Thietkenghien ctfu: md ta hoi cUu, cac xet nghiem ALT va ALP dupe truy xuat tU phan mem lUu trU dU lieu ket qua xet nghiem can lam sang tai khoa Hda sinh, thong tin trong benh an dup[r]
Trang 6Tdm seat ton Hwang gan do thuoc thong
qua ket qua xet nghiem can lam sang
tqi Benh vien Huu Nghi
Tran Thj Ngoc\Tran Ngan Ha1, Nguyen Khac Dung1, Tran Thu Thuy1, Nguyen Thj Phuong Ngoc2, Hoang Thj Minh Hien2,
PhamThj Dieu Huyen2, Nguyen Hoang Anh1
'Tn/dng Dai hoc DUpc Ha Npi
2 Benh vien HCfu Nghi SUMMARY
This study revised data of inpatients at Huu Nghi hospital to determine incidence of drug-induced liver injuries (DILI) based
on laboratory database of alkaline phosphatase (ALP), alanine aminotransferase (ALT) laboratory signals and the descriptions
of DILI Screening was performed with the help of biochemistry database followed by detail medical record review for suspected cases and the assessment was made in accordance to the definition of DILI Of 369 patients with abnormal liver lab tests, 22 suspected drug-induced liver injuries (6.0%) cases were identified The incidence of DILI among inpatients was 22/20088 (0.11 %) Antibiotics were the leading therapeutic class implicated in DILI, in which flouroquinolones like levofloxacin, ciprofloxacin were
of most common The severity of liver injuries in most of the casess were found serious and life-threathening, with short lag time of less than one week and without clear clinical symptoms DILI took about one month to be resolved Results of this study suggested the usefulness of new method to detect incidence of DILI in routine practice
TCtkhoa: ALP, ALT, ton thaong gan do thuoc, DILI, tarn sodt
Dot van de
Ton thoong gan do thuoc (DILI) la mot van de an
toan thuoc dupe quan tarn dac biet hien nay, ty le
dao dpng tU 4 - 10% cac phan Ung co hai do thuoc
gay ra, dong thdi la ly do quan trpng nhat dan den
rut so dang ky va dinh chl Idu hanh thuoc tren thj
trudng [6], [9].Tren the gidi, cac nghien cdu danh gia
DILI da dupe tien hanh tai Phap, Tay Ban Nha,
Australia, vdi nhieu hudng tiep can khac nhau [3], [8],
[9] Tai Viet Nam, viec danh gia DILI van con han che
va chua cd nghien cUu nao dupe thuc hien theo
hudng tiep can tarn soat cac xet nghiem can lam
sang de sang Ipc ra cac ca ton thuong gan Hon nUa,
trong thuc hanh lam sang, cac ca ton thuong gan
thudng dupe phat hien chu yeu bdi bac si hoac dieu
dudng thong qua dien bien lam sang cua benh nhan
va sp tham gia cua dupe si lam sang con han che Vi
vay, de md rpng phuong phap phat hien DILI va tang
cUdng vai trd cua dupe si lam sang, dong thPi ho trp
phat hien ton thuong gan thong qua sang Ipc xet
nghiem enzym gan chung tdi thpc hien nghien cUu
nay vdi muc tieu phat hien nhUng bat thudng chUc nang gan thong qua ket qua xet nghiem can lam sang va phan tich dac diem ton thuong gan nghi ngd do thuoc tren nhUng benh nhan cd bat thudng chUc nang gan tai Benh vien HUu Nghj
Doi tirong va phuong phap nghien cuv
Doi twang nghien cdfu
Tat ca cac xet nghiem enzym gan alanin aminotransferase (ALT) va alkalin phosphatase (ALP)
cd ngay lam xet nghiem tU 01/01/2015 den 31/12/2015 va benh an cua nhUng benh nhan nghi ngd cd ton thuong gan do thudc
Phuang phap nghien cWu
Thietkenghien ctfu: md ta hoi cUu, cac xet nghiem
ALT va ALP dupe truy xuat tU phan mem lUu trU dU lieu ket qua xet nghiem can lam sang tai khoa Hda sinh, thong tin trong benh an dupe thu thap theo mau phieu thu thap thong tin benh nhan bao gdm: cac thong tin hanh chinh, xet nghiem enzym gan va cac gia trj xet nghiem khac, dien bien lam sang va cac thudc benh nhan sUdung trong thdi gian nam vien
1481 Nghien cull duflc Thong tin thuoc IS64+5/2016
Trang 7Khoa Hoa sinh
Khoa Dirge
va Phong liru
tru h6 so'
Tat ca cac xet nghiem ALT va ALP
Xet nghiep ALT, ALP thoa man tieu chuan lira chgn
Benh nhan thoa man dinh nghTa
Dinh nghTa ton thirong gan
Benh nhan thoa man tieu chuan
bo sung
Tieu chuan
bo sung
Thu ttiap thong tin benh nhan ~~~^D
DILI theo thang RUCAM
Hinh 1 So do quy trinh tarn Qua trinh tarn sodt ton thuong gan do thuoc
- Tieu chuan Ida chpn: tat ca cac xet nghiem ALT
va ALP cua benh nhan nbi tru co ngay lam xet
nghiem tU 01/01/2015 den ngay 31 /12/2015
- Dinh nghia ton thuong gan: Vdi benh nhan cd
ca xet nghiem ALT va ALP: ton thuong gan la khi ALT
> 2Ni hoac ALP > 2N2 VPi benh nhan chi cd xet
nghiem ALT va khdng cd xet nghiem ALP: ton
thuong gan dupe xac djnh khi ALT > 5Ni Trong do:
Ni, N2 la gidi han tren binh thudng cua xet nghiem
ALT va ALP [3], [7], [8], [9]
- Tieu chuan bo sung:
+ Tieu chuan 1: loai nhUng benh nhan khdng cd
it nhat 1 gia trj xet nghiem ALT trudc khi gap bat
thudng < 2Ni va 1 gia trj ALT sau khi gap bat thudng
<2Ni
+ Tieu chuan 2: loai nhUng benh nhan tUvong do
khdng tiep can dupe benh an
- Quy trinh tarn soat:
Tai Khoa Hda sinh: lay thong tin xet nghiem ALT
va ALP cua benh nhan tUngay 01/01/2015 den ngay
31/12/2015, tien hanh tarn soat dua tren tieu chuan
lUa chpn va dinh nghia ton thuong gan, tieu chuan
bd sung
Tai Khoa Dupe: tU danh sach nhUng benh nhan
cd ton thuong gan, tien hanh ra soat ma lUu trUtU
benh an dien tU, xac djnh cac benh an cd thong tin
lien quan den ton thuong gan (do mot benh nhan
sodf ton thuong gan do thuoc
cd the cd nhieu benh an)
Tai phdng lUu trU ho so benh an: thu thap benh
an va truy xuat thong tin benh nhan
Danh gia mdi quan he nhan qua giUa thudc nghi ngd va ton thuong gan: sU dung thang RUCAM cap nhat nam 2015 de danh gia mdi quan he nhan qua giUa thudc nghi ngd va ton thuong gan xay ra tren benh nhan [5] Mdi thudc nghi ngd se dupe cho diem theo 7 tieu chi: thdi gian bat dau dung thudc/ngUng thudc, dien bien ALT/ALP sau ngUng thudc, yeu to nguy co, thudc dung ddng thdi, nguyen nhan khac
cd the gay ton thuong gan, thong tin ve ton thuong gan do thudc dupe ghi nhan trong y van, dien bien cua ton thuong gan khi tai sU dung thudc nghi ngd (neu cd) Can cU vao tdng diem cua 7 tieu chi de quy ket mdi quan he nhan qua giUa thudc nghi ngd va ton thuong gan theo 5 mUc: "chac chan la DILI" (> 9 diem), "cd kha nang la DILI" (6 - 8 diem), "cd the la DILI" (3 - 5 diem), "khdng nghT den DILI" (1 - 2 diem) hoac "loai trU DILI" (< 0 diem) NhUng thudc ngUng trudc thdi diem bat thudng > 15 ngay (doi vdi ton thuong te bao gan) va > 30 ngay (doi vdi ton thuong mat hoac ton thuong hdn hop), trU amoxicilin/ clavulanat [2], [4] va nhUng thudc tiep tuc sCf dung sau khi enzym gan da giam se khdng dupe dua vao danh gia theo thang RUCAM cap nhat nam 2015
Chi tieu nghien c(Su:
- So lupng benh nhan dupe nhan djnh nghi ngd
S64+5/20161 Nghien cuudwc Thong tin thuoc 1 1 4 9
Trang 8co ton thuong gan thoa man djnh nghTa ton thuong
gan va cac tieu chi bo sung dupe dua ra trong
nghien cUu
- Danh gia mdi quan he nhan qua giUa thuoc
nghi ngd va ton thuong gan tren nhUng benh nhan
co ton thUOng gan theo thang RUCAM cap nhat nam
2015
- Ty le gap ton thuong gan nghi ngd do thuoc
(nhUng trUdng hop dupe danh gia d mUc "cd the",
"cd kha nang" va "chac chan" theo thang RUCAM cap
nhat nam 2015 dupe coi la ton thUOng gan nghi ngd
do thuoc)
- Dac diem ton thUOng gan nghi ngd do thuoc
theo thang RUCAM cap nhat nam 2015: Phan loai
mUc do nang cua ton thuong gan theo thang phan
loai cua WHO [10], thdi gian tiem tang, thdi gian hoi phuc
- Dac diem thudc gay ton thuong gan theo thang RUCAM cap nhat nam 2015: phan loai thudc theo nhdm tac dung dupe ly dua tren ma ATC cua thudc [1],[11]
Xd ly so lieu: so lieu dupe ma hda, nhap lieu va xU
ly bang phan mem Microsoft Excel 2016 Ket qua dupe xU ly thong ke md ta va tinh toan theo ty le phan tram
Kef qua nghien cuv
Dgc diem benh nhan nghi ngd co ton thaong gan
Dpa tren tieu chuan lUa chpn, tU 01/01/2015 den 31/12/2015 sang Ipc dupe 36.771 xet nghiem ALT va
53 (77,9%) BN
co xet nghiem ALT > 2N|
hoac ALP
>2N 2 va khong
co gia tri ALT tnroc hoac sau hat thuong
<2N,
3 (20.0%)
BN tti vong
10 831 (97,3%)
BN khong co xet nghiem ALT > 5Ni
274 (91.0%)
BN co xet nghiem ALT >
5N| va khong
co gia tri ALT truoc hoac sau bat thuong
<2N,
2 (7,4%)
BN h i vong
Hinh 2 Ket qua tarn soat ton thUOng gan
1501 Nghien cufli dUcfc Thdng tin thuoc IS64+5/2016
Trang 9BAl NGHIEN CLTU
Bang 1 Dae diem benh nhan nghi ngdeo ton thuong gan
Dac diem So lupng Ty le %
(n=37)
Tuoi
Tuoi trung binh: 74,1 ±9,1
Gia tri Idn nhat: 93 Gia tri nhd nhat: 52
Giditinh
Khoaphdng
Than tiet nieu-Loc mau 4 10,8
Chan dodn binh chinh
BiTdu tan sinh (C00-D48) 13 35,1
Benh he ho hap (J00-J99) 9 24,3
Benh nhiem trung va ky sinh trung
Benh he tuanhoan (100-199) 4 10,8
Benh he sinh duc-tiet nieu
881 xet nghiem ALP cua benh nhan npi tru tai Benh
vien Hub Nghi, thong Ung vdi 11.809 benh nhan chia
benh nhan thanh 2 nhdm: nhdm 1 co (Jong thdi ket
qua xet nghiem ALT va ALP (677 benh nhan) va nhom
2 chi co ket qua xet nghiem ALT (11.132 benh nhan)
Doi chieu vdi djnh nghia ton thuOng gan, 369 benh
nhan thoa man djnh nghTa nay (chiem 3,1%), bao
gom 68 benh nhan nhom 1 (chiem 10,0%) va 301
benh nhan nhom 2 (chiem 2,7%) NhUng benh nhan
nay <JuOc tarn soat tiep theo tieu chuan bo sung 1 thu
dope 15 benh nhan nhom 1 (22,1%) va 27 benh nhan
nhom 2 (9,0%) Tiep tuc ap dung tieu chuan bo sung
2, loai them 3 benh nhan nhom 1 va 2 benh nhan
nhom 2 NhP vay, ket qua co 37 benh nhan thoa man
dupe dua vao nghien cUu, trong do co 12 benh nhan
thupc nhom 1 va 25 benh nhan thupc nhom 2
Trong 37 benh nhan nghi ngd co ton thuong
gan, nam giPi chiem da so (91,9%), vPi tuoi trung
binh la 74,0 (± 9,1), trong do 97,3% benh nhan tren
55 tuoi Khoa Ung budu va khoa Ho hap Dj Ung la 2 khoa co lupng benh nhan nhieu nhat, ty le Ian lupt
la 21,6% va 16,2% TUOng Ung vPi nhom benh chinh
la budu tan sinh (35,1%) va benh he ho hap (24,3%) Tong cpng 423 thuoc da dupe sU dung tren 37 benh nhan nghi ngd cd ton thUOng gan do thuoc Vdi so thuoc trung binh dupe sd dung la 11,4 thuoc/1 benh nhan Nhdm thuoc chiem ty le nhieu nhat la nhdm thudc dieu trj benh gan (9,7%) Moi benh nhan khi dUOc phat hien tang enzym gan hau het deu dupe sU dung cac thudc trj benh gan vdi 2 hoat chat chinh la arginin (biet dupe hay dung la Euformin, Apharmincap) va I - ornithin -1 - aspartat (biet dupe hay dung la Hepaur, Qyliver) Khang sinh nhdm quinolon (6,9%), cephalosporin/carbapenem (6,4%)
va cac penicillin (3,8%) la cac nhdm thuoc dupe sU dung pho bien d cac benh nhan ndi tren
Danh gia moi lien quan giiita thuoc nghi ngd va ton thUctng gan
Trong 423 thuoc, chung toi loai trU 315 thudc do khdng thda man tieu chuan danh gia cua thang RUCAM cap nhat nam 2015 Con lai 108 thuoc (25,5%) dUOc dUa vao danh gia, cho ket qua 31 cap thudc - ton thuong gan (chiem 28,7%) tuong Ung vdi
22 benh nhan dupe danh gia la cd mdi lien quan giUa thuoc va ton thUOng gan (bang 2)
Bang 2 Ket qua danh gia ton thuong gan do thuoc
Diem Mile danh
gia
So cap thuoc -ton thuong gan
Ty le (%) (n=108)
< 0 diem Loai tru" DILI 32 29,6
1 - 2 diem Khdng nghi
3 - 5 diem Co the la DILI 31 28,7
6 - 8 diem Co kha nang
> 9 diem Chacchan la
Ty le gap ton thuong gan nghi ngd do thuoc
Ty le gap ton thUOng gan nghi ngd do thuoc tren tong so benh nhan cd xet nghiem chUc nang gan bat thudng la 22 benh nhan/369 benh nhan (6,0%)
Ty le gap ton thuong gan nghi ngd do thudc tren tong so benh nhan npi tru cua benh vien nam 2015
la 22 benh nhan/20.088 benh nhan (0,11 %)
Ty le gap ton thuong gan nghi ngd do thuoc tren tong so xet nghiem ALT va ALP cua benh nhan npi
S64+5/2016 1 Nghien culidifcfc Thong tin thuoc 1151
Trang 10tru la 22 benh nhan/37.652 xet nghiem ALT va ALP
(0,058%)
Dgc diem ton thuong gan nghi ngd do thuoc
Dac diem ton thuong gan dPOc danh gia tren 22
benh nhan co cac cap thuoc - ton thoong gan danh
gia 6 mile "co the" Oac diem ton thUOng gan bao
gdm: mbc do ton thoong gan, thdi gian tiem tang va
thdi gian hoi phuc cua ton thoong gan dude mo ta
trong bang 3
Bang 3 Dgc diem ton thUOng gan nghi ngd do thuoc
Dac diem So lufcfng benh nhan
(n=22)
Mile do ton thtfdng gan theo WHO
Mtfcdol (nhe): ALT hoac 0
ALP 1,25N - 2,5N
Mile do 2 (trung binh): ALT hoac 2
ALP 2,6N-5N
Mufc do 3 (nang): ALT hoac 12
ALP 5,1N - ION
Mufc do 4 (de dpa tinh mang): ALT 8
hoacALP>ION
Thdi gian tiem tang*
Thdi gian hoi phuc**
Ghi chu: N la gidi han tren binh thudng
* Thdi gian tiem tang Id khodng thdi gian td luc bat dau
sddung thuoc nghi ngd den khiphdt hien bat thudng ket qua
xet nghiem chdc nang gan
**Thdi gian hoi phuc la khoang thdi gian td khi enzym
gan dgt dinh den khi enzym gan trd ve binh thddng (nhd hon
gidi hgn tren binh thudng)
***Khdng ro: gom 2 trUdng hop ALT gidm xuong dudi
2NI trong vdng 1 thdng nhUng sau do khdng cd thong tin ve
gia tri xet nghiem enzym gan
Mile do ton thoong gan chu yeu 6 mile do nang
va de dpa tfnh mang (20/22 benh nhan nghi ngp co
DILI) Tuy nhien, da so cac trOdng hop ton thuong
gan deu khong co trieu chdng lam sang dien hinh
nhd man ngila, vang da, tang bach cau ai toan, mot
so trdPng hop co sot, met moi Thdi gian tiem tang
ngan, dao ddng t i l vai ngay den 1 tuan, 2 trddng
hop thdi gian tiem tang keo dai nhat la gemcitabin
va carboplatin (hda chat chdng ung tho) Thdi gian hoi phuc da so la sau 1 tuan den 1 thang (15/22 benh nhan nghi ngd cd DILI) Cd 4/22 benh nhan nghi ngd cd DILI hoi phuc sau thdi gian 1 thang, trPdng hop hoi phuc mudn nhat la sau 102 ngay (khoang 3 thang)
Dgc diem thuoc gay ton thuong gan
Phan loai cac thuoc nghi ngd gay ton thdong gan theo nhdm tac dung dupe ly dupe trinh bay trong bang 4
Bang 4 Dgc diem nhdm thudc gay ton thuong gan
m a H I v MhniYi t h n n r
NIIUIII U I U U L
So cap thuoc ton thuong gan
Ty le (%) (n=31)
J01M Khang khuan nhdm quinolon 5 16,1 J01D
Khang khuan nhdm betalactam khac (cephalosporin, carbapenem)
J01C Khang khuan betalactam, nhdm penicillin 2 6,5 J01F Khang khuan nhdm macrolid 2 6,5 J01X
Cacthuockhang khuan khac (fosfomycin, metronidazol)
N02B Thudc giam dau, ha nhiet khac (paracetamol) 3 9,7 B01A Thudc chdng huyetkhdi 2 6,5 L01X
Cac hda chat chdng ungthu khac carboplatin, gemcitabin)
Khang sinh la nhdm thuoc dupe ghi nhan gay ton thuong gan nhieu nhat (14/31 cap thuoc - ton thdong gan) Thdng tin ve tilng thuoc cu the gay ton thdong gan dPOc tong hop trong bang 5 Trong
do ciprofloxacin, diazepam, paracetamol (dang don chat hoac phoi hop) la 3 hoat chat cd tan suat gay ton thdong gan nhieu nhat lien quan den 3 ca ghi nhan bien cd tPOng dng vdi mdi hoat chat Ben canh do, amoxicilin/clavulanat, levofloxacin, clarithromycin cung cd tan suat gap ton thdong gan (2 ca ghi nhan bien co tuong ilng vdi mdi hoat chat)
cao hon cac thudc con lai {bang 5)
152I Nghien cull dircfC;Th6ng tin thuoc IS64+5/2016
Trang 11Bang 5 DO lieu Hen quan 22 benh nhan nghi ngdco DILI
Tuoi Gidi Thudc nghi ngd Thdng tin tren SPC Trieu chUng lam sang Gia trj dinh
MUc dp ton thUOng gan Tuoi Gidi Thudc nghi ngd Thdng tin tren SPC Trieu chUng lam sang
ALT ALP
85 Nam Ciprofloxacin Cd: khdng phd' bien Khdng 236 Nang
73 Nam Clarithromycin Cd' khnnn nhn hipn L U , fXIIUMLJ U I I U U l L I f Khdng 323 Nang
Cpftriaxnn
U L 1 LI IUAUI 1
f 6* hiem nan
L.U IIIX.MI U U U
80 Nam Paracetamol Co: khi qua lieu Met khd thd va mo I ' L L , i\l I U L I I U ; VCJ I I I U
hoi (benh ly) 1490 Oedga tinh mang
finrnflfiY^r in
V.IUI U l I U A U L I I 1
f h' khhnn nhn hipn
V.U l U I U I I U U I I U U l U l l BN met, the trang
58 Nam Amoxicilin/
flaviilanat
L I U V U I U I I U L
Co: khong pho bien
BN met, the trang
70 Nam f inrofloxacin
L I Ul U II U A { 1 L 1 1 1
f h- khhnn nhh hipn
L U IXIIUIIli U I I U UIL-IT Khdng 234 Nang
85 Nam Amoxifilin/ Ml 1 1 U A 1 L I 1 III/
87 Nam f pfonprazon fhL-U U I I U U l u 11 - nhh hipn Khdng 246 Nang
D i a 7 P n s m
L/ICILCUQI11 fh' hihm nan
L.U 111 L 1 1 1 U u U
1 CI 1 u L L LCI 1 1 1 Ul •
Codein
fh- khi nna lihn
U U m i l U U u I I C U
paracetamol
63 Nam Aspirin Khong (co mota tren trang 1 ivertoxl
LI l L 1 L U A !
Nitrnnlvcprin
M i l l U U 1 y X-l_ 1 II 1
Khhnn
IU I U I I U
Carbamazepin Co: hiem gap
66 Nam Clarithromycin Cd: khdng phd' bien ^htJUL, dll K c l l l , 11 idU pile an khm ri ran nhp
nann niam fhhnh lul
I I C I I I U u i u i i i I U C I I I I lyj
n l MlUUdlUll f h ' rat nnh hipn uu I d l pilU Ulcll Khdng 557 De dga tfnh mang
74 Nam AciH tranpxamir
ML 1LJ L I U I I U A U I I I I l
Khhnn
l\l 1 Ul 1 u
Thp trann Irt mrt cnt
1 1 It LI til IU IU 11IU, oUL
J\J V_, l l l v l l l IIIUX 1 11 1U L,
thieu mau
78 Nam Paracetamol/
Codein
Cd: khi qua lieu
64 Nam Gemcitabin Cd: rat phd bien Khdng 665 137 Dedga tinh mang
57 Nam Carboplatin Khdng (cdmdta tren trang
'Thdng tin tren tdtdm tat dgc tinh san pham ve ton thuong gan, dupe tra tren EMC [13]
(neu khong cd tren EMC, tra tren FDA [12])
S64+5/20161 Nghien cCru dUgfc Thdng tin thuoc 1 1 5 3