Tdm 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 Ha 1, Nguyen Khac Dung 1, Tra

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6 Tdm 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 Ha 1, Nguyen Khac Dung 1, Tran Thu Thuy 1, Nguyen Thj Phuong Ngoc 2, Hoang Thj Minh Hien 2, PhamThj Dieu Huyen 2, Nguyen Hoang Anh 1 '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) base on laboratory database of alkaline phosphatase (ALP), alanine aminotransferase (ALT) laboratory signals and the description of DILI. Screening was performed with the help of biochemistry database followed by detail medical record review for suspecte 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 we 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 stud 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 Nghien cull duflcthong tin thuoc IS64+5/2016

7 B A I N G H I E N C L T U Tat ca cac xet nghiem ALT va ALP Khoa Hoa sinh Khoa Dirge va Phong liru tru h6 so' Xet nghiep ALT, ALP thoa man tieu chuan lira chgn Benh nhan thoa man dinh nghta Benh nhan thoa man tieu chuan bo sung Thu ttiap thong tin benh nhan ~~~^D Dinh nghta ton thirong gan Tieu chuan bo sung c Danh gia DILI theo thang RUCAM 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/ 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 Hinh 1. So do quy trinh tarn 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 Chi tieu nghien c(su: - So lupng benh nhan dupe nhan djnh nghi ngd S64+5/20161 Nghien cuudwc Thong tin thuoc 1149

8 BAl N G H I E N C U D co 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 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 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 xet nghiem ALT va (97,3%) BN khong co xet nghiem ALT > 5Ni 53 (77,9%) BN co xet nghiem ALT > 2N hoac ALP >2N2 va khong co gia tri ALT tnroc hoac sau hat thuong <2N, 274 (91.0%) BN co xet nghiem ALT > 5N va khong co gia tri ALT truoc hoac sau bat thuong <2N, 3 (20.0%) BN tti vong 2 (7,4%) BN hi vong Hinh 2. Ket qua tarn soat ton thuong gan 1501 Nghien cufli ducfc Thdng tin thuoc IS64+5/2016

9 BAl NGHIEN CLTU Bang 1. Dae diem benh nhan nghi ngdeo ton thuong gan Dac diem Tuoi So lupng Ty le % (n=37) Tuoi trung binh: 74,1 ±9,1. Gia tri Idn nhat: 93. Gia tri nhd nhat: 52 Giditinh Nam 34 91,9 Nuf 3 8,1 Khoaphdng Ung bifdu 8 21,6 Ho hap di ilng 6 16,2 Than tiet nieu-loc mau 4 10,8 Benh nhiet ddi 3 8,1 Tim mach 3 8,1 Than kinh 3 8,1 Hoi sure tich cue 2 5,4 Truyen nhiem 2 5,4 Cac khoa khac 6 16,2 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 (A00-B99) 4 10,8 Benh he tuanhoan ( ) 4 10,8 Benh he sinh duc-tiet nieu (N00- N99) 2 5,4 Cac benh ly khac 5 13,5 881 xet nghiem ALP cua benh nhan npi tru tai Benh vien Hub Nghi, thong Ung vdi 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 ( 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 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 Mile danh So cap thuoc - Ty le (%) Diem gia ton thuong gan (n=108) < 0 diem Loai tru" DILI 32 29,6 Khdng nghi 1-2 diem den DILI 45 41,7 3-5 diem Co the la DILI 31 28,7 6-8 diem > 9 diem Co kha nang la DILI Chacchan la DILI 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/ 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+5/20161 Nghien culidifcfc Thong tin thuoc 1151

10 tru la 22 benh nhan/ 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* < 1tuan 17 1 tuan den 1 thang 10 >1thang 4 Thdi gian hoi phuc** Sau 0-1 tuan 1 Sau 1 tuan -1 thang 15 Sau1thang 4 Khong ro*** 2 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 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 ma HI v MhniYi thnnr NIIUIII UIUUL So cap thuoc ton thuong Ty le (%) (n=31) gan J01M Khang khuan nhdm quinolon 5 16,1 Khang khuan nhdm J01D betalactam khac (cephalosporin, 3 9,7 carbapenem) J01C Khang khuan betalactam, nhdm penicillin 2 6,5 J01F Khang khuan nhdm macrolid 2 6,5 Cacthuockhang khuan J01X khac (fosfomycin, 2 6,5 metronidazol) N05B Thuoc giai loau 3 9,7 N02B Thudc giam dau, ha nhiet khac (paracetamol) 3 9,7 B01A Thudc chdng huyetkhdi 2 6,5 Cac hda chat chdng L01X ungthu khac 2 6,5 carboplatin, gemcitabin) Cac nhdm khac 9 29,0 Khang sinh la nhdm thuoc dupe ghi nhan gay ton thuong gan nhieu nhat (14/31 cap thuoc - ton 2NI trong vdng 1 thdng nhung sau do khdng cd thong tin ve thdong gan). Thdng tin ve tilng thuoc cu the gay gia tri xet nghiem enzym gan. ton thdong gan dpoc tong hop trong bang 5. Trong Mile do ton thoong gan chu yeu 6 mile do nang do ciprofloxacin, diazepam, paracetamol (dang va de dpa tfnh mang (20/22 benh nhan nghi ngp co don chat hoac phoi hop) la 3 hoat chat cd tan suat DILI). Tuy nhien, da so cac trodng hop ton thuong gay ton thdong gan nhieu nhat lien quan den 3 ca gan deu khong co trieu chdng lam sang dien hinh ghi nhan bien cd tpong dng vdi mdi hoat chat. nhd man ngila, vang da, tang bach cau ai toan, mot Ben canh do, amoxicilin/clavulanat, levofloxacin, so trdpng hop co sot, met moi. Thdi gian tiem tang clarithromycin cung cd tan suat gap ton thdong gan ngan, dao ddng til vai ngay den 1 tuan, 2 trddng (2 ca ghi nhan bien co tuong ilng vdi mdi hoat chat) hop thdi gian tiem tang keo dai nhat la gemcitabin cao hon cac thudc con lai {bang 5). 152I Nghien cull dircfc;th6ng tin thuoc IS64+5/2016

11 Bang 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 71 Nam Thuoc dong y Khong rd Khdng 284 Nang 77 Nam Fosfomycin Co: khdng phd bien Khong 231 Nang ALT ALP MUc dp ton thuong 85 Nam Ciprofloxacin Cd: khdng phd' bien Khdng 236 Nang 73 Nam Clarithromycin Cd' khnnn nhn hipn LU, fxiiumlj UIIU UlLIf Khdng 323 Cpftriaxnn f 6* hiem nan Nang U L. 1 LI IUAUI 1 L.U. IIIX.MI UUU Met khd thd va mo 80 Nam Paracetamol Co: khi qua lieu I'LL, i\l IU LIIU; VCJ IIIU 1490 Oedga tinh mang hoi (benh ly) 58 finrnflfiy^r in f h' khhnn nhn hipn V.IUI Ul IUAULII 1 V.U. luiuiiu UIIU UlUll BN met, the trang Nam Amoxicilin/ Co: khong pho bien gay, an kern flaviilanat 274 Nang LIU V UIUIIUL 70 Nam f inrofloxacin f h - khhnn nhh hipn Khdng 234 Nang LU. IXIIUIIli UIIU UIL-IT LI Ul U II U A { 1 L 1 1 Amoxifilin/ 1 85 Nam Ml 1 1 UA 1 LI 1 III/ Co: khong pho bien Khdng 210 Nang Clavulanat 87 Nam f pfonprazon fh - nhh hipn L-U. UIIU Ulu 11 Khdng 246 Dia7Pnsm fh' hihm nan Nang L/ICILCUQI11 L.U. 111 L Uu U 1 CI 1 u LL LCI Ul. fh - khi nna lihn UU. mil UUu IICU Codein paracetamol 63 Nam Aspirin Khong (co mota tren trang Khdng 1 ivertoxl 508 Qe dpa tinh mang LI l L 1 L U A! Nitrnnlvcprin Khhnn Mill U U 1 y X-l_ 1 II 1 Carbamazepin IU IUIIU Co: hiem gap 66 Nam Clarithromycin Cd: khdng phd' bien 84 Nam Enoxaparin nl MlUUdlUll Cd: pho bien fh' rat nnh hipn uu. Idl pilu Ulcll ^ht an khm ri ran nhp JUL, dll Kclll, 11 idu pile nann niam fhhnh lul IICIIIU uiuiii IUCIIII lyj 219 Nang gan Khdng 557 De dga tfnh mang Thp trann Irt mrt cnt 74 Nam AciH tranpxamir ML 1LJ LIUIIUAUIIIIl. Khhnn l\l 1 Ul 1 u 1 1 It LI til IU IU 11IU, oul 38 f nipmmarnhrft 223 Nang J\J V_, lllvlll IIIUX U L, 78 NO Levofloxacin Cd: pho bien thieu Khdng mau 1490 De doa tinh mang Paracetamol/ Cd: khi qua lieu 78 Nam Khdng Dedga tinh mang Codein paracetamol 64 Nam Gemcitabin Cd: rat phd bien Khdng Dedga tinh mang Khdng (cdmdta tren trang 57 Nam Carboplatin Khdng 3020 De dga tinh mang Livertox) 65 Nam Diazepam Cd: hiem gap Khdng 410 De dga tinh mang 85 Nam Omeprazol Cd: khdng phd bien Sot 224 Nang 79 Nam Enalapril Cd: hiem gap Khdng 124 Trung binh 72 Nam Diazepam Cd: hiem gap Khdng 309 Nang 67 Nam Levofloxacin Meropenem Cd: phd' bien Cd: phd' bien Sot 182 Trung binh '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 1153

12 Ban luqn Ket qua dang chu y trong nghien cufu nay la khao sat dupe ty le gap ton thupng gan nghi ngd do thuoc va ghi nhan cac thuoc co the gay ton thuang gan cung nhu mo ta dupe dac diem ton thupng gan nghi ngd do thuoc gay ra. Ty le gap ton thuong gan do thuoc tren tong so benh nhan cd bat thudng chile nang gan trong nghien cilu cua chung tdi la 6,0%, tuong tu ket qua da cong bo trudc do tai Phap nam 2000 [3], Tay Ban Nha nam 2010 [8] va Australia nam 2013 [9] vdi ty le tuong ling la 6,8%, 6,8% va 6,4%. Nguyen nhan cua sil khac nhau tudng doi nhd gida cac nghien cilu cd the do khac biet ve quy md va djnh nghia ton thuong gan. Chung tdi sil dung djnh nghia ton thuong gan cd mile gidi han cao hdn cac nghien cilu khac (> 5Ni) nen cd the bo qua nhilng trudng hop ton thuong gan ma enzym gan tang dudi 5Ni dan den ty le gap ton thuong gan do thuoc tren tong so benh nhan cd bat thudng chile nang gan cd the thap hon. Ngoai ra, viec ap dung thang RUCAM cap nhat nam 2015 de danh gia ton thuong gan do thuoc trong nghien cilu nay con han che do thieu du lieu xet nghiem dan den ket qua cd the thap hon cac nghien cilu khac. Ty le gap ton thuong gan do thuoc tren tong so benh nhan npi tru cua benh vien trong nam 2015 la 22 benh nhan/20088 benh nhan (0,11%) cao hon so voi ty le nay trong nghien cilu cua Sistanizad va cpng su nam 2013 tai Australia la 30 benh nhan/ benh nhan (0,03%) [9]. Nguyen nhan chinh cua su khac biet nay la do dac thu benh nhan cua moi benh vien la khac nhau, tai Benh vien HOu Nghj benh nhan phan Idn la ngudi cao tuoi, trong khi do, tai benh vien d Australia benh nhan thupc nhieu nhdm doi tupng khac nhau (ngudi trudng thanh, ngudi cao tuoi...). Nhdm doi tupng ngudi cao tuoi la nhdm doi tupng nhay cam hon vdi cac phan ilng cd hai cua thuoc, dong thdi tinh trang benh ly philc tap hon, sil dung dong thdi nhieu thuoc han do do ty le gap ton thuong gan do thuoc tinh tren toan the benh nhan npi tru cua Benh vien HUu Nghj se cao hon. Khang sinh la nhdm thuoc dupe ghi nhan gay ton thuong gan nhieu nhat (14/31 cap thuoc - ton thuong gan), thupc ve 5 nhom penicilin, betalactam khac, quinolon, macrolid va nhdm khang khuan khac. Quinolon la nhom khang sinh chiem ty le cao nhat la 5/14 cap thuoc - ton thuong gan (35,7%) trong tong so cac khang sinh gay DILI. Ramirez va cpng su (2010) tien hanh nghien cilu tren CP sd du lieu tai Tay Ban Nha cho thay ty le DILI do khang sinh la 19,5%. Con theo nghien cilu cua Sistanizad va cpng sutai Australia (2013), ty le nay len tdi 65%. Khang sinh dupe ghi nhan gay DILI nhieu nhat trong cac nghien cilu nay deu la amoxicilin/ clavulanati8], [9]. Mile dp ton thuong gan theo WHO d mile nang va de dpa tinh mang la 20/22 benh nhan nghi ngd cd DILI, trong do dinh gia trj ALT cao nhat la 3020 Ul/ml (gap 75,5 Ian gidi han tren binh thudng). Trong khi do, da so cac benh nhan khong cd trieu chilng lam sang cua ton thuong gan nhu sot, vang da, ngila, met mdi, tang bach cau Ua acid... NhUng trudng hop nay neu khdng dupe can thiep kjp thdi se cd nguy co dan den suy gan va til vong. VI vay, trong thuc hanh lam sang, can bp y te can luu y han den xet nghiem enzym gan va kiem tra, danh gia chat che nhung trudng hop cd tang enzym gan de cd bien phap xil trf phu hop. Viec xac djnh thuoc nghi ngd gay ton thuong gan sau do rat quan trpng de du phdng khdng tai xuat hien phan ilng cd the do benh nhan vd tinh dung lai thuoc. Lan dau tien nghien cilu tarn soat ton thuong gan do thuoc thdng qua ket qua xet nghiem can lam sang dupe thile hien tai Viet Nam, do do khdng tranh khdi mot so han che ve hinh thile trien khai (hoi cilu, khdng can thiep) va chat lupng du lieu (cu the chua day du, benh nhan cd nhieu benh mac kern va sil dung dong thdi nhieu thuoc). Tuy nhien, ket qua thu dupe da tao co sd cho cac phan tich giam sat tien cilu day du hon thdng qua hoat dpng dupe lam sang ve ton thuong gan do thuoc ndi rieng va phat hien phan ilng cd hai cua thuoc ndi chung thong qua tarn soat cd chu dich cac ket qua xet nghiem can lam sang trong qua trinh dieu trj cua ngudi benh. Ket luqn Ty le gap ton thuong gan cd the do thuoc tren tong so benh nhan cd bat thudng chile nang gan la 6,0%, tuong ilng vdi 0,11 % benh nhan dieu trj npi tru 154I Nghien cull dtigfccthong tin thudc IS64+5/2016

13 trong Benh vien HOu Nghj. Khang sinh la thuoc thudng dupe ghi nhan gay ton thuong gan, trong do hay gap nhat la quinolon. Mile dp ton thuong gan chu yeu la mile dp nang va de dpa tinh mang xuat hien vdi thdi gian tiem tang ngan (vai ngay den 1 tuan), da so hoi phuc sau 1 tuan den 1 thang. Ket qua nay bo sung dcf lieu ve ty suat benh, dac diem ton thuong gan nghi ngd do thuoc thong qua giam sat phan ilng cd hai cua thuoc, gdp phan tang cudng sil dung thuoc an toan, hop ly trong benh vien. TAI LIEU THAM KHAO 1. Bp Y te (2015), Dupe thuquoc gia Viet Nam, NXB Y hoc. Ha Npi. 2. Andrade R.J. et al (2005), "Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period", Gastroenterology, 129(2), pp Bagheri H. et al (2000), "Detection and incidence of drug-induced liver injuries in hospital: a prospective analysis from laboratory signals", British Journal of Clinical Pharmacology, 50(5), pp Danan G., Benichou C. (1993), "Causality assessment of adverse reactions to drugs-l. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries", Journal of Clinical Epidemiology, 46(11), pp Danan G., Teschke R. (2015), "RUCAM in Drug and Herb Induced Liver Injury: The Update", International Journal of Molecular Sciences, 17(1). 6. Larrey D. (2000), "Drug-induced liver diseases". Journal of Hepatology, 32(1), pp Levy M., Azaz-Livshits T., Sadan B., Shalit M., Geisslinger G., Brune K. (1999), "Computerized surveillance of adverse drug reactions in hospital: Implementation", Eur J Clin Pharmacol, 54, pp Ramirez E., Carcas A.J., Borobia A.M., Lei S.H., Pihana E., Fudio S., Frias J. (2010), "A pharmacovigilance program from laboratory signals for the detection and reporting of serious adverse drug reactions in hospitalized patients", Clinical Pharmacology and Therapeutics, 87(1), pp Sistanizad M., Peterson G.M. (2013), "Drug-induced liver injury in the Australian setting", Journal of Clinical Pharmacy and Therapeutics, 38(2), pp WHO (2003), "WHO Toxicity Grading Scale for Determining The Severity of Adverse Events". 11. Worth Health Organization (2016), " ddd index/". 12. " drugsatfda/index.cfm" (Ngay truy cap cuoi cung 05/05/2016). 13. " (Ngay truy cap cuoi cung 05/05/2016). (Ngay gdi dang: 16/8/ Ngay duyet dang: 10/10/2016) S64+5/20161 Nghien culi ducic Thdng tin thuoc 1155