TAP CHlY DUOC L A M SANG 108 Tap 10-S64/2015
Danh gia mu'c do xcr hoa gan va mot so yeu to lien quan tren benh nhan viem gan virus C man tinh
Accessment of liver fibrosis and some relateted factors in chronic hepatitis C patients
Ngo Anh The*, Than Manh Hiing*" * Binh vien Hiru nghi Viet Tiep, Hdi Phong Benh vien Binh Nhiit d&i Trung ircmg
Tom tat
Sinh thiet gan la tieu chuan vang dung de danh gia giai doan xo hoa gan ciing vdi mot so phddng phap mdi can dupc danh gia dp nhay cung nhd dp dac hieu. Muc tieu: Nghien ciiu nham danh gia miic dp xO hoa gan bSng sinh thiet va fibroscan, tim hieu mot so yeu to lien quan den miic dp xa hoa gan. Doi tUang vd phuang phdp: Benh nhan vien gan C (VGC) man khong co chong chi djnh sinh thiet gan. Ket qua: Cho thay 94,5% benh nhan co ton thuong xd hoa. Do nhay va dp dac hieu cua fibroscan tai cut-off F2 tUOng iing la 70,3% va 76,9%, tai cut-off F3 la 94,5% va 93,4%. Cac yeu to c6 lien quan den miic dp xo hoa bao gom tuol, glcfi va sCf dung rdpu (p<0,05). Cac yeu to khong anh hudng bao gom thdi gian nhiem HCV, nong do ARN- HCV va genotype-HCV (p>0,05). Kit lugn: 94,5% benh nhan c6 ket qua sinh thiet xo hoa gan. Fibroscan co dp nhay va dp dac hieu cao. Cac yeu to anh hudng tdi mu'c dp xd hoa gan bao gom tuoi, gidi va sii dung rupu;
khong ^nh hu'dng bao gom thdi gian nhiem HCV, nong do HCV-RNA va genotype-HCV.
Tlf khoo: Viem gan virus C, sinh thiet gan, fibroscan, metavir.
Summary
Liver biopsy is still the gold standard for accessing liver fibrosis, but new non- invasive methods have been developed. Objective: To assess the degree of liver fibrosis in chronic hepatitis C patitens by liver biopsy, fibroscan, and some other related factors. Subject and method: All chronicaly HCV infected patients, who had no contraindications for liver biopsy perform, were selected. Result: Almost of the patients (94.5%) were developed fibrosis lesions. The sensitivity and specificity of fibroscan at the cut- off F2 were 70.3% and 76.9% while those at the cut off F3 were 94.5% and 93.4%, respectively. The factors related t o fibrosis included age, gender and alcohol consumption (p<0.05) while as the duration of HCV infection, HCV-RNA levels and HCV genotype were all not related closely (p>0.05). Conclusion:. In our study, most of patients (94.5%) had fibrosis. Fibroscan had high sensitivity and specifidty for diagnosing fibrosis. Some factors related to the liver fibrosis including age, sex, and alcohol consumption while the connection among the duration of HCV infection, HCV-RNA levels and HCV genotype with liver fibrosis were not cleariy.
Keywords: Hepatitis chronic C, metavir, liver biopsy, fibroscan.
Phan bi^n khoa hpc: PGS.TS. vO VAN KHIEN
JOURNAL OF 108 - CLINICAL MEDICINE AND PHARMACY Vol.lO-NM/2015
1 . D a t v a n de
Viem gan virus C (VGC) dang la m p t van de quan t r o n g doi vdi siic khde cpng dong. Theo LTdc t i n h tren toan The gidi hien co khoSng 170 trieu ngudi nhiem virus viem gan C (HCV) man tfnh [1]. d Viet Nam, ty le nhiem HCV dao dpng tiS 1-2% [2]. HCV la m p t t r o n g nhOfng nguyen nhan gay viem gan man t i n h , x d gan va ung t h a te bao gan nguyen phat [3].
Xd hoa la hau quci cCia qua trinh hoai tCfva viem man t i n h [3]. Trong VGC man tfnh, ty' le tien trien xo hoa khac nhau d tilng ca the. Mpt so benh nhan qua trinh x d hoa cd the tien trien nhanh den. giai doan cuoi va xuat hien cac bien chiing n h i i xd gan, x d gan mat bu va ung t h u gan. Trong m p t so trUdng hop cd the khong tim thay xo hda gan hoac x d hoa gan rat ft. Vi ly do tren, theo ddi miic do x d hda d d n g vai tro quan t r p n g trong chan doan, tien lUdng tien trien cung n h u quyet djnh thdi diem dieu tri bang thuoc khang virus [4]. Hien cd nhieu bSng phan loai khac nhau de xac dinh giai doan va miic dp x d hoa [5][6].
Tuy nhien bSng phan loai metavir dddc sCr dung rpng rai do sU don gi3n, de sCr dung. BSng phan loai n^y danh gia theo miic dp hoat d p n g va giai doan xo hda. Trong do miic dp hoat d p n g (active: A) dapc chia thanh 4 mac do sau AO: Khong hoat dpng, A l : hoat d p n g miic dp tdi thieu, A2: Hoat d p n g miic dp trung binh va A3: Hoat d d n g manh. Tmh trang x d hda (fibrosis: F) dapc chia thanh 5 giai doan sau FO:
k h d n g x d hda, F l : Xo nhe, F2: x d hoa t r u n g binh, F3:
xo hda nang va F4: Xo gan [5].
Hien tai mac du cd nhieu ky thuat khdng xam nhap n h a Fibroscan, Fibro test dapc sCf d u n g de danh giS miic dp xd hoa, nhdng sinh thiet gan van dapc coi la tieu chuan vang de danh gia phan loai mac dp va giai doan x d hda. Trong nhiing nam gan day tai Viet Nam dang ap d u n g m p t so p h a o n g phap danh gia miic dp xo hda gan. NhSm xac d m h mac dp x d hda gan d benh nhan viem gan virus C man t i n h va tim hieu m p t so yeu t o lien quan den qua trinh x d hoa, c h i j n g tdi tien hanh nghien cau nay vdi cac muc tieu sau:
1) Xac dinh mac dp x d hda cCia benh nhan viem gan virus C man tfnh daa theo ket quk sinh thiet gan va fibroscan.
2) Xac dinh mpt so yeu t o 3nh hadng den mac dp x d hda gan d benh nhan viem gan C man tinh.
2 . D o i t U t f n g va phifcfng p h a p
Thiit ke nghien cuiu: Nghien cau md t^ c3t ngang.
Cd mau va chgn mdu: Chgn mau thuan tien.
Thdi gian vd dja diem
Nghien cau diidc tien hanh t a thang 01 nam 2012 den het t h a n g 12 nam 2013 tai Khoa Viem gan, Benh vien Benh Nhiet ddi T r u n g aong.
2.1. Doi tlf Cfng
Cac benh nhan VGC man tfnh co 66 tuoi > 18, nhap vien tai Benh vien Benh nhiet ddi Trung Udng t r o n g t h d i gian n g h i e n ciiu cd dO cac tieu chuan sinh t h i e t gan va d o n g y t h a m gla nghien ciiu.
2.2. Phifcfng phdp
Cac benh nhan d a p c t h u thap t h d n g tin ve cac, yeu t o n g u y cd lay nhiem HCV, trieu chang cd nang, t h a m kham lam sang, xet n g h i e m sinh hda mau, d m h lupng RNA-HCV, d j n h type HCV, fibroscan gan va sinh thiet gan. Sinh t h i e t gan dapc thuc hien tai Benh vien Benh nhiet ddi Trung Udng dadi hudng dan sieu am. Chan d o a n mo benh hpc dapc thiic hien tai Khoa G i i i phau benh Benh vien Bach Mai.
Fibroscan 6Udc t h a c hien tai Khoa kham benh yeu cau, Benh vien Bach Mai sa d u n g may Fibroscan EchoSens* - Paris, France. Mac dp x d hoa daoc xac d m h daa theo bang phan loai Metavir [5),[7],[6], D i n h Iapng RNA-HCV, d j n h type HCV va cac xet nghiem sinh hda mau dUdc thi/c hien tai Khoa Xet nghiem Benh vien Benh Nhiet ddi Trung adng.
2.3. Tbu tbgp vaxCftysoUeu
Thdng tin cCia benh nhan dapc t h u thap theo m p t mau benh an t h o n g nhat. Cac so lieu thu dUdc 6uclc quSn ly va phan tich t h o n g ke bSng phan m^m SPSS 16.0 cd sa d u n g cac t h u a t t o a n so sanh va vdi gia t n p<0,05 Quae coi la cd y nghia t h o n g ke.
2.3. Dgo dO^c nghiin cifu
Nghien ciiu nay d a p c tien hanh ma khdng lam thay doi quy t r i n h chan d o a n , eham sdc, dieu trj cua cac benh nhan.
3. Ket quS
Trong t h d i gian nghien cau, 91 benh nhan VGC man tfnh cd du tieu chuan da d a p c laa chon vao
TAP CHI Y c a g e LAM SANG 108 Tap10-S64/2015
n g h i e n cijfu. Oac diem chung ciJa cac benh nhan Co 53/91 benh nhan I<h6ng xac d j n h dapc d u d n g lay (Bang 1) bao g o m . Tuoi t r u n g binh cDa cac b e n h truyen HCV chiem 58,3%; cac yeu t o n g u y c o co lien nhan la 48,25±12,0 t u o i t r o n g do dai da so benh quan den lay truyen HCV la phau t h u a t (15,4%), nhan t h u o c n h o m t u o i tCf 30 den 60 (68/91; 74,7%). truyen mau (12,1 %) va tiem chi'ch ma t u y (6,6%).
Bang 1 . Oac diem chung ci!ia cac benh nhan nghien cuTu (n= 9 1 )
Gicfi (Nam/Nuf) Tudi tai thdi diem sinh thiet
£ 3 0 30-39 40-49 50-59 a 60 Uong n/pu Lydo nhap vien IVlet m6i Chan an Vang da KhSc TiensCr Lay truyen me con Truyen m^u Tiem chich ma tuy Quan he tinh due TiensCr phau thuat Khong rd
Ude thdi gian nhiem HCV (nam)
< 1 0 1 0 - 1 9 2 0 - 2 9
> 3 0
n 69/22
8 18 24 26 15 61
52 17 5 16
2 11 6 4 14 53
24 43 21 3
%
3/1
8,8 19.,8 26,4 28,6 16,4 67,0
57,1 18,7 5,5 17,6
2,2 12,1 6,6 4,4 15,4 58,3
26,4 47,2 23,1 3,3
Cac trieu chu'ng iam sang chu yeu khi nhap vien la m e t m d i (52/91; 57,1%), vang da (14/91; 15,4%), p h i i ( 1 0 / 9 1 ; 11%), CO chirdng (8/91; 8,8%). Tai lUOng virus HCV t r u n g b i n h la l , 4 1 x l 0 ' ± 8 , 3 x l O ' copies/ml.
Hau het cac benh nhan nhiem HCV genotype 1 (50,6%) va g e n o t y p e 6 (46,2%), chi cd 2 t r u d n g h o p n h i e m g e n o t y p e 3 (2,2%) va 1 benh nhan nhiem g e n o t y p e 2.
Theo ket qua sinh thiet gan, h o n 90% cac t r u d n g h p p benh nhan co t o n t h a o n g xo hda, t r o n g d d t o n t h u p n g xO hda nang (F3, F4) chiem 42,9%
cdn lai la khdng xo hda hoac xo hda nhe (FO, F l va F2). Ket qua fibroscan: FO 6,5%; Fl 16,5%; F2 16,5%, F3 27,5% va F4 33,0% (Bang 2).
JOURNAL OF 1 OS - CLINICAL MEOICINE AND PHARMACY VoMO-N" 4/2015
100% -
50%- / FO
SB 945% VPP 844%
S[)93 4% VPN'97 8%
S e 7 0 3 % W P 5 3 6 % ^^^ So 769% VPN 8 7 ^ ^ ^
^ ^ > T F 2 / F l
'
^ F 4 F3
'
0 50% 100% Specificity Bi^u do 1 .F)6 nhay va do dac hieu cOa fibroscan
Tai cut-off F2, do nhay cua xet nghiem Fibroscan so vdi sinh thiet gan la 70,3%, dp dac hieu la 76,9%, gia tri d u bao di(0ng.tinh la 53,6% va gla tri dU b i o am tinh la 87,2%, p<0,01. Tai cut-off F3 la 94,5% va 93,4%, gia tri diT b i o duong tinh la 84,4% va gla tri d u bao am t i n h la 97,8%, (p<0,01) (Bleu d d 1).
Bdng 2. Dac diem lam sang va can lam sang (n= 9 1 )
BMI Vang da P h j Co chudng Sao mach Xuat huyet dudi da Khdng trieu chu'ng HCV-ARV Genotype
o Genotype 1 o Genotype 2 o Genotype 3 o Genotype 6
MiJc dd xo hda gan theo sinh thiet oFO
o F l o F 2 oF3 o F 4
MOfc do xo hda theo Fibroscan oFO
o F I o F 2 oF3 o F 4
n 21.6 + 2.3
38 10 8 2 1 32 1.4xl0'±8.0xl0'
46 2 1 42
5 22 25 27 12
6 15 15 25 30
Tyle%
41,8 11,0 8,8 2,2 1,1 35,2
50,6 2,2 1,1 46,1
5,5 24,2 27,5 29,7 13,1
6,5 16,5 16,5 27,5 33,0
TAP CHi Y oaOC LAM SANG 108 Tap 10-564/2015
T r o n g n g h i e n ciiu cua chung tdi n h d m t u o i , gidi t i n h cua b e n h nhan va lam d u n g rUdu cd ^ n h h a d n g d e n m i i c d p xa hda 6 b e n h nhan viem gan C man (p<0,05). Cac y e u t o khac n h a chi so BMI, tA\ l a o n g
HCV t r o n g mau, genotype HCV, t h d i gian nhiem HCV t r u n g blnh khong anh h a d n g den m a c d p x d hda {p>0,05) {Bang 3}.
Bang 3. Cac yeu t o nguy ctf anh hudng den m i i c d o xef h o a gan (n=91)
Gidi (nam/nOr) 0 6 tudi
< 3 0 30-40 40-50 50-60
> 6 0 Uong rupu Genotype T y p e l Type 2 Type 3 Type 6 HCV-ARN (xlOT
FO 4/1
1 2 1 0 1 4/1
5 0 0 0 1,8±1,6
Mijrc do xa hoa (co/khdng) Fl
18/4
3 6 7 3 3 14/8
13 0 0 9
F2 20/5
0 8 6 8 3 18/7
13 0 0 12 2,5±3,4 1 38±15
F3 19/8
2 2 8 7 8 17/10
9 2 0 16 6,8±11
F4 8/4
2 0 2 8 0 8/4
6 0 1 5 7,1±11
P 0,049"
0,03"
0,045'
ns*
ns*
Khoang thdi gian nhiem HCV (nam)
< 1 0 10-20 20-30
> 3 0
1
"
0 0
6 10 6 0
6 12 6 1
7 14 6 0
4 3 3 2
ns*
Test Idem djnh: * test chi2, 4 . Ban luan
Hau qua c h u yeu cua qua t r i n h nhiem HCV man t m h la sa t i e n trien tdi x o gan va cac hau qua cua x d gan n h a suy gan, x u a t huyet tieu hda va ung t h u gan n g u y e n phat. Cac phat hien gan day g i u p chung ta hieu biet h d n ve qua t r i n h xd hda theo d d x a hda la hau q u a c d hai cua viem man t i n h daoc dac trOng bdi sa lang d p n g cac t o chac x o ngoai bao dan den s a b i e n d a n g cua cau true n h u m d gan t a d d lam
test ANOVA, p<0,05 cd y nghTa thdng ke.
thay doi chac nang cua he vi mach c u n g n h a chac nang te bao gan. Mac dp x d hda la ket qua cua sa mat can bang giaa t o n g h p p va thoai hda cua cac to chUc Xd ngoai bao. Do do, danh gia mUc dp x o hda cd vai t r d quan t r p n g t r o n g viec d a n h gia tien trien cua benh. Mat khac, xac d j n h mac d p xo hda cung la yeu t d g d p phan xac d j n h m a c dp tac d p n g cua lieu phap dieu tri bang t h u d c khang virus ddi v6i dien bien t a nhien cua benh [8]. Dga t h e o ket qua sinh thiet gan, chung t d i nhan thay cd h d n 9 0 % cac
JOURNAL OF 108 - CLINICAL MEDICINE AND PHARMACY VDL10-NM/201S
tradng h d p cd ton thUdng x d hoa t i i mCfc dp nhe t r d len trong do 42,9% cac trudng hop cd x d hda nang (F3, F4). Ket q u ^ nay cho thay sU can thiet phSi tien hanh dieu tri bang thuoc khang virus cho cac benh nhan nay.
Fibroscan la mdt p h u o n g phap danh gia miic dp xd hda gan khdng xam nhap va t h u d n g cd dp nhay va do dac hieu kha cao [7]. Trong nghien ciiu cua chung tdi, do nhay va do dac hieu cOa Fibroscan tai cut-off F2 la 70,3% va 76,9% tang len 94,5% va 93,4%
tai cut-off F3. Ket q u ^ nay cung phu hpp vdi ket qu5 cua Sporera.l va cdng sii khi dp nhay va dp dac hieu cOa Fibroscan tai cut-of F2 la 77,5% va 86,5% [6]. Vdi ket qua nay c-ho thay trong cac t r u d n g hpp cd chdng chl dinh sinh thiet gan, co the Ung d u n g ky thuat fibroscan de xac dinh miic do xd hda tren lam sang.
0 benh nhan VGC man tfnh, co rat nhieu yeu to 3nh hudng den tien trien xd hda gan bao gdm yeu t d vat chu va yeu t d virus. Trong nghien cau ciia chung t d i , do tuoi cua benh nhan cd lien quan chat che vdi mac dp xd hda gan (p=0,03). Theo nghien Cliu cua Poynard.T va cpng su, moi nam miic do xd hda gan tang t h e m 0,13 do Metavir [6]. Nghien cau tren cung cho thay, do t u o i d t h d i diem nhiem HCV la m p t trong nhu'ng yeu t d quan trpng ^nh hUdng den tien trien x d hda gan. Tuy nhien tren thuc te, rat khd xac d m h duoc thdi diem nhiem HCV. Trong nghien cQu nay, thdi gian nhiem HCV khong cd mdi lien quan chat che vdi mac do tien trien xd hda gan (p>0,05) dupc giSI thich do khong the xac djnh dUdc chinh xac t h d i diem nhiem HCV nen khoang t h d i gian mSc benh chi la ude tinh vi vay ket qua cd the bi sai lech.
Gidi tinh la mpt yeu to cd lien quan den qua trinh xd hda d benh nhan VGC man tfnh. Nghien ciiu cCia Wiese.M va cpng sg [9] thUc hien tren 2867 benh nhan na mac VGC man tfnh, chl cd 0,4% cac trudng hpp tien trien den x d gan. Sg tac dpng cua gidi tinh len qua trinh x d hda chua thuc sg ro rang. Cd the, d phu na, ft cd sg lam dung rUpu hoac chi so khdi cd the thap cd lien quan den k h i nang tien trien xd hda gan.
Mdt yeu t o khac co the ^ n h hadng den tien trien x d hda gan d benh nhan VGC man tfnh do la lam d u n g rupu. (3 nhCfng ngudi sCf d u n g tren 50g rapu/ngay, mac d d xd hda gan t h u d n g cao hon d
n h a n g ngUdi khong sir d u n g r u p u [3]. Ket qua n g h i e n ciiu cOa chung tdi cho thay, cd m o l lien quan giaa Sli d u n g rUdu va mac dp x o hda (p<0,05).
Trong nghien culi cCia chung t d i , khdng cd sa lien quan giaa cac yeu t o virus hpc n h u nong dp ARN-HCV t r o n g mau, genotype HCV va mac dp xo hda gan {p>0,05). Nghien cau cua Poynard.T [3] va Zeuzem. S [10] cung thay r i n g ndng do virus HCV t r o n g mau va genotype HCV khdng anh hUdng den mac dp x d hda.
5. Ket luan
Ket qua sinh thiet gan cua 91 benh nhan VGC man t i n h cho thay, hdn 90% cac t r u d n g hop cd xd hda t r o n g d d 42,9% x d hoa nang (F3, F4). Fibroscan la m p t ky thuat khong xam lan d u n g de xac dinh mac dp xo hda gan cd d p nhay va dp dac hieu cao vl vay cd t h e ap d u n g rpng rai tren lam sang dac biet d n h a n g t r u d n g h p p cd chdng chi d j n h vdi sinh thiet gan. 6 benh nhan VGC m a n , cac yeu to i n h hudng den mac do x d hda gan bao g d m tuoi, gidi tinh, sCf d u n g rupu.
Lcrl cSm d n
Chung tdi xin tran t r p n g cam dn Ban Giam doc Benh vien Benh Nhiet ddi Trung UOng, lanh dao khoa Viem gan cung n h u t o a n bp nhan vien trong khoa da tao m p i dieu kien cho c h i i n g tdl thgc hien de tai nay. Tran t r p n g Ceim d n sg t h a m gla nhi&t tinh cua cac benh nhan t r o n g nghien cau.
Tai lieu t h a m khSo
1. Lavanchy 0(2011) Evolving epidemiology of hepatitis Cw'ms. Clin Microbiol Infect 17(2): 107-115.
2. DoSH eta\{20^4) High prevalences of hepatitis Band C vims infections among adults living in Blnh Thuan province, Vietnam. Hepatol Res 45(3): 259-68 3. Poynard T,Bedossa P,Opolon P. (1997) Natural
history of liver fibrosis progression In patients with chronic hepatitis C The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. The Lancet 349(9055): 825-832.
4. Marcellin P, Asselah T, and Boyer N (2002) Fibrosis and disease progression in hepatitis C Hepatology 36(5 Suppl 1): 547-56.
TAP CHi Y DUOC LAM SANG 108 Tap 10-564/2015
Bedossa P, Poynard T (1996) An algorithm for the grading of activity in chronic hepatitis C The METAVIR Cooperative Study Group. Hepatology 24(2): 289-293.
Sporea I, et al (2011) Is it better to use (wo elastographic methods for liver fibrosis assessment?
World J Gastroenterol 17(33); 3824-3829.
Wong G.L (2013) Update of liver fibrosis and steatosis with transient elastography (Fibroscan). Gastroenterol Rep (Oxf) 1(1): 19-26
Paradis V, etal (1996) Histological features predictive of liver fitirosis In chronic hepatitis C infection. J Clin Pathol 49(12): 998-1004.
Wlese M, et al (2000) Low frequency of cirrfiosis in a hepatitis C (genotype lb} single-source outbreak in germany: A 20-year multicenter study. Hepatology 32(1): 91-96.
Zeuzem 5, et al (1996) Phylogenetic analysis of hepatitis C virus isolates and their correlation to viremia, liver function tests, and histology. Hepatology 24(5): 1003-1009.
