6'$.

>nsulin levels are usually higher than e@pe3ted for the glu3ose 3on3entration and

may suggest the p resen3e o f an insu linoma. However , -pep tide l eve l s a re

usually part ia l ly or 3ompletely suppressed. The 3ause of the nonsuppressed

insu l in l eve l s i s no t known and may be re la ted to de3reased 3 learan3e o f

3i r3ulat ing insul in by re3eptor-mediated endo3ytosis and)or a3t ivat ion of the

insulin re3eptors on pan3reati3 I-3ells , whi3h may augment insulin produ3tion

#6$ . The p rognos i s o f hypogly3emia asso3 ia ted wi th an tibod ies to insu l in

r e3 ep to r i s p oo r, w it h a h ig h m or ta li ty r at e d ue t o s ev er e 3 on 3o mi ta nt

au to immune d i sease o r malignan3y and potent i al ly severe hypogly3emia .

H ypo gl y3 emi a ma y r es pond to a hi gh- do se gl u3 o3 or ti3 oi d t her ap y.

Plasmapheresis and 3ytoto@i3 drugs su3h as 3y3lophosphamide 3an also be used

to redu3e the t i ter of antibodies to insulin re3eptorG however, the 3l ini3al effe3t

is in3onsistent and the e@perien3e with these therapies for hypogly3emia indu3ed

by insulin-re3eptor antibody is limi ted #6'$.

.umor-!ssociated Hypoglycemia

INSULINOMA

>nsul in-produ3ing is let -3el l tumors o33ur wi th an in3iden3e of 5 per ( mi l l ion

person-ye ars. The onset is usually insidious. *bout 857 of the tumors are

sporadi3, while the rest o33ur as part of the multiple endo3rine neoplasia type (

s yn drome R< 1( G en de li an >nh er it an 3e i n an #>$ n o. ( ( (' 'G a t

http4))www.n3bi.nlm.nih.gov)/mim) S . % et we en 97 a nd (' 7 of t umor s a re

+6
http://www.ncbi.nlm.nih.gov/Omim/http://www.ncbi.nlm.nih.gov/Omim/


29/59

malignant #65$. Diagnosis is made by submitt ing the patient to a prolonged fast ,

whi3h is terminated ei ther when neurogly3openia i s demonstrated or af ter &+

hours . The defini t ive diagnosis i s based on the ;hipple t r iad , 3ombined wi th

levels of nonsuppressed insulin, -peptide, and proinsulin. * re3ent publi3ation

suggests that a 56-hour fast may be suffi3ient to 3onfirm the diagnosis in almost

all 3ases #69$. >t is of 3ri t i3al importan3e to differentiate tumor hyperinsulinism

from fa3ti t ious hyperinsulinism 3aused by surrepti t ious inje3tion of insulin or by

ingestion of I-3ell-st imulating drugs #see above$. >nsulinomas are dis3ussed in

more detail in hapter &'.

NON+ISLE( )ELL (UMOR H0POGL0)EMIA

Hypogly3emia may rarely o33ur in asso3iat ion wi th non-is let 3el l tumors . The

maj or it y a r e l arge mes en 3h ymal and epi th el ia l t umors s u3h a s s ar 3oma,

mesothelioma, fibroma, hemangioperi3ytoma, and hepatoma. Two thirds of the

tumors a re e i ther re troper itonea l o r abdominalG mos t o f the rest a re in the

thora@. /ther 3ommon 3an3ers o33as iona l ly asso3 ia ted with hypogly3emia

in3lude 3an3er of the lung, breast , k idney, and the gas trointes t inal t ra3t and

endo3rine tumors su3h as 3ar3inoid and adreno3orti3al 3ar3inoma. Patients with

hematologi3 malignan3ies su3h as leukemia and lymphoma may rarely develop

hypogly3emia . >n these pat i en t s, tumor-asso3 iated hypogly3emia must be

dist inguished from pseudohypogly3emia 3aused by in vi tro glu3ose metabolism

by the markedly elevated white blood 3ells #see above$. Carely, hyp ogly3 emia

may be the presenting symptom in patients with non-islet 3ell tumors, al though

it is more 3ommon for i t to develop in a patient with a known malignant tumor.

The 3lini3al symptoms resemble those of an insulinoma, with neurogly3openia

being the promi nent feature. "l u3ose uti li=ation is markedly in3reased, and

patients may re?uire large ?uanti ties of intravenous glu3ose to ma intain normal

plasma glu3ose 3on3entrations. Hyp ogly3 emia ma y be severe and refra3tory to

medi3al treatment. ;hen possible, 3omplete surgi3al rese3tion will ameliorate

the hypogly3emia. Pat ients for whom 3omplete rese3t ion is not feas ible may

benefit from partial removal of the tumor, whi3h 3an be asso3iated with

prolonged remi ssion of hyp ogly3 emia.

The pathogenesis of non-islet 3ell tumor hypogly3emia #1>TH$ is 3 omple@, and

mult ip le fa3tors may be involved. The tumor i t sel f u t i l i=es large amounts of

glu3oseG however , g lu3ose uptake by peripheral t i ssues i s a lso in3reased and

+8


30/59

hepat i3 g lu3ose p rodu3t ion i s inhib it ed, suggest ing in3reased insu lin -l ike

a3t ivi ty #6:,6&$ . evels of 3i r3ulat ing insul in , -pept ide, and proinsulin are

suppressed.

The presen3e of a humoral fa3tor that mediates the tumor-indu3ed hypogly3emia

has been s tudied e@tensively . >nsul in- l ike growth fa3tor >> # >"E->>$ , a protein

with high homology to proinsulin, is e@pressed and se3reted from mesen3hymal

tumors that 3ause hypogly3emia #6&,66$. >"E->> 3an bind to the insulin re3eptor,

3ausing insulin-l ike a3tivity in the absen3e of insulin. ir3ulating levels of >"E-

> > a re modest ly in3reased in some but no t a l l pa ti ent s with tumor-indu3ed

hypogly3emia and return to normal af ter surgi3al rese3t ion of the tumor and

resolution of hypogly3emia #68$. /verprodu3tion of an in3ompletely pro3essed

form of >"E->> wi th a h igher mole3ular weight #NbigO >"E->>$ i s found in most

patients with non-I-3ell tumo rs and hyp ogly3 emi a #8',8($.

nder physiologi3 3ondi t ions , >"E->> forms a (9'-kDa 3omple@ together wi th

insu l in - like g rowth fa3to r-b ind ing p rote in # >"E%P-$ and an a3 id - lab il e

subunit #*!$. 1ormally, the majori ty of the 3ir3ulating >"E->> is transported as

part of the (9'-kDa 3omp le@, only +97 being in a free form. The large 3omp le@

3rosses the 3apil lary bed very poorlyG thus, only a small fra3tion of >"E->> 3an

bind to insul in re3eptors in the target t issues and e@ert its hyp ogly3 emi 3 effe3t.

>n some pat ients wi th tumor-indu3ed hypogly3emia, b ig >"E->> forms smal ler

3omple@es and the (9'-kDa 3omple@ is absent or de3reased. The 3ause of th is

fa i lu re to fo rm the NnormalO (9'-kDa 3omple@ i s no t 3 l ear and may vary in

different patients. *bnormal gly3osylation of big->"E->> has been proposed, but

i t i s not 3er tain that th is i s responsible for the abnormal 3omple@ format ion

#8+,8$. /ther possible me3hanisms in3lude defe3ts in the se3retion of the *!

and preferent ial b inding of the big >"E->> to proteins other than >"E%P- and

*!. %a@ter et al . #85$ suggested that big >"E->> i tself may inhibit a3id-labile

subuni t b inding to the >"E%P- di re3t ly , thus prevent ing the format ion of the

(9'-kDa 3omple@. Cegardless of the me3hanism involved, fai lure to form the

(9'-kDa 3omple@ 3auses a larger fra3t ion of >"E->> to be t ransported in smal l

3omple@es o r as a f ree p rote in that i s more read i ly avai l ab le fo r b ind ing to

insulin re3eptors. Therefore, al though total >"E->> may be normal or only mildly

elevated, the levels of the bioa3tive >"E->> are typi3ally in3reased #8',8(,8+$.

'


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Patient s wi th 1>TH f re?uen t ly have low serum leve l s o f g rowth hormone ,

whi3h may fu rther de3rease hepa t i3 g lu3ose p rodu3t ion and e@a3erba te the

hypogly3emia #68$. *lthough insulin and total >"E-> levels are typi3ally low in

patients with 1>TH, free >"E-> levels in plasma re3ently we re shown to be

markedly elevated, suggesting a possible me3hanism to e@plain the low levels of

g ro wt h h ormo ne s een i n t he se p at ient s #8 ( $. T he d iagn os is o f 1 >TH i s

suggested when hypogly3emia is

P.((98

found in 3ombina t ion with suppressed insu lin , -pep tide, and to ta l >"E->

3on3entrations. >"E->> levels may be elevated, but the measurement of big >"E-

>> may be superior for the definit ive diagnosis of 1>TH.

t was

3onvin3ingly shown in one re3ent 3ase report of a patient with 3ar3inoma of the

uterine 3ervi@ #89$. Celative hyperinsulinemia was demonstrated in a few other

patientsG however, e3topi3 insulin se3retion by the tumo r was not proven

#8:,8&$.

NONINSULINOMA9 PAN)REA(OGENOUS H0POGL0)EMIA S0NDROME

Hyperinsulinemi3 hypogly3emia not 3aused by an insulinoma was des3ribed in

five patients evaluated at the a yo li ni3 # 86$. *ll patients had

neurogly3openi3 symptoms + to 5 hours after a meal but not during a prolonged

#&+ hour$ fast . 1o insu linoma was found during opera tion by pa lpa tion and

in traopera t ive u lt rasound . *ll pa ti ent s had a posi t ive response to a r te r ia l

3al3ium s t imulat ion and underwent gradient-guided part ial pan3reate3tomy.

There was no re3urren3e of symptoms during prolonged follow-up after surgery.

Pan3reati3 t issue from all patients showed islet hyperplasia and nesidioblastosis.

1o insulinoma was found in the rese3ted pan3reati3 tissue. utations in the

SUR1 and Kir6.2 genes that are 3ommon in pat ients wi th famil ial pers is tent

hyperinsulinemi3 hypogly3emia of infan3y were not identified in these patients.

This syndrome is rare , as there were only nine adul t pat ients wi th his tologi3

f indings of nes idioblas tos is among '' pat ients who underwent surgery for

suspe3ted insul inoma at the ayo l ini3 . The pre3ise et io logy of th is ent i ty,

w hi 3h may r ep re sent a n ov el me3hani sm o f h yp og ly3emi a , i s n ot k no wn .

P re vio us st udi es ha ve de s3 ri bed ra re 3a ses of h ypo gl y3 emi a du e t o

(


32/59

Nnesidioblas tos isO in adul ts , but the genet i3 s tudies were not done at the t ime

#88,(''$.

C ar el y, p at ie nt s wi th h yp er in su li ni sm d ue t o m ut at io ns o f g lu ta ma te

dehydrogenase, g lu3okinase, or of ei ther of the I-3el l K* T P-3hannel genes #see

below$ ma y have mi ld disease that only 3omes to medi3al at tention during

adul thood. * 3omplete medi3al h i sto ry may revea l epi sodes o f id iopathi3

ep il epsy o r o ther s igns o f neurogly3open ia a f te r p rolonged fast o r during

inter3urrent i l lness in the neonatal period or during 3hildhood.

Reactive Hypoglycemia

Cea3t ive hypogly3emia re fers to d i so rders in whi3h hypogly3emia o33urs

e@3lusively after meals and not in the postabsorptive state. *ll the disorders that

3ause pos tabsorp tive hypogly3emia a l so 3an p rodu3e hypogly3emia in the

postprandial state. Thus, the term Nrea3tive hyp ogly3 emiaO does not have any

impli3at ion regarding the et iology, and the presen3e of a syndrome 3ausing

postabsorptive hyp ogly3 emi a should always be 3onsidered in patients with

postprandial hyp ogly3 emia.

ongeni t al defe3 ts in 3arbohydra te metabo l ism, su3h as ga la3 tosemia and

heredi tary fru3tose in toleran3e, 3ause postprandial hypogly3emia in 3hi ldren

#see be low$. >n adul t s rea3 t ive hypogly3emia 3an be subd ivided into three

3ategories4 #a$ hypogly3emia af ter surgery of the upper gas t rointes tinal t ra3t

#alimentary hypogly3emia$, #b$ hypogly3emia in patients with elevated glu3ose

i n an o ra l g lu 3o se t ol er an 3e t es t # ea rl y d iabe te s h yp og ly3emi a $, and # 3$

idiopathi3 fun3tional hypogly3emia.

ALIMEN(AR0 H0POGL0)EMIA

*limentary hypogly3emia o33urs in some pat ients af ter gas tre3tomy with or

without gastri3 drainage pro3edure and rarely in the absen3e of gastrointestinal

surgery #('($. The hypogly3emia results from a33elerated movement of ingested

food into the smal l in tes tine, fo llowed by rapid absorpt ion o f g lu3ose that

s t imula tes insu l in se3ret ion . ! t imula tion o f en ter i3 hormone se3re tion may

further augment insu l in se3ret ion . The hypogly3emi3 e f fe3 t o f the se3reted

insu l in pers is t s a f te r the g lu3ose load i s 3 l eared f rom the 3 i r3u la t ion, thus

leading to hypogly3emia. Typi3al ly, hypergly3emia develops wi thin hal f an

h ou r, f ol lo wed b y h yp og ly3emi a app ro @i ma te ly ( .9 t o h ou rs a ft er f oo d

ingestion. !ymptoms may be severe, in3luding sei=ures, 3oma, and even death.

+


33/59

*limentary hypogly3emia should be dist inguished from the dumping syndrome

that may 3ause s imi lar symptoms wi thin ( hour af ter eat ing in the absen3e of

hypogly3emia. The dumping syndrome is 3aused by 3ontra3t ion of the plasma

volume due to f lu id shi f t in to the gas t rointest inal t ra3t # +$ . %oth dumping

syndrome and a l imentary hypogly3emia have be3ome very ra re , s in3e mos t

patients with pepti3 ul3er disease are now treated medi3ally.

REA)(I*E H0POGL0)EMIA ASSO)IA(ED 8I(H EARL0 DIA"E(ES

MELLI(US

Cea3t ive hypogly3emia was reported to be an early mani fes ta t ion o f type +

d iabe tes more than four de3ades ago #('+$ . Diabe ti 3 pa ti ent s with rea3 t ive

hypogly3emia usua l ly have mild hyperg ly3emia and develop symptoms of

hypogly3emia to 9 hours after a meal. >t was suggested that the hypergly3emia

provokes a gradual in3rease in insulin se3retion, wh i3h may persist after the

d is po sa l o f t he i ng es ted g lu 3o se , l eadi ng t o t he l at e h yp og ly3emi a . T he

prevalen3e and signifi3an3e of rea3tive hyp ogly3 emia in patients with diabetes

is 3ontrovers ial . Type + diabetes i s a 3ommon diseaseG however , spontaneous

postprandial hyp ogly3 emi a has been do3umented in very few patients. oreover,

in some pa ti ent s the d iagnos i s was based on an o ral g lu3ose to le ran3e t est

#/"TT$ that showed elevated blood glu3ose levels within the first + hours after

g lu3ose load , fo llowed by g lu3ose l eve l s be low 9' mg)d. The 3orre la t ion

between low blood glu3ose 3on3entrations several hours after an oral glu3ose

load and postprandial hypogly3emia is poor. Eor e@ample, only 97 of pat ients

with early diabetes and hypogly3emia after an oral glu3ose load had symptoms

of hypogly3emia a f te r meal s #('$ . > t i s poss ib le that pa ti ent s f re?uen t ly

develop asymptomat i3 hypogly3emia during the early s tages o f d iabe tes G

however, there are no data to support this hypothesis.

IDIOPA(HI) $UN)(IONAL H0POGL0)EMIA

!ymptoms suggest ive of hypogly3emia several hours af ter a meal are 3ommon.

The appearan3e of postprandial autonomi3 symptoms is 3ommonly diagnosed as

Nrea3tive hypogly3emiaOG however, blood glu3ose 3on3entrations are not usually

measured during su3h Nhypogly3emi3O episodes and when measured are usually

normal . ost pa ti ent s wi th au tonomi3 symptoms af te r meal s evaluated fo r

hypogly3emia have been found to have psy3honeuro ti 3 d i stu rban3es wi th

fre?uent somat i3 3omplaints #('5,('9$. *n effort to do3ument the 3orrelat ion


34/59

between gly3 emi a and symptoms was ma de by measuring blood glu3ose in +6

patients during a total of (+ reported episodes of symptomati3 hyp ogly3 emi a.

/nly si@ #97$ of these episodes were asso3iated with blood glu3ose levels below

9' mg)d #+ .6 mmol)$, and these o33urred in f ive #(67$ di fferent pat ients .

Celief of symptoms by ingesting food was more often asso3iated with low than

with normal blood glu3ose levels #+5$ . >n another s tudy of ((6 pat ients wi th

suspe3ted pos tprand ial hypogly3emia , on ly f ive #57$ were found to have

hypogly3emia after a glu3ose load and after meals # (':$.

>n many pa ti ent s , low g lu3ose l eve l s dur ing an /"TT are used to d iagnose

rea3tive hypogly3emia be3ause i t may be diffi3ult

P.((:'

to do3ument g lu3ose l eve l s during symptomat i3 epi sodes. However , when

3ri t i3al ly evaluated, no 3orrelat ion was found between plasma glu3ose levels

measured after oral glu3ose administrat ion and glu3ose levels measured during

symptoms. Eurthermore, most pat ients wi th low blood glu3ose levels af ter an

oral glu3ose load have normal glu3ose levels after a mi@ed meal #+$. >n a large

study of :9' healthy subje3ts who remained asymptomati3 during a (''-g /"TT,

+97 had a 3ir3ulating glu3ose nadir below 95 mg)d, ('7 below 5& mg)d, 97

below 5 mg)d, and +.97 below 5' mg)d # (':$. The fa3t that appro@imately

('7 of the general heal thy populat ion has nadir g lu3ose levels lower than 9'

mg)d indi3ates that a low glu3ose level on /"TT is not a rel iable 3ri terion for

the diagnosis of rea3tive hypogly3emia, and thus this test should not be used for

this purpose. nsulin

sensit ivity is in3reased in patients with idiopathi3 rea3tive hypogly3emia #('&$.

The 3hanges in insu lin sens i tivi ty a re p robably no t e@p lained by in3reased

binding of insulin to its re3eptor, and there is no eviden3e that insulin se3retion

is in3reased. * redu3ed glu3agon response may play a role in the development of

late hypogly3emia af ter g lu3ose ingestionG however , there are few data that

support this hypothesis #('6$.

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(REA(MEN(

ow-3arbohydrate o r h igh- fiber d iet s , avoidan3e o f s imple sugars tha t a re

rapidly absorbed , and the use o f mul t ip le smal l meal s a re re3ommended fo r

patients with rea3tive hyp ogly3 emi a. * high-protein diet is often admi nistered to

patients with rea3tive hyp ogly3 emi aG howe ver, this diet is also high in fat and i ts

3l in i3al eff i3a3y is unknown. Therefore, i t should no longer be re3ommended.

ornstar3h, do@epin, -glu3osidase inhibitors, biguanides, and anti3holinergi3

agents have been su33essful in some pat ients wi th rea3t ive hypogly3emia. The

eff i3a3y and the pre3ise role of su3h t reatments in the management of rea3tive

hypogly3emia need to be determined in larger studies # +$.

DIAGNOS(I) AND (HERAPEU(I) APPROA)H (O (HE

H0POGL0)EMI) PA(IEN(

Diagnoi dan Penatalakanaan Hi-oglike!ia

The symptoms and s igns of hypogly3emia are nonspe3if i3G therefore, the f i rs t

s tep in the evaluat ion of a pat ient wi th suspe3ted hypogly3emia is a lways to

d o3u ment l ow b lo od g lu 3o se w hen t he p at ient e@p er ien3es s po nt an eo us

symptoms.

"eja la-geja la dan t anda-tanda h ipogl ikemi bers ifa t non spes i fik, sehingga

langkah awal dalam mengevaluasi pasien yang diduga mengalami hipoglikemia

adalah dengan menentukan kadar glukosa darah.

The demonstration that symptoms are rel ieved by an in3rease in blood glu3ose

level fo l lowing ingest ion of food or g lu3ose fur ther supports the diagnosis of

hypogly3emia #;hipple triad$.

Cep ea ted n orma l b lo od g lu 3o se measu rement s d ur in g t he o 33ur ren3e o f

symptoms e@3lude the possibil i ty of hypogly3emia, and no further evaluation is

re?uired for th is d iagnosis . >n some pat ients , do3umentat ion of b lood glu3ose

d ur in g s po nt an eo us s ympt oms may b e d if fi 3u lt b e3au se t he s ympt o ma t i3

episodes are infre?uent, the duration of symptoms is short , and the patient is far

from a medi3al fa3il i ty. "lu3ose-meter measurements of 3apil lary blood glu3ose

3an be used to 3orre la te pa ti ent symptoms with b lood g lu3ose l eve l s and to

e@3lude hypogly3emia as the 3ause o f the symptoms. However , the resu lt s

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should be in terpreted wi th 3aut ion be3ause the measurement of b lood glu3ose

may be te3hni3al ly poor be3ause i t i s performed by an ine@perien3ed pat ient

suffering from autonomi3 and potential ly neurogly3openi3 symptoms.

* 3areful h i sto ry o f the o33upat ion o f the pa ti ent G the e@ is t en3e o f fami ly

members with diabetes being treated with sulfonylureas or insulinG and al3ohol

abuse, predisposing i l lnesses, and medi3ations taken by the patient is 3ru3ial to

making the 3orre3t diagnosis. The patient should be asked about the fre?uen3y

and duration of symptomati3 episodes, the presen3e of neurogly3openia and)or

autonomi3 symptoms, whether they are rel ieved by ingest ion of g lu3ose, and

when the symptoms o33ur # fas ting vs . postp randia l$ . Pa ti ent s who develop

hypogly3emia only during the postprandial period may have idiopathi3 rea3tive

hypogly3emia. However, o ther hypogly3emi3 disorders , in3luding insul inoma,

may present as postprandial hypogly3emia, and therefore prompt evaluation of

other 3auses of hypogly3emia should be performed.

>f hypogly3emia is 3onfirmed or the 3l ini3al suspi3ion for hypogly3emia is high

but me asuring blood glu3ose during spontaneous symptoms is not feasible, the

patient should be admi tted for further testing # Eig. :8.5$. The ne@t diagnosti3

step is to measure insulin, -peptide, and, if possible, proinsulin levels. *l3ohol

and medi3ations known to 3ause hypogly3emia should always be 3onsidered and

dis3ont inued before the pat ient i s evaluated. This may prevent unne3essary,

t ime-3onsuming , and e@pensive t est s . > f the ep isodes o f hypogly3emia a re

infre?uent, i t may be ne3essary to provoke hypogly3emia by a prolonged 56- to

&+-hour fast or by insulin infusion to test -peptide suppression. Celatively high

leve l s o f insu lin , -pep tide, and p roinsu lin dur ing spon taneous o r indu3ed

hypogly3emia and the fai lure to suppress -pept ide se3ret ion in response to

insulin-indu3ed hypogly3emia suggest the diagnosis of insulinoma #see hapter

&' on i s le t -3e ll tumors$ . %lood l eve l s o f o ral insu lin se3re tagogues shou ld

always be measured during hypogly3emia to e@3lude surrepti t ious administration

of drugs. Care patients with insulin antibody-mediated hypogly3emia may also

h av e h yp er in su li ne mi 3 h yp og ly3 em ia w it h n on su pp re ss ed -p ep ti de .

Hypogly3emia asso3iated with high levels of insulin and suppressed -peptide

s ug gest s s ur r ep ti ti ou s admin is tr at io n o f i ns ul in G h ow ev er , p at ient s w it h

autoimmune antibodies to insulin re3eptor may also present with inappropriately

h ig h l ev el s o f i ns ul in and s up pres sed -p ep ti de d ur in g h yp og ly3emi a.

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!uppression of both insulin and -peptide levels during hypogly3emia suggests

the diagnosis of tumor-indu3ed hypogly3emia, and determination of plasma >"E-

> > and app ro pr ia te i magi ng s tu di es s ho ul d b e p er fo rmed . D ef i3 ien3 ie s i n

g lu3oregula to ry hormones, in3luding 3or t iso l and g rowth hormone , shou ld

always be e@3luded, al though defi3ien3ies in glu3oregulatory hormones alone in

o th erwi se h ea lt hy s ub je3t s w il l r ar el y 3au se h yp og ly3emi a u nd er n orma l

3ondit ions.

$igure 12/:/ ;orkup of hypogly3emia in the non-a3utely i l l patient . a!ee te@t for

defini t ion of t rue hypogly3emia. bCare patients with insulin antibody-mediated

hypogly3emia may also have hyperinsulinemi3 hypogly3emia with nonsuppressed

-pept ide. The endogenous insul in ant ibodies may interfere wi th the insul in

assay, leading to spuriously high or low results , depending on the insulin assay

used. easurement of antibodies to insulin is not part of the routine workup of

hypogly3emiaG however, i t should be 3onsidered in some patients. 3Patients with

autoimmune antibodies to insulin re3eptor may also present with inappropriately

h ig h l ev el s o f i ns ul in and s up pres sed -p ep ti de d ur in g h yp og ly3emi a.

easurement of antibodies to insulin re3eptor is not part of the routine workup

of hypogly3emiaG however , i t should be 3onsidered in some pat ients . dTH$. Treatment of the underlying a3ute i l lness , improvement in 3r i t i3al -organ fun3tion, and 3areful monitoring of the drugs administered to the patient

result in resolut ion of hypogly3emia, and e@tensive hormonal evaluat ion is

usually not re?uired.

P.((:(

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H0POGL0)EMIA IN DIA"E(ES

MELLI(US

)lini6al )onte;t

!aat ini telah disepakati bahwa penatalaksanaan yang kompre-

hensif sangat penting bagi pasien diabetes, yaitu berupa kendaliglikemik. Kendali glikemik yang optimal dapat men3egah atau

menghambat progresivitas penyulit kronik #retinopati, nefropati

dan neuropati$ serta dapat men3egah komplikasi makrovaskular.

1amun demikian, timbulnya efek samping hipoglikemi iatrogenik

dalam penatalaksanaan D baik pada D tipe ( maupun D

tipe + merupakan kendala yang patut diperhitungkan.

on3eptually,were it not for the potentially devastating effe3ts

of hypogly3emia on the brain, hypergly3emia would be

rather easy to treat. *dministration of enough insulin #or any

effe3tive medi3ation$ to lower plasma glu3ose levels to or below

the normal range would eliminate symptoms of hypergly3emiaG

prevent diabeti3 ketoa3idosis and hyperosmolar 3omaG

almost assuredly prevent diabeti3 retinopathy,nephropathy,

and neuropathyG and probably redu3e atheros3leroti3 risk. The

devastating effe3ts of hypogly3emia are real,however, and the

gly3emi3 management of diabetes is therefore 3omple@.>n pra3ti3e,eugly3emia,even near eugly3emia, 3annot

be a3hieved and maintained safely in most patients with

T(D&9,&: and many patients with T+D&& be3ause of the

barrier of iatrogeni3 hypogly3emia. %e3ause of that barrier,

retinopathy,nephropathy, and neuropathy develop or progress

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in some patients with T(D&9,&: or T+D&& despite aggressive

attempts to a3hieve gly3emi3 3ontrol,albeit at lower rates

than during less aggressive therapy. >ndeed,the inability to

maintain eugly3emia over time,be3ause of the barrier of

hypogly3emia,may e@plain the limited impa3t of aggressivegly3emi3 therapy on the atheros3leroti3 3ompli3ations of diabetes.

&9B&&

>n T(D,aggressive attempts to a3hieve gly3emi3 3ontrol

in3rease the risk of severe,at least temporarily disabling, iatrogeni3

hypogly3emia #i.e.,that re?uiring the assistan3e of another

individual$ more than threefold #Eig. +&$. Do3umented

in both of the 3ontrolled 3lini3al trials with sample si=es large

enough to demonstrate benefi3ial effe3ts of intensive therapyon the long-term 3ompli3ations of diabetes,the Diabetes ontrol

and ompli3ations Trial #DT$&9,&8,6' and

hypoglycemia william

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