JOURNAL OF 108 - CLINICAL MEDICINE AND PHARMACY Vol 9 - N 1 /2Q14
Nghien cii-u ung dung FibroTest trong danh gia muc do xo hoa gan o benh nhan nhiem HBV man tinh
Applied Research of FibroTest for Estimating Liver Fibrosis on the Patients Infected with Chronic Hepatitis B Virus
Le Thanh Ha, Pham Van Tran Benh vien 103 - Hoc vien Qudny
XO gan la benh ly hay gap, tan suat benh khac nhau tuy theo khu vUc tren the gidi. Muc tieu: BUdc dau xac dinh gia trj chan doan cua FibroTest tren benh nhan xO gan cd nhiem vi rut viem gan B man tinh tai Viet Nam. Ddi tUpng 90 ngudi dupc chia lam 2 nhdm: Nhdm chUng gdm 30 ngUdi tinh nguyen khde manh va nhdm benh gdm 60 benh nhan dUpc chan doan xac djnh xo gan giai doan Child A va Child B.
Phuong phdp: tien hanh cac xet nghiem sinh hda va tinh toan chi sd FibroTest tren nhdm chUng va nhdm benh. Ket qud nghien cdu: CW\ sd FibroTest d benh nhan x o g a n cd nhiem vi rut viem gan B man tinh (0,82
± 0,21) cao hon so vOi nhom chUng (0,17 ± 0,07), Chi so FibroTest d nhdm benh nhan xO gan Child B (0,94 ± 0,05) cao hon so vdi nhdm benh nhan xo gan Child A (0,6 ± 0,21) va cac sU khac biet nay cd y nghia thong ke vdi p < 0.001. Ket/udn;Chi so FibroTest cd gia tri trong chan doan va tien lUpng xflgan tren benh nhan nhiem HBV man tinh.
Tdkhoa: Xo gan, FibroTest, Child A, B.
Summary:
Liver fibrosis is a common disease with prevalence rates varied by regions of the world. The aim of this research is to initially determine the diagnostic value of FibroTest in liver cirhotic patients with chronic hepatitis B virus infection in Vietnam. Objects: 90 people were divided into 2 groups' the control group consisted 30 healthy volunteers and the patient group consisted 60 patients with a confirmed diagnosis of iiver cirrhosis Child A and Child B. Methods: Measuring the biochemical parameters and calculated FibroTest on the control group and the infected group. Results: The FibroTest value on the cirrhotic patients with hepatitis B virus chronic infection (0.82 ± 0.21) is higher than the control group (0.17 ± 0.07), FibroTest value on the patients with cirrhosis Child B (0.94 ± 0,05) is higher compared with Child A (0.6 ± 0-2; p <0,001) Conclusions: The FibroTest is highly significant in the diagnosis and prognosis of the patients infected with chronic hepatitis B virus.
Keywords. Fibrosis, FibroTest, Child A, B,
I'liaii bit'ii khoii hoc: TS, LE HUU SONG 40
TAP CHi Y D l / g C LAM S A N G 108 Tap 9 - S 6 1/2014
1 . Dat van d e
Xo gan la m p t b e n h ly hay gap, tan suat benh khdc nhau t u y t h e o khu vUc tren t h e gidi. Cd nhieu nguyen nhan gay x o gan nhU viem gan do vi rut, do rUpu, do hda chat, d o thude, rdi loan chuyen hda, mien d i c h . . . Trong d o viem gan vi rut B m a n tfnh la nguyen nhan phd bien nhat gay xo gan.
Viec chan doan d u n g giai doan xo gan cd y nghta t r o n g theo ddi dieu trj va tien luong xo gan.
Hien nay cd nhieu p h u o n g phap chan doan xo gan nhu phuong phap sU d u n g cac marker sinh hoc, phuong phdp sinh hpc phan tCf, p h u o n g phap protein, chan doan hinh anh, sinh thiet gan.
Hien nay m d bdnh hpc van dupc lua chpn la
"Tieu chuan vang" de chan doan xo gan. Tuy nhien sinh thiet gan la m d t t h u t h u a t xam lan gay dau, cd the cd m p t sd bien chUng n h u chay mau, bpi nhiem... Mac du dp dac hieu cao t r o n g chan doan nhung ket qua sinh thiet gan phu thudc vao chu quan cua ngudi dpc va quy trinh lay mau sinh thiet.
Mat khac, viec chi djnh sinh thiet gan d giai doan . sdm chua cd trieu chUng rat khd dUpc benh nhan , chap nhan. Sinh thiet gan cung khong t h e thUe hien
nhieu lan t r o n g qud t r i n h theo ddi dieu trj.
Vi nhUng ly do tren, ngay cang ed nhieu p h u o n g . phap chan doan xo gan khdng xam lan dang Uu tien lua chpn nhU: FibroScan, FibroTest, chi sd APRl va chi sd Forn [5], [6].
Xo gan t h u d n g dan tdi giam ndng dp mdt sd protein dac biet, tang cac enzyme gan va tang bilirubin. SU thay ddi cac chi sd hda sinh nay neu xet don le thi ft cd gia trj, nhUng khi tap hpp lai se cho ta gia trj chan dodn cao. FibroTest la chi sd dUpc tinh todn dua tren 5 xet nghiem hda sinh: alpha-2- macroglobulin (A2M), haptoglobin (HP), apolipoprotein A l (ApoAl), bilirubin toan phan (BilTP), gamma - glutamyl transferase (GGT) ddng thdi k^t hop vdi cdc yeu t d tudi, gidi cua ngUdi benh. Tren the gidi dae biet cac nude chau Au nhU Anh, Phap, mdt sd nude chau A nhU Nhat Ban, Han Quoc da ed nhieu nghien cUu Ung dung FibroTest t r o n g chan doan va theo ddi dieu trj xO gan. Gia tri chan doan cua FibroTest dUpc danh gid t u o n g d u o n g vdi ket qua sinh thiet gan [3].
Hien nay d Viet Nam cd ft nghien eufu ve viee Lfng d u n g cac xet nghiem FibroTest tren benh nhan x o g a n .
Vi vay de danh gia dUpc gid trj chan dodn cCia FibroTest tren benh nhan xo gan, chung tdi tien hanh d§ tai vdi muc tieu bUdc dau xac d i n h chi so FibroTest tren benh nhan xo gan cd nhiem vi rut viem gan B man tfnh tai Viet Nam.
2. D o i tuong va phu'Ong phap nghien cufu 2.1. Doi tupng nghien cUu
Gom 90 ngUdi dUpc chia lam 2 n h d m : Whom chUng gom 30 ngUdi t i n h nguyen khde manh diigc sang Ipc t h d n g qua kham lam sang va lam cac xet nghiem can lam sang. Nhom benh gom 60 benh nhan dupc chan dodn xae djnh la xo gan giai doan Child A va Child B dUa tren cac trieu ehUng lam sang, xet nghiem hda sinh, sinh thiet gan, sieu am, ed xet nghiem HBsAg dUOng tfnh dang dUpc dieu trj tai Khoa Ndi tieu hda Benh vien 103.
* Tieu chuan loai trd: Benh nhan xo gan nhung xet nghiem HBsAg am tinh. Benh nhan xo gan nhung cd HCV(-i-), HlV(-i-). Benh nhan xo gan kem ung t h u gan. Xo gan do ruou, thudc, hda chat, ky sinh trung.
2.2. Phuong phip nghien cUu
Lap hd so benh an, tuyen chpn benh nhan, tuyen chpn ngUdi tinh nguyen khde manh t h a m gia nghien eUu. Lam cac xet nghiem FibroTest tren cdc ddi t u p n g khde manh va benh nhan xo gan do HBV.
Cac chi sd hda sinh dupe thUe hien tren he t h d n g may hda sinh t u ddng AU 640 (Beckman Coulter, Nhat ban), sU dung kich hda chat xet nghiem va huyet thanh kiem tra eua hang Beckman Coulter (Nhat Ban), Diasys (CHLB DCfc). Cac xet nghiem dupe tien hanh tai Khoa Sinh hda - Benh vien 103.
*Xdc dinh cdc chi so FibroTest:
Ndng dp A2M, HP va a p o A l dupe djnh iUpng theo p h u o n g phap hda mien djch do dp due. Hoat dp GGT huyet t u o n g dugc xac djnh theo p h u o n g phap d d n g hpc enzym va ndng dp BilTP huyet t u o n g dupc xac d j n h dua tren phdn Ung giUa
JOURNAL OF 108 - CLINICAL MEDICINE AND PHARMACY Vol 9 - N°1 /2014
bilirubin va m u o i 3,5 - dichlorophenyl diazonium tetrafluoroborate (DPD).
* Pht/ang phdp tinh chi so FibroTest
Chi so FibroTest = 4,467 x lg[A2M (g/l)] -1,357 X lg[HP (g/l)] -F 1,017 x lg[GGT (lU/l)] + 0,0281 x (tuoi (nam)] -i- 1,737 x lg[BilTP (pmol/l)] - 1,184 x [ApoAl Cdng thUe tfnh chi sd FibroTest da dupc d a n g ky ( g / l ) ] + 0,301 x chi sd gidi tfnh (nLf=0, n a m = l ) - 5 , 5 4 , ban quyen tac gid cua cdng ty BioPredictive. Cdng
thUc dupe t i n h nhUsau:
3. Ket qua nghien cuTu
Chi so FibroTest dao d d n g t r o n g khodng tCf 0 den 1, t y le vdi mUc d p x o hda cua gan dUOc quy chieu t h e o he t h d n g METAVIR (tU FO den F4).
3.1. Die diem lam sing cua cic binh nhin xogan
73.3 73.3
Bieu do 3.1. Trieu chUng Idm sdng cua nhom benh nhdn
Nhdn xet: Sd lupng benh nhan xo gan vao vien cd trieu chUng met m d i chiem t y le eao nhat la B,33%. C h i c d 19/60 (31,67%) benh nhan vao vien cd trieu chUng gan t o .
3.2. Ket qua phan loai Child -Pugh
Bang 3 . 1 : Phan bo benh nhan theo phan loai C h i l d - P u g h
Loai ton thuong
Child A Child B Tong so
Nhom x o g a n (n) 21 39 60
Tyle(%)
35 65 100 3.3. Kit qua gia tri chi so FibroTest & binh nhan xogan co nhiem HBV man tinh
3.3.1. Ket qud gid tri chi so FibroTest theo nhdm ^ benh vd nhom chdng
Bang 3.2: Gia trj chi sd FibroTest t h e o nhom benh va n h o m chufng
^~'~^--,„^^^ Nhom doi
^~~"----,^^^^ tutJng Chi tieu nghien d J u " " - - , ^
FibroTest X ± S D Toi thieu -
tdi da P
Binh thucrng (n = 30) 0,17 ±0,07
0,03-0,3 Xogan (n = 60) 0,82 ± 0,21
0,16-1
< 0,001
TAP CHi Y DUQC LAM S A N G 108 Tap 9 - S o 1/2014
0.00 0.01 0.02 0.03 0.04 Phdn bo chi so Fibre Test tr£n nhdm chihig
0.00 0.02 0.04 0.06 0.08 1.0 ^J2 Phfin b6 chi s6 FIbro Test tr6n bdnh nhSn xorgan
Bieu do 3.2. Phdn bo chi so FibroTest tren benh nhan va nhom chu'ng
Nhdn xet:
- Chi sd FibroTest d n h d m benh nhan xo gan (0,82 ± 0,21) cao hon so vdi n h d m chUng (0,17 ± 0,07) va su khac biet nay cd y nghla t h d n g ke vdi p < 0,001 (Bang 3.2).
Tren bieu d d cho thay sU phan bo chi sd FibroTest cua n h d m ehUng theo dang dUdng cong phan phdi chuan, dinh do thj d khoang 0,15 - 0,2 trong khi d benh nhan xo gan bieu d d lech phai, dinh cao nhat nam d khoang 0,8 - 0,9 (chu y thang chia dp tren hai bieu do khdng gidng nhau).
3.3.2. Ch! so FibroTest d benh nhdn xa gan theo phan loai Child - Pugh
Bang 3.3: Gia tri chi so FibroTest cr cac nhom nghien CU^J theo phan loai Child - Pugh
•—J^om doi tupng Chiti^u nghienahj--,,,^^^
FibroTest X ± S D Toi thieu -
tdi da P
Child A (n = 21) 0,6 ±0,21 0,16-0,84
Child B (n = 39) 0,94 ± 0,05
0,81 - 1
< 0,001
Nhdn xet:
Chi sd FibroTest d nhdm benh nhan xo gan Child B (0,94 ± 0,05) cao hon so vdi n h d m benh nhan xo gan Child A (0,6 ± 0,21) va sU khac biet nay cd y nghia t h d n g k e v d i p < 0,001.
3.3.3. Ket qud gid tri chi so FibroTest 6 benh nhdn xagan theo gidi
Bang 3.4: Gia trj chi so FibroTest theo gidi
^"'---,,,^^^ Nhdm
^ " ' ' - - ^ ^ d d i tuong Chi tieu nghien CULT""---.,^^^
FibroTest X ± S D Tdi thieu -
tdi da Nam (n = 51) 0,83 ± 0,2
0,16-1 NU (n = 9) 0,80 ± 0,3
0,21 - 1
Nhdn xet:
Chi sd FibroTest trung binh cua benh nhan xo gan d ca nam (0,83 ± 0,2) va nU (0,80 ± 0,3) la tUong d u o n g nhau.
3.3.4. Phdn logi mo hoc (METAVIR) dua tren gid tn chi so FibroTest d nhdm xagan
JOURNAL OF 108 - CLINICAL MEDICINE AND PHARMACY Vol 9 - N"1 /2014
Bang 3.5: Bang doi chieu so sanli giuTa plian loai m o hoc (JVIETAVIR) va gia tri c h i so FibroTest cr n h o m xor g a n
FibroTest 0.75-1.00 0.73 - 0.74 0.59-0.72 0.49 - 0.58 0.32 - 0.48 0.28-0.31 0.22 - 0.27
M U c d 6 x a g a n { F ) METAVIR
F4 F3-F4
F3 F2 F1-F2
Fl FO-Fl
Sd BN (n) 44
2 8 2 0 1 1
i T J I e % '
73,3 3,3 13,3
3,3 0,0 1,7
1,7 •
So benh nhan x o gan d mUc dp F4 cao nhat vdi 44/60 (73,3%) t r o n g khi sd benh nhan x o gan d mUe d d F3 dUng thU 2 vdi 13,3%.
4. Ban l u a n
4.1. Trieu chUng lam sang cua cic benh nhan xogan
Ket qua nghien cUu theo bieu do 3.1 cho thay t^
le benh nhan vao vien vdi ly d o met m d i chiem ty le cao nhat (88,33%). Tuy nhien, day la trieu chUng khong dac hieu va rat de nham lan vdi cac benh ly khac. Hai trieu chUng khac la vang da va tuan hoan bang he cung gap t u o n g ddi phd bien d n h d m benh nhan xo gan (73,33%). Ngoai ra, cac trieu chUng cd gia tri t r o n g chan doan xo gan la gan t o , lach t o , phii, cd c h u d n g chi xuat hien khong qua 50% t r o n g so cac benh nhan nghien cUu.
Theo nghien eUu cua Tran Hdng Ha (2007), eae trieu ehUng lam sang noi bat la met m d i (83%), vang da (61,8%), cd c h u d n g (89%), t u a n hoan bang he (73%), gan t o (26,3%), lach to (17%), phu (22,4%) [1].
Tham khao nghien cUu cua Pham Van Thang (2005), cac trieu ehUng lam sang d benh nhan xo gan: met m d i (100%), rdi loan tieu hda (100%), cd chudng (80%), vang da (72%), tuan hoan bang he (67,5%), gan to (42,5%), lach t o (38%) [2].
Tdm lai, t r o n g eae trieu chUng lam sang d benh nhan xo gan thi n h d n g t n e u ehUng dac hieu cho
benh gan m a t khdng phai la trieu chdng thudng xuat h i e n nhat. Hau het eae benh nhan deu c6 nhUng dau hieu lam sang chung chung khdng dac hieu n h u m e t m d i , rdi loan tieu hda. Neu chi di/a tren cac trieu chUng lam sang t h i rat khd chan doan sdm va chinh xac cac benh nhan xo gan. Vi vay, cac bac sy hien nay phcii ket h g p giUa kham lam sang v6i ket qu5 nhieu p h u o n g phap can lam sang khac de cd chan doan xae d j n h cudi cung.
4.2. Gia trj FibroTest d binh nhan xagan co nhiem vi rut viim gan B man tinh
Hien nay d Viet Nam, de t h e o ddi, danh gia xfl gan van chu yeu dua vao sieu am va sinh thiet gan.
Phuong phap sieu a m nhieu khi khdng chinh xac, phu thupc vao kinh n g h i e m bac sy. Sinh thiet gan la tieu chuan vang n h u n g cung rat it khi dUOC thUc hien vi ddi hdi benh nhan phai nam vien, gay dau va cd m d t sd bien chUng. Chi so FibroTest la mot p h u o n g phap chan d o a n d o n gian va cd the trien khai d cac benh vien cung n h u cac ca sd y te. D3c biet FibroTest cd t h e thUc hien d u g c nhieu lan trong qua trinh t h e o ddi dieu trj b e n h nhan xo gan.
FibroTest la p h u o n g phap m d i d u n g de chan doan, t i e n lugng va t h e o ddi dieu tri xo gan dUa tr^n cac xet n g h i e m mau. D e t i n h t o a n FibroTest, can phai lam du cac xet n g h i e m A 2 M , HP, A p o A l , BilTP va GGT. TU d d dua vao c d n g thUc de dien giSI ket qua danh gia mUc dp xOgan.
TAP CHi Y DLraC L A M S A N G 108 T|ip9-S6l/2014
Trong nghien cufu cua chung tdi thay gia trj cua chi sd FibroTest d nhdm benh nhUn xo gan (0,82 ± 0,21) cao hon so vdi nhdm chUhg (0,17 ± 0,07) va su khae biet nay cd y nghia t h d n g k§vcS p<0,001 (Bang 3.13).
Gia trj chi sd FibroTest t r u n g b m h cua benh nhan xo gan theo gidi t i n h : d nam (0,83 ± 0,2) va nCf (0,80 ± 0,3) la t u o n g d u o n g nhau va khdng cd su khac biet ve gidi t m h (Bang 3.4).
Chi so FibroTest dao d p n g t r o n g khoang tU 0 den 1, ty le vdi mufe do x o hda cua gan duge quy chieu theo he t h o n g METAVIR (tU FO den F4).
FibroTest dugc quy doi theo phan loai m d hpc t h u d n g duge sd d y n g nhat la METAVIR, Knodell va Ishak. d Viet Nam, phan loai m d hgc cua METAVIR duoc sU dung phd bien nhat. Dua tren khuyen cao eua BioPredietive de quy chieu mUc phan loai md benh hgc va gia trj chi sd FibroTest thi 44/60 (73,3%) benh nhan trong nghien cUu cua chung tdi bj xo gan d mUc dd F4, t^ le benh nhan xo gan mUe do F3 la 13,3%, eae mUc dd F2, Fl, FO ratthap <4% (Bang 3.16).
Tham khcio cac nghien cUu eCia Thierry Poynard va cdng sU nghien cUu tren 1270 benh nhan nhiem HCV man tinh thi ty l# n h u sau: 7,08% d mUc do FO, 54,17% d mUc do F l , 19,92% d mUc do F2,16,11% d mUc do F3,1,81% d mUe do F4 [7].
Tac g i ^ Mircea Grigorescu va CS (2007), nghien cUu gta tri khac biet cua FibroTest d benh nhan xo gan va chua ed xo gan cd nhiem HCV man tai Romani cho ket q u ^ 7,8% FO, 2 9 , 1 % F l , 34% F2, 21,3%F3,7,8%F4[4].
Ty le x o g a n tUong d u o n g m U c d d phan loai md benh hgc F3 va F4 t r o n g nghien eUu cua chung tdi eao hon nhieu so vdi eae nghien cUu khac, bdi vi trong nghien ccfu cua chung tdi ddi t u g n g n h d m benh nhan nghien cdu da nhap vien nhieu lan, trieu chdng lam sang xo gan da rd, theo phan loai md benh hgc giai doan F3, F4 t u o n g d u o n g vdi ton thuong xo gan thuc su.
Chung tdi chu yeu dUa tren phan loai Child - Pugh d ^ ddi chieu so sanh mUc d d benh vdi ehi sd FibroTest, ty le benh nhan chia n h d m theo phan loai Child B \k 39/60, b # n h nhan xo gan giai doan Child A (35%). K^t quS nghien cdu cung chi ra r i n g chi sd FibroTest 6 n h d m b e n h nhan xo gan Child B
(0,94 ± 0,05) cao hon so vdi n h d m benh nhan x o gan Child A (0,6 ± 0,21) va su khac biet nay cd y nghTa t h d n g ke vdi p < 0,001 (Bang 3.1). NhU vay chi sd FibroTest ed gia trj t r o n g viec danh gia mCfc do t i e n t h e n eua benh ly x o gan cung n h u theo ddi va tien lugng benh. NhUng xet nghiem nay cd t h e de dang chi d j n h va tien hanh nhieu lan t r o n g qua trinh theo ddi dieu trj benh nhan xo gan. Trong khi ddi vdi sinh t h i e t gan, khdng t h e tien hanh m g t each t u o n g tU.
5. Ket l u a n
Chi sd FibroTest d benh nhan xo gan cd nhiem vi rut viem gan B man tinh cao hon so vdi n h d m chUng va chi sd nay cao hon d n h d m benh nhan xo gan Child B so vdi Child A (p<0,001). Vi vay, FibroTest ed gia trj trong chan doan va tien lugng xo gan tren benh nhan nhiem HBV man t i n h . Tai lieu t h a m k h a o
1 Tran Hdng Ha (2006), Nghien cUu ndng do alpha- fetoprotein huyet thanh d benh nhan xo gan v& ung thu gan, tuan van thac syy hqc, Hgc vien quan y.
2. Pham Van Thang (2005). Nhan xet mgt sd dac diem lam sang, can lam sang cua benh nhan xO gan va ung t h u bieu md te bao gan sau xO gan, Luan van thac sy y hgc, Hgc vien quan y 3 Cacoub P, Carrat F, Bedossa P, Lambert J, Penaranda
G, Perronne C, Pol S, Halfon P (2008). "Comparison of non-invasive liver fibrosis biomarkers in HIV/HCV co- infected patients: The Fibrovic study - ANRS HC02". J Hepatol. 48 {5]:765-73.
4. Mircea Grigorescu, Mihaela Rusu, Daniela Neculoiu, Corina Radu, Alexandru erban, Mihaela Capana, Mircea (2007). The FibroTest Value in Discriminating between Insignificant and Significant Fibrosis in Chronic Hepatitis C Patients.
The Romanian Experience, J. Gastrointestin liver d/seoses. Vol.16. Noi,34,37.
5. Nguyen-Khac E, Chatelain D, Tramier B, Decrombecque C, Robert B, Joly JP, Brevet M, Grignon P, Lion S, Le Page L, Dupas JL. (2008).
"Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan- prospective
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comparison with seven non-invasive laboratory lesxs". Aliment Pharmacol Ther. 15;28(10):1188-98.
Pucci P, Siciliano R, Malorni A, Marino G, Tecce MF, Ceccarini C, Terrana B (1991). "Human alpha- fetoprotein primary structure: a mass spectrometrie study". Biochemistry 30 (20): 5061-6.
Thiery poynard, Francoise Imbert- Bismut, Mona Munteanu, Djamila Messous, Robert P Myers,
Dominique Thabut, Vlad Ratziu, Anne Mercadier, Yves Benhamou and Bernard Hainque (2004)."Overview of the diagnostic value ol biochemical marker of liver fibrosis (FibroTest HCV Fibrosure) and necrosis (ActiTest) in patiens with chronic hepatitis C". Compara^
Hepatology.3:8 .
