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Contents Alexandria Journal of Hepatogastroenterology Volume IIIX ( II ) August 2013

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manuscripts please contact the editors by e-mail at

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Disclaimer The Publisher the Egyptian Society of

Hepatology Gastroenterology and Infectious Diseases in

Alexandria and Editors cannot be held responsible for errors

or any consequences arising from the use of information

contained in this journal the views and opinions expressed

do not necessarily reflect the those of the Publisher The

Egyptian Society of Hepatology Gastroenterology amp

Infectious Diseases in Alexandria Editors neither dose the

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Original Article

Hemostatic Disorders in Egyptian Chronic Hepatitis C

Patients with Liver Cirrhosis Possible Mechanisms and

Relation to Portal Vein Thrombosis

Ali El Kady1 Magdi El Bordini2 Ayman El Shayeb1 Nihal El Habachi3 and Reem Sherif1

Tropical Medicine1 Clinical Pathology2 and Physiology

Departments3 Faculty of Medicine Alexandria University

-------------------------------------------

Original Article

Last Minute Donor Exclusion in Living Donor Liver

Transplantation Impact on Evaluation Program

Hany Shoreem1 Hossam Eldeen Soliman1 Osama Hegazy1

Sherief Saleh1 Wael Abdelrazek2 Nirmeen Fayed3 Taha

Yassen1 Kalied Abuelella1 Tarek Ibrahim1 Ibrahim Marwan1 1Department of HBP Surgery National Liver Istitute Egypt

2Department of Hepatology National Liver Institute Egypt

3Department of Anaesthesia National Liver Institute Egypt

-------------------------------------------

Original Article

The Impact of Interleukin 28B Tumor Necrosis Factor

Alpha Gene Polymorphisms on Therapeutic Response in

Chronic HCV Egyptian Patients

Hamouda S Hanno A El-Shayeb A Mansour A

Elwazzan D

Department of Tropical Medicine Department of Clinical

Pathologyy Alexandria UniversityEgypt

-------------------------------------------

2

12

23

Original Article

Hemostatic Disorders in Egyptian Chronic Hepatitis C Patients with Liver

Cirrhosis Possible Mechanisms and Relation to Portal Vein Thrombosis


Tropical Medicine1 Clinical Pathology2 and Physiology Departments3 Faculty of Medicine Alexandria University

ABSTRACT

Liver cirrhosis is frequently accompanied by complex alterations in the hemostatic system Von Willebrand factor

(vWF) which is considered as a marker of endothelial cell activation plays an essential role in hemostasis ADAMTS13

(a distintegrin- like and metalloproteinase with thrombospondin type 1 motifs 13) which is produced exclusively in

hepatic stellate cells (HSCs) cleaves multimeric vWF Although the interaction between ADAMTS 13 and vWF could

be considered as initial step in hemostasis little information has been available on this interaction in Egyptian cirrhotic

hepatitis C virus (HCV) patients Aim of the work this study aimed at exploration of the possible relationship

between plasma level of Von Willebrand factor (vWF) and ADAMTS13 implicated in hemostatic disorders in Egyptian

cirrhotic HCV patients and its relation to portal vein thrombosis Methods The study was conducted on 40 cirrhotic

HCV patients who were further subdivided according to Child Pugh classification Moreover 20 healthy subjects were

enrolled as controls Plasma vWF and ADAMTS 13 were measured by ELISA Results Mean plasma vWF was

significantly higher in patients with liver cirrhosis than in controls (P lt 005) In patients plasma vWF was significantly

higher in those with Child C than those with Child B and A On the other hand plasma ADAMTS 13 was significantly

lower in patients than controls In patients with liver cirrhosis plasma ADAMTS 13 was significantly lower in Child C

than Child B and A ones Furthermore a significant negative correlation was observed between ADAMTS 13 and vWF

in the studied group (P lt 005)Cirrhotic patients with portal vein thrombosis had significantly lower level of

ADAMTS 13 and higher level of vWF than controls (plt 005) Conclusion Egyptian cirrhotic chronic HCV patients

may experience a hemostatic disorders which are evidenced by high levels of vWF and concomitant low levels of

ADAMTS 13 suggesting the possible role of both endothelial and liver dysfunction in those patients Moreover

further studies are needed to explore different therapeutic areas aiming at elevating levels of ADAMTS 13 particularly

in those patients with portal vein thrombosis

Introduction

Hepatitis C virus (HCV) is estimated to infect

approximately 180 million people worldwide (1) However the prevalence of HCV infection

varies through out the world Egyptian

Demographic health survey (EDHS) in 2009

reported an overall anti-HCV antibody

prevalence of 147 and the number of

Egyptians estimated to be chronically infected

was 98 (2) Cirrhosis develops in

approximately 10 to 15 of individuals

with chronic HCV infection (3) There are

external and host factors such as older age at

time of infection male gender coinfection

with hepatitis B virus (HBV) and comorbid

conditions such as schistosomiasis that can

increase the risk of progression of liver

disease (4) Normal hemostasis results from

well regulated processes that maintain blood

in a fluid clot free state in normal vessels

while inducing rapid formation of a localized

plug at the site of vascular injury(5) The liver

plays a major role in hemostasis by

synthesizing all clotting factors (except von

Willebrand factor (vWF) coagulation

inhibitors and several fibrinolytic proteins

The hepatic reticuloendothelial system clears

activated clotting factors proteolytic enzyme

inhibitor complexes and fibrin degradation

products The normal hemostatic system

becomes severely impaired in cases of end

stage liver disease predisposing to bleeding (6) Intact blood vessels are the main

moderators of bloods tendency to clot The

endothelial cells of intact vessels prevent

blood clotting with the protein

thrombomodulin which facilitates anti-

coagulant and fibrinolytic activity by conv-

erting Protein C (PC) to activated Protein C

(APC)(7) Endothelial cells also prevent

platelet aggregation and promote vasodilation

with nitric oxide and prostacyclin Add-

itionally normal endothelium expresses other

anticoagulants such as glycosamino-glycans

and heparinoids and promotes fibrinolysis by

producing tissue plasminogen activator

(tPA)(8) In liver cirrhosis a sinusoidal

microcirculatory disturbance occurs when the

normal hepatic structure is disrupted by fibrin

deposition (9) or by impaired balance between

the action of vasoconstrictors and vasodilators

in hepatic vascular circulation (10) Various

classifications have been used to assess

severity of liver disease In patients with

chronic liver disease Childs grading with

Child Pughs classification modification is

frequently used It is useful in assessing

prognosis and estimating the potential risk of

variceal bleeding and operative mortality

This system uses a combination of clinical

and laboratory parameters (serum bilirubin

serum albumin prothrombin time ascites and

hepatic encephalopathy) The Child grade has

been equated with survival and Child C is the

most severe with an overall mortality of 88 (11) When endothelial injury occurs the end-

othelial cells stop secretion of coagulation and

aggregation inhibitors and instead secrete Von

Willebrand factor (vWF) (12) which is

considered as a marker of endothelial cell

activation (damage) and plays an essential

role in hemostasis(1314) vWF is a multimeric

large adhesive glycoprotein It mediates

platelet adhesion to exposed sub-endothelium

at sites of vascular injury under conditions of

stress Unusual large vWF multimers

(ULvWFMs) are produced exclusively in

vascular endothelial cells (ECS) and stored in

an intracellular organelle termed Weibel-

Palade bodies (WPBs) and released into the

circulation upon stimuli (15) The A1 domain

of VWF forms the principle binding sites for

platelet glycoprotein 1b (Gp1b) that promotes

platelet aggregation (16) ADAMTS13 (a

distintegrin- like and metalloproteinase with

thrombospondin type 1 motifs13) is a

metalloproteinase that specifically cleaves

multimeric vWF in the A2 domain (1314)

ADAMTS13 is produced exclusively in

hepatic stellate cells (HSCs)(17) Platelets (18)

vascular endothelial cells (19) and kidney

podocytes but the amount produced by these

cell types appears to be far less than that

produced by HSCs On the occurrence of liver

injury accompanied by a necroinflammatory

process the sinusoidal endothelial cells

become positive for vWF in association with

the capillarization of hepatic sinusoids(9) Sub-

sequently platelets adhere to subendothelial

tissue mediated by ULvWFMs ADAMTS13

then cleaves ULvWFMs into smaller vWF

multimers This interaction of ADAMTS13

and ULvWFMs is indeed the initial step in

hemostasis (1314) In the absence of ADAMTS

13 activity ULvWFMs are released from

vascular endothelial cells and improperly

cleaved causing them to accumulate and to

induce the formation of microvascular platelet

thrombi in the microvasculature under

conditions of high shear stress (14) However

little information has been available on the

interaction between vWF and ADAMTS 13 in

liver cirrhosis in Egyptian patients

Aim of Work

Our study aimed to explore the possible

relationship between plasma level of Von

Willebrand factor (vWF) and ADAMTS 13

implicated in hemostatic disorders in Egypt-

ian cirrhotic HCV patients and occurrence of

portal vein thrombosis

Subjects amp Methods

The protocol of the study was approved by

the Ethics committee of the Faculty of

Medicine University of Alexandria The

study was carried out on 60 patients classified

into two groups Group I included 40 patients

with chronic HCV with liver cirrhosis who

were subdivided according to Child- Pugh

classification (11) into three subgroups Group

Ia 10 patients with Child class A Group Ib

12 patients with Child class B and Group Ic

18 patients with Child class C Furthermore

20 healthy individuals with matching age and

sex were taken as controls (Group II) Patients

with history of alcohol abuse heart disease

kidney disease diabetes mellitus HBV

infection or malignancy were excluded from

the study All patients within group I were

HCV positive (HCV Ab +ve and confirmed

by PCR for HCV-RNA) All patients and

controls were interviewed and subjected to

the following 1Clinical evaluation and ultra-

sound examination for evidence of cirrhosis

2Routine laboratory investigations including

Complete blood picture Liver functions tests

(serum ALT AST GGT Alkaline phos-

phatase serum bilirubin serum albumin

prothrombin time and activity)(20) 3 Viral

markers for hepatitis B (HBs Ag) and

hepatitis C (Anti HCV) by ELISA(21) 4

Abdominal imaging using Ultrasound for

evidence of portal vein thrombosis

5Estimation of plasma ADAMTS13 levels

Estimation of plasma ADAMTS 13 activity

level was done using the Technozym

ADAMTS 13 ELISA test (22) 6- Plasma level

of von Willebrand factor using (vWF Ag

ELISA kit Technoclone Vienna Austria) (23)

Statistical Analysis

Data were collected revised and transferred

into the Statistical Package for social science

(SPSS version 10) Results were expressed

as means and standard deviation Statistical

tests used in this study were student t-test F-

test and Pearson correlation A level of 5

was considered as the cut off level of

significance

Results

The mean levels of plasma vWF was

significantly higher in patients compared to

control group (20012plusmn9544 and 7840plusmn331

μmoll respectively t= 523 p = 0001) (Table

I) In patients with liver cirrhosis (Gp I) the

mean value of plasma vWF was significantly

higher in Child C patients than Child B and A

ones (2697plusmn9633 17050plusmn1140 and 8530

plusmn4415 μmoll respectively) (F= 25 p= 000)

Moreover it was significantly higher in Child

B patients than A (Fig 1) On the other hand

the mean Plasma ADAMTS 13 activity was

significantly lower in patients than controls

2930plusmn1744 and 6540plusmn2303 respectively

(t= 677 p= 000)(Table I) Furthermore in

group I patients the mean values of

ADAMTS 13 activity were significantly

lower in Child C patients than Child B and A


plusmn590 respectively) (F= 60 p= 000) and in

child B than in Child A patients (Fig 2)

Table I Mean plasma vWF and ADAMTS 13 in patients and controls

vWF(μmoll) ADAMTS 13 activity ()

Patients(n=40) 20012plusmn9544 2930plusmn 1744

Controls (n=20) 7840plusmn331 6540plusmn 2303

T 532 677

P 0001 0000

In group I 10 patients had portal vein

thrombosis when evaluated by ultrasound

examination ( 8 of them were Child C while 2

were Child B) however the remaining 30

patients had not The mean value of plasma

vWF was significantly higher in those with

portal vein thrombosis than those without it

(28840plusmn 10527 and 17070plusmn 7231 μmoll

respectively)(t= 393 P=0002) On the other

hand in the same group I the mean value of

ADAMTS 13 activity was significantly lower

in those with portal vein thrombosis than in

those without (1650plusmn 1000 and 335plusmn

1744 respectively) (t= 292 p= 0001)

(Table II)

Table II Mean plasma vWF and ADAMTS 13 in patients with and without PV thrombosis

vWF(μmoll) ADAMTS 13 activity ( )

PV Thrombosis (n=10) 28840plusmn 10527 1650plusmn 1000

No PV Thrombosis (n=30) 17070plusmn 7231 335plusmn 1744

T 393 292

P 0002 0001

Correlation studies (Table III) revealed that

significant positive correlation was found

between vWF and Child Pugh score ( r= 072

p= 000) (Fig 3) On the other hand

significant negative correlation was noticed

between ADAMTS 13 activity and each of

vWF and Child Pugh score in patients with

liver cirrhosis (GpI) ( r= - 051 and ndash 077 p=

000 0001) (Fig 4)

Table III correlation between ADAMTS 13 vWF and Child Pugh Score

ADAMTS 13 Child Pugh Score

vWF r= -051

p= 000

r= 072

p= 000

ADAMTS 13 r= -077

p= 0001

Figure 1 Mean Plasma vWF (umoll) in patients Figure 2 Mean Plasma ADAMTS 13 activity in patients

Child Score

141210864

vW

F

600

500

400

300

200

100

0

Figure 3 Correlation between vWF and Child Pugh score in patients

Figure 5 correlation between ADAMTS 13 and Child Pugh Score in patients

Adamts 13

706050403020100

Ch

ild S

co

re

14

12

10

8

6

4

Figure 4 Correlation between ADAMTS 13 and Child Pugh score in patients

Discussion

Liver cirrhosis is frequently accompanied by

complex alterations in the hemostatic system

resulting in bleeding tendency Although

many hemostatic changes in liver disease

promote bleeding compensatory mechanisms

are found (24) There is indirect evidence that

there may be an endothelial perturbation in

liver cirrhosis which might explain some of

the clinical and biochemical changes as well

as the hyperdynamic circulation and

coagulation changes seen in cirrhosis (25)

Considering that ADAMTS 13 is synthesized

in HSCs and ULvWFMs is produced in

transformed sinusoidal endothelial cells

(SEC) during liver injury decreased plasma

ADAMTS13 may involve not only sinusoidal

microcirculatory disturbances but also

subsequent progression of liver disease

finally leading to multiorgan failure (26) In the

present work mean value of vWF was

significantly higher in liver cirrhotic patients

than in controls Similar findings were

reported by ferro et al (27) Kulwas et al (28)

and La Mura et al (29) Our findings support

the hypothesis of endothelial activation in

liver cirrhosis In the present study


between plasma vWF and Child Pugh

scoreSimilar findings were reported by La

Mura et al ( 29) Albornoz et al(30)demonstrated

that the increased plasma levels of vWF

paralleled the degree of liver failure (30) High

circulating levels of vWF in cirrhosis might

be a consequence of endothelial perturbation

induced by endotoxin Ferro et al reported a

strong correlation between endotoxemia and

high circulating levels of vWF(27) Increased

serum levels of vWF could be due to

endothelial activation by cytokines and or

endothelial damage (27) Also it has been

suggested that high vWF levels can be

probably explained by increased synthesis

release of this protein since it is an acute

phase reactant to tissue injury Furthermore

high vWF levels could be associated with a

compensatory regulation mechanism for the

hemostatic disorders of chronic liver disease (31) Another hypothesis of high vWF is that

local damage to endothelial cells could result

in the disruption of Weibel- Palade bodies and

endothelial membrane leading to vWF

multimers release (32) Studies have shown

that ADAMTS13 is significantly decreased in

patients with hepatic veno-occlusive disease

(VOD) (33) alcoholic hepatitis(34) liver

cirrhosis (35) Furthermore HCV related liver

cirrhosis patients with ADAMTS13 inhibitors

typically developed thrombotic thrombo-

cytopenic purpura (TTP) (36) In the present

work plasma ADAMTS13 activity was

significantly lowered in patients with liver

cirrhosis than in controls Furthermore in

patients with liver cirrhosis plasma

ADAMTS 13 was significantly lower in Child

C patients than in Child B and A patients and

also in Child B patients than Child A patients

In our work ADAMTS13 decreased signify-

cantly with advanced cirrhotic process by the

observed negative correlation between

ADAMTS13 and Child Pugh Score Our

results were in agreement with that of

Mannucci et al (37) who reported a reduction

in ADAMTS13 activity in advanced liver

cirrhosis and the decrease of plasma

ADAMTS 13 activity in patients with chronic

liver disease has been associated with disease

progression In addition Uemeura et al (38)

reported that both ADAMTS13 and its

antigen decreased in cirrhotic patients and

such decrease was positively correlated with

increasing severity of cirrhosis assessed by

Child Pugh criteria Moreover Matsumoto et

al (39) demonstrated that decreased plasma

ADAMTS13 in patients with cirrhotic biliary

atresia can be fully restored after liver

transplantation indicating that the liver is the

main organ producing ADAMTS13 On the

other hand Lisman et al (40) showed that

plasma ADAMTS13 and its antigen were not

significantly different between various stages

of liver cirrhosis The discrepancy between

our results and that of Lismanrsquos is attributed

to the fact that all of our cirrhotic patients are

secondary to chronic HCV infection whereas

in Lismanrsquos study half of the cirrhotic

patients were alcoholic The mechanism

responsible for the decrease in ADAMTS13

in advanced liver cirrhosis may include

enhanced consumption due to the degradation

of large quantities of vWF (41) inflammatory

cytokines(4243) andor ADAMTS13 plasma

inhibitor(4445) It is controversial whether

ADAMTS 13 deficiency is caused by

decreased production in the liver Some

studies have shown that HSC apoptosis plays

an essential role in decreased ADAMTS13

(46) Other studies demonstrated the presence

of the inhibitor to ADAMTS 13 in 83 of

patients with moderate to severe ADAMTS

13 deficiency (47)Alternatively cytokinemia (48) and endotoxemia (49) are additional

potential candidates for decreasing plasma

ADAMTS13 Recent investigations demon-

strated that IL-6 inhibited the action of

ADAMTS13 and both IL-8 and TNF-α

stimulated the release of ULvWFMs in

human umbilical vein endothelial cells in

vitro (42) IFN-γ IL-4 and TNF- α also inhibit

ADAMTS13 synthesis and activity in rat

primary HSC (43) To the best of our

knowledge no available studies in literature

demonstrated the relationship between

ADAMTS 13 and vWF in HCV induced liver

cirrhosis in Egyptian patients so we have

tried to explore this point in the current study

Our results revealed significant ndashve

correlation between ADAMTs 13 and vWF in

the studied patients group this was supported

by the study that IV infusion of endotoxin to

healthy volunteers caused a decrease in

plasma ADAMTS 13 together with the

appearance of ULvWFMs (49) Additionally

in patients with alcoholic hepatitis especially

in severe cases complicated with liver

cirrhosis ADAMTS 13 is concomitantly

decreased and vWF antigen is progressively

increased with increasing concentration of IL-

6 and IL-8 above 100pgml (50) The

relationship between ADAMTS 13 and vWF

in the above mentioned studies supports our

finding of the presence of significant negative

correlation between vWF and ADAMTS 13

Patients with advanced liver cirrhosis may

frequently develop hepatic and portal vein

thrombosis (5152) Such a hyper-coagulable

state in liver diseases may be involved in

hepatic parenchymal destruction acceleration

of liver fibrosis and disease progression

leading to hepatorenal syndrome porto-

pulmonary hypertension and spontaneous

bacterial peritonitis (SBP) (53) In our work

plasma ADAMTS 13 was significantly

lowered in those with portal vein thrombosis

(10 patients) than in those without it (30

patients) On the other hand high vWF levels

were noticed in those with portal vein

thrombosis This observation was in agree-

ment with that of Uemura et al (38) who

propose that ADAMTS13 deficiency might

contribute to the development of portal vein

thrombosis in patients with advanced

cirrhosis Although ADAMTS13 deficiency

creates a prethrombotic state it may not

appear because of the presence of

thrombocytopenia and coagulation factor

deficiencies in liver cirrhosis (54)

Conclusion

Egyptian cirrhotic chronic HCV patients may

experience a hemostatic disorders which are

evidenced by high levels of vWF and

concomitant low levels of ADAMTS 13

suggesting the possible role of both

endothelial and liver dysfunction in those

patients Moreover further studies are needed

to explore different therapeutic areas aiming

at elevating levels of ADAMTS 13

particularly in those patients with portal vein

thrombosis

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Med 1998 339(22) 1578-84

45 Tsai HM Lian EC Antibodies to von Willebrand

factor-cleaving protease in acute thrombotic

thrombocytopenic purpura New Engl J Med 1998

339(22) 1585-94

46 Kume Y Ikeda H Inoue M Tejima K Tomiya T

et al Hepatic stellate cell damage may lead to

decreased plasma ADAMTS13 activity in rats

FEBS Letters 2007 581(8) 1631-4

47 Niiya M Uemura M Zheng XW Pollak ES

Dockal M et al Increased ADAMTS-13

proteolytic activity in rat hepatic stellate cells upon

activation in vitro and in vivo Journal of

Thrombosis and Haemostasis 2006 4(5) 1063-70

48 Claus RA Bockmeyer CL Sossdorf M Losche

W The balance between von-Willebrand factor

and its cleaving protease ADAMTS13 biomarker

in systemic inflammation and development of

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10(2) 236-48

49 Reiter RA Varadi K Turecek PL Jilma B Knobl

P Changes in ADAMTS13 (von-Willebrand-

factorcleaving protease) activity after induced

release of von Willebrand factor during acute

systemic inflammation Thrombosis and

Haemostasis 2005 93(3) 554-8

50 Ishikawa M Uemura M Matsuyama T

Matsumoto M Ishizashi H et al Potential role of

enhanced cytokinemia and plasma inhibitor on the

decreased activity of plasma ADAMTS13 in

patients with alcoholic hepatitis relationship to

endotoxemia Alcoholism Clinical and

Experimental Research 2010 34(1) 25-33

51 Amitrano L Guardascione MA Brancaccio V

Margaglione M Manguso F et al Risk factors and

clinical presentation of portal vein thrombosis in

patients with liver cirrhosis Journal of Hepatology

2004 40(5) 736-41

52 Wanless IR Wong F Blendis LM Greig P

Heathcote EJ et al Hepatic and portal vein

thrombosis in cirrhosis possible role in

development of parenchymal extinction and portal

hypertension Hepatology 1995 21(5) 1238-47

53 Pluta A Gutkowski K Hartleb M Coagulopathy

in liver diseases Advanced Medical Science 2010

55 16-21

54 Banno F Kokame K Okuda T Honda S Miyata S

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2006 107 3161-6

Original Article

Last Minute Donor Exclusion in Living Donor Liver Transplantation Impact

on Evaluation Program

Hany Shoreem1 Hossam Eldeen Soliman1 Osama Hegazy1 Sherief Saleh1 Wael Abdelrazek2 Nirmeen Fayed3 Taha

Yassen1 Kalied Abuelella1 Tarek Ibrahim1 Ibrahim Marwan1

1Department of HBP Surgery National Liver Istitute Egypt 2Department of Hepatology National Liver Institute

Egypt 3Department of Anaesthesia National Liver Institute Egypt

ABSTRACT

Minimizing the risk imposed to a healthy donor is one of the complex aspects of living donor liver transplantation

(LDLT) and implies a highly scrutinized evaluation process Nevertheless late events could lead to exclusion of some

of those evaluated donors Aim To investigate the late causes of exclusion of a potential LDLT donor and how far

these reasons contributed to changing our donor evaluation program Method Throughout 10 years more than 2500

potential living donors had been evaluated for liver donation for about 1500 potential recipients who presented for

LDLT at transplantation unit National Liver Institute (NLI) Menoufyia university Egypt from them only 194 were

transplanted The evaluation records of those donors were retrospectively analyzed for causes of late exclusion

Results Only 15 of the evaluated potential donors were accepted for donation and only 78 were donated

Exclusion reasons included late psychological instability in 4 donors and family pressure to withdraw consent in one

donor substance abuse in 2 donors Early pregnancy was discovered in one female donor week pre-transplantation The

pre-operatively revised blood group of another donor was discovered to be incompatible as the previously determined

blood group was wrong The presence of Factor V Leiden homozygous mutation was diagnosed in 2 donors In four

cases LDLT was aborted after donor laparotomy due to macroscopic diffuse hepatic changes considering the liver

unsuitable for donation One donor was convicted and imprisoned 2 weeks before LDLT Most of these exclusions

evoked discussions led to modifications in the evaluation protocol in addition to its impact on both donors and

recipients Conclusion Late pre-transplantation donor exclusion had its impact in donors recipients and resources

Reassessment of the donor evaluation protocol should be a dynamic process and it found to be greatly affected by these

late exclusions

Introduction

Donor safety is the most crucial aspect of

LDLT programs The aim of donor evaluation

protocols is to completely avoid donor

mortality and minimize both the incidence

and degree of donor morbidity Living liver

donation is associated with a small but real

possibility of mortality that may approach 05

(1 2) Due to the high costs most centers

have developed a stepwise evaluation

program to identify contraindications to

donation as early as possible (3) The

published donor evaluation protocols are all

very similar Most potential donors are

excluded based on the initial studies to rule

out underlying conditions that represent

increased surgical risk Immediate exclusion

criteria include donors who are currently

pregnant less than 18-year-old or older than

55-years old with co-morbidities Selection

criteria are rigid to ensure donor safety with

no exception to accommodate the needs of the

recipients (4) Acceptance rate for donors

undergoing the evaluation process is reported

to vary between 22 and 66 Taken into

consideration that not all recipients qualify for

LDLT and that not all potential recipients can

present a possibly suitable donor the chances

for a LDLT candidate to receive a living

donor graft are quite low and that only 13

of prospective recipients were able to find

suitable living donors(5 6) Other authors

reported that only 49 of 100 potential

recipients were found to be suitable for

LDLT Of these only 25 had a potential

donor of whom 15 were finally accepted(7)

Throughout the previous 10 years we faced

some problems and pitfalls during donorsrsquo

evaluation that led to their late exclusion from

donation soon before transplantation This

exclusion had effect on donor recipient

resources and the evaluation protocol

therefore some modifications had been raised

in the four steps of our protocol The aim of

this study is to investigate the late causes of

exclusion of a potential LDLT donor and how

far these reasons contributed to changing our

donor evaluation program

Patients and Methods

Throughout 10 years (from start of

transplantation program in April 2003 till

October 2012) more than 2500 potential

living donors had been evaluated for

suitability for liver donation for about 1500

potential recipients who presented for LDLT

at National Liver Institute Menoufyia

university from them only 194 finally

donated for LDLT after proceeding all of the

phases of donor selection in our protocol The

evaluation protocol that had been adopted at

the start of the transplantation program in our

center on April 2003 is illustrated in table 1

The donors were evaluated in four steps Step

one of this evaluation included a clinical and

social evaluation A liver profile hepatitis

marker assessment renal profile complete

blood count and abdominal ultrasound with

Doppler were performed in this step Step two

included an ultrasound-guided liver biopsy

Step two also included an imaging and

evaluation for cardiopulmonary status Step

three included an imaging evaluation of the

liver vascular anatomy using computed

tomography (CT) angiogram and imaging

evaluation of biliary anatomy and using

magnetic resonance cholangiopancreatogra-

phy A CT volumetric study was used to

calculate the volume of the liver parenchyma

Step three also included a screening of

procoagulation disorders Step four consisted

of final medical and anesthesia evaluation

blood preparation final psychological and

ethical evaluation scheduling of the surgical

date and consent of the donor

Table 1 Initial NLI stepwise donor evaluation protocol

Step 1

Clinical evaluation Medical history and physical examination relation to recipient age weight and size medical

history ABO compatibility

Laboratory tests Erythrocyte sedimentation rate differential blood count electrolytes liver kidney and pancreas

profile glucose coagulation profile urine analysis Serology for HBV HCV HIV CMV EBV HSV

Abdominal ultrasound

Step 2

Liver biopsy

Cardiopulmonary evaluation Electrocardiography Stress electrocardiography Chest radiography Pulmonary function

test Echocardiography (if age of donor gt 40)

Step 3

special investigations CT-scans abdomen and hepatic vasculature with volumetry MRI biliary system and Doppler

ultrasound of the carotid arteries (if age of donor gt 40)

screening of procoagulation disorders protein C protein S antithrombin III cardiolipin and anti-phospholipid

antibodies

Step 4

Final medical evaluation

Preoperative anesthesia evaluation and consent of the donor

Planning of the surgical date and availability of ICU facilities

blood preparation and autologous blood donation

The evaluation records of excluded donors

were retrospectively studied to classify causes

of late donor exclusion moreover the impact

of donor exclusion in changing the evaluation

protocol was addressed According to our

protocol of evaluation step 1-3 included the

main fundamental procedures for evaluation

however step 4 was constructed to include

final preoperative preparation measures

Donors were considered to be accepted for

donation when he she approved in steps 1-3

without any contraindication of donation but

who were not chosen to be donors for medical

andor psychological reasons during any of

the first three steps were considered excluded

In this study we considered and defined

patients to be late excluded (last minute

exclusion) if they were eliminated for any

reason during step 4 (of final preoperative

preparation) including after donor laparo-

tomy

Results

Of the 2500 potential living donor that had

been evaluated for suitability for liver

donation 375 (15) were accepted and only

194 (78) were donated Sixteen potential

donors were imposed to late donor exclusion

that caused by 8 different groups of cause

Exclusion reasons included late psychoso-

matic reasons in 4 donors family pressure to

withdraw consent in one donor and substance

abuse in 2 donors Early pregnancy was

discovered in one female donor week pre-

transplantation The pre-operatively revised

blood group of another donor was discovered

to be incompatible as the previously

determined blood group was incorrect The

presence of Factor V Leiden homozygous

mutation was diagnosed late in 2 donors In

four cases LDLT was aborted after donor

laparotomy due to macroscopic diffuse

hepatic changes considering the liver

unsuitable for donation Most of these

exclusions evoked discussions that led to a

sort of modifications in the evaluation

protocol and had an impact on both donors

and recipients One donor was convicted and

imprisoned 2 weeks before LDLT

Psychosomatic Reasons

We reported late psychosomatic reasons of

late donor exclusions in 4 donors The causes

were psychological instability with intense

psychological stress in two donors and

continuing hesitancy made another two

donors to withdraw their consent one day pre-

transplantation The former psychological

assessment carried a drawback of being

disorganized non-specialized and inefficient

So it was blamed to delay such exclusions

with resultant loss of the resources in

addition to its psychological impact for

recipients Subsequently early specialized

psychological assessment for all donors in

step 1 with stepwise protocol of psychoso-

matic assessment were added to our protocol

of donor evaluation

Social Problem

Donor family pressures prohibited a mother to

donate to her baby with liver failure

secondary to biliary atresia and they

prevented her from hospital admission three

days before the date of operation While

additional social problem in the form of

family opposition to the concept of donation

had been noticed it was under estimated and

donor evaluation proceeded till its end

Afterward early specialized psychological

assessment for all donors contributed to early

recognition of these pressures Moreover

Initiating of a family directed discussion

session to clarify justification of the LDLT

riskbenefit of the procedure and donor safety

led to a subsequent improvement in the family

acceptance of the concept of transplantation

with avoidance of such late exclusion

Substance Abuse

Donors with a history of previous occasional

drug abuse was not excluded and donated

without additional problems Two patients

denied drug abuse in history given on step 1

but they declared of ongoing addiction to

drugs in step 4 (opiates in one potential

donor and mixed drugs opiates and canna-

benoids in another one) and they were

excluded from donation for fear of associated

psychological instability and withdrawal

symptoms Accordingly after a short

discussion drug assay was added routinely to

step 2 of the evaluation protocol for all

potential donors

ABO-Incompatible Blood Group

According to our protocol potential donors

should have a blood group compatible with

that of the recipient (as our centre does not

accept incompatible transplantation) In one

case we faced a very unusual problem as the

reported ABO blood group of one donor

revealed to be incorrect and incompatible to

the recipient blood group during check of

blood matching day before operation after

being accepted and fully evaluated till blood

preparation for transplantation and that donor

was excluded This mistake was owed to the

dependence on small not credited laboratory

Although it is rare extraordinary mistake

from that time the decision had been taken to

do double check for ABO blood group in

credited laboratory for all cases

Donor Pregnancy

According to our protocol potential female

donor in child bearing period should stop

receiving oral combined contraceptive pill

(OCCP) 4-6 weeks pretransplantation due to

fear from hypercoagulable state with possible

serious thrombotic complications Early

pregnancy was discovered in one female

donor week pre-transplantation She was

taking OCCP that was stopped 6 weeks

before the scheduled date of transplantation

depending for contraception on safty periods

only Unfortunately she got pregnancy and

excluded from donation and this led to lose of

chance for transplantation as she was the only

suitable donor for her recipient As a result

double contraceptive measures to insure the

effectiveness of contraception became

recommend for any potential female donor

with stoppage of OCCP

Factor V Leiden Homozygous Mutation

As regard the initial protocol screening of

procoagulation disorders included protein C

protein S antithrombin III anti-cardiolipin

and anti-phospholipid antibodies If a liver

transplant donor or recipient has a personal

history of thrombosis a full pre transplant

hypercoagulable workup including Factor V

Leiden (FVL) mutation was done Later on

with availability of screening test for FVL

mutation and dating from 2009 (case number

70 and the subsequent cases) fully screening

of all procoagulation disorders including

FVL mutation became performed for all

donors as a routine in step 3 of evaluation

with exclusion of FVL homozygous

individuals from donation As a result the

presence of FVL homozygous mutation was

diagnosed late in 2 donors (as step 4 was

proceeded awaiting FVL result) so these two

donors were excluded late pretransplantation

In the later cases step 4 evaluation did not

start till the result of FVL to avoid such late

exclusion

Unexpected Finding During Donor

Laparotomy

Liver biopsy which is a mandatory part of the

evaluation performed routinely in step 2 of

our donor evaluation protocol this process

was performed under ultrasound guidance and

consisted of three core biopsies results of

10 or less fat infiltration were accepted

Four LDLT were aborted after donor laparo-

tomy due to macroscopic diffuse hepatic

changes considering the liver unsuitable for

donation Unpredicted findings at the time of

surgery included the presence of grossly

abnormal liver appearance with significant

gross hepatic fibrosis (figure 1) While these

donors were accepted for donation their

pathological reports showed mild periportal

infiltration in two cases presence of few

inflammatory cells of uncertain cause in one

case and presence of few unexplained

epitheloid granuloma in the last one These

exclusions after donor laparotomies evoked a

decision of double pathological revision of

the liver biopsy by two different expert

pathologists in the presence of any abnormal

finding even if very minimal Also laparo-

scopic assessment for debatable donors had

been suggested whenever liver biopsy results

for steatosis percentage did not give solid

satisfaction unexplained fibrosis or uncertain

finding with bizarre inflammatory cells

Fig 1 liver unsuitable for donation during donor laparotomy

Subsequently laparoscopic assessment had

been performed in step 2 of evaluation for

24 donors with debatable findings using two

ports of 3 and 5 mm during which gross

evaluation of the donor liver was performed

in addition large wedge biopsies were taken

for confirmation Depending on the results of

laparoscopic assessment 9 donors were

excluded early in stage 2 while the other 15

donors were accepted and the evaluation

proceeded of whom eight donors had been

finally donated

Donor Imprisoning

Unfortunately one donor was convicted and

imprisoned week before LDLT and this led to

his exclusion Several changes that had been

imposed to our initial protocol were

illustrated in table 2

Step 1

Clinical evaluation Medical history and physical examination

relation to recipient age weight and size medical history ABO compatibility

Laboratory tests Erythrocyte sedimentation rate differential blood count electrolytes liver kidney and

pancreas profile glucose coagulation profile urine analysis Serology for HBV HCV HIV CMV EBV

HSV


Initial expert psychological and ethical evaluation

Step 2

Liver biopsy double assessment

Laparoscopic assessment in uncertain cases

Cardiopulmonary evaluation Electrocardiography Stress electrocardiography Chest radiography

Pulmonary function test Echocardiography (if age of donor gt 40)

Drugs assay

Step 3

Special investigationsCT-scans abdomen and hepatic vasculature with volumetry MRI biliary system

and Doppler ultrasound of the carotid arteries (if age of donor gt 40)

Detailed screening of procoagulation disorders protein C protein S antithrombin III factors V Leiden

mutation prothrombin mutation homocystein factor VIII cardiolipin and anti-phospholipid antibodies

Step 4





Final psychological and ethical evaluation

Table 2 final protocol after modifications

Discussion

Donor safety has always been a major

concern and potential risk to the donor must

be balanced against recipient benefit

However lack of a standardized and uniform

evaluation of perioperative complications is a

serious limitation of the evaluation of donor

morbidity(8) Top priority must be given to

developing guidelines for effective donor

selection for each medical discipline

involved(9) only 89 (14) of the first 622

donors for adult recipients were considered

suitable for donation after the evaluation

potential donors for living-donor liver trans-

plantation in a single center(1) Moreover

Emond et al 1996(5) and Chen et al 1996(6)

reported that acceptance rate for donors

undergoing the evaluation process vary

between 22 and 66 Also Trotter et al

2002(7) reported that only 49 of 100 potential



donor of which 15 were finally accepted

Similar to these results of the 2500 person

that had been evaluated for suitability for liver

donation in our centre only 15 were

accepted for donation and 194 (78) were

finally donated Psychosocial assessment is

one of the most important steps in donor

evaluation(10) Psychosocial problems are one

of the most frequent reasons for excluding

donor candidates for LDLT(11) It is important

that patients and their families feel no

pressure in seeking an appropriate person for

donation The ideal situation is one in which

the potential donor spontaneously presents

himself for evaluation(12 13) Six candidates

were rejected after the psychosomatic

interview because of family coercion in the

report by Erim et al 2008(10) In our centre

we faced family pressures against

transplantation fearing from operative

outcome At that time this was explained by

the culture of our community which was

relatively against the concept organ donation

Under estimation of this social problem in

addition the inefficient psychological assess-

ment led to this case of late exclusion

Specialized psychological assessment contri-

buted to early recognition of these pressures

with avoidance of such late exclusion Donors

should never be compelled to donate The

psychological evaluation focuses on the

emotional stability of the potential donor and

is used to verify the informed consent Donors

should be permitted to change their mind up

until the induction of general anesthesia and

they should be given every opportunity to

withdraw at any time if they have any fears

Psychological counseling can be very helpful

and multiple consents encourage donors to

reconsider their decision(14) Valentin-Gamazo

2004(1) presented 5 steps of course of the

psychosomatic assessment protocol for

potential living liver donors Also results of

Erim et al 2008(12) indicated that candidates

with mental disturbances and additional social

distress ambivalent candidates and those in

difficult family relationship were excluded in

the psychosomatic evaluation accordingly

eleven donor candidates were rejected

because of mental vulnerability and three

donor candidates were excluded because of

indecisiveness In our centre donors

permitted to withdraw at any time if they have

any fears Psychological instability and

continuing hesitancy caused late exclusion in

4 donors pre-transplantation The drawback

was the dependence on disorganized non-

specialized and inefficient psychological

assessment There were discussions about

whether these donors might be excluded early

with saving of resources if proper

psychosomatic assessment was done Sub-

sequently early specialized psychological

assessment for all donors in step 1 with

stepwise protocol of psychosomatic asse-

ssment were added to our protocol of donor

evaluation Erim et al 2008(12) excluded six

patients had a diagnosis of ongoing addiction

to alcohol or other drugs In our centre two

potential donors with ongoing substance

abuse were excluded and this was justified by

the inability to expect severity of post-

operative withdrawal symptoms and to

estimate the probable increase in post-

operative risk Moreover the probability of

worse outcome if donor hepatectomy per-

formed for individual with substance abuse

did not studied before Accordingly drug

assay were added to step 2 of the evaluation

protocol for all donors aiming to detection of

donors with drug abuse with early exclusion

of them Potential donors should have a blood

group compatible with that of the recipient

ABO - incompatible donors have been

described but should remain exceptional(15 16)

we do not accept incompatible transplantation

in NLI Surprisingly blood group of one

donor was discovered to be incompatible

during preoperative blood matching as the

previously determined blood group was found

to be incorrect and this donor was excluded

Although it is a very rare and unusual error



credited lab as a protocol in all cases Post-

operative complications in live donors

especially during the first few months include

pulmonary embolism with an incidence of

7 so of which were fatal(17) Deep venous

thrombosis spleen and portal vein thrombosis

have been reported as part of the serious

thrombotic complications Overall there is

underestimation and under-appreciation of the

thromboembolic risks in the living donors(17)

Living donors progressively developing

hypercoagulable state even in the presence of

anti-thrombotic prophylaxis(18) Hypercoagul-

able states are relative contraindications for

donation for fear of increase donor mortality

from pulmonary embolism(19) Several large

studies have confirmed a two-fold to six-fold

increased risk of deep venous thrombosis

associated with current oral contraceptive

use(20-23) later on Tan and Marcos 2004(24)

recommended cessation of oral contraceptives

4-6 weeks prior to LDLT in summarizing the

ideal LDLT donor profile This was also

adopted in our protocol for all women donors

in child bearing period however early



receiving OCCP that was stopped 6 weeks

preoperative and she depended for contra-

ception on safety periods only Unfortunately

she got pregnant and excluded from donation

and this led to lose of the chance of

transplantation for this recipient as she was

the only suitable donor Therefore double

contraceptive measures to insure the

effectiveness of contraception became recom-

mend for potential female donors with

stoppage of OCCP Up to 50 of patients

with hepatic artery thrombosis (HAT) may

require retransplantation(25) A thrombotic

event in the liver graft all too often results in

prolonged hospitalization graft loss retrains-

plantation or patient death In fact about

16 of all liver allograft failures were

secondary to thrombotic events These events

are associated with an increased use of

resources and costs(26-28) The Factor V Leiden

(FVL) mutation is the most common genetic

defect predisposing to venous thrombosis(29)

FVL heterozygosity increases the life time

risk of venous thrombosis by 5- to 10-fold

and 50- to 80 - fold in homozygous

individuals (30) The FVL mutation causes

factor Va to be resistant to cleavage by

activated protein C (APC) resulting in more

factor Va being available thereby increasing

the generation of thrombin Thus the FVL

mutation and the resultant APC resistance

cause a hypercoagulable state (31 32)

Identifying APC resistance in liver donors

could allow the clinician to expectantly care

for liver recipients according to known risk

factors and should decrease hepatic vascular

thromboses As we strive toward decreasing

morbidity and cost testing for APC resistance

will further improve outcome parameters(33)

On the other hand Gideon et al 1998(34)

reported that the factor V Leiden mutation in

the donor liver is not a major risk factor for

hepatic vessel thrombosis and subsequent

graft loss after liver transplantation Also

Brian 2004(35) stated that venous thrombosis

does not appear to be increased in the

presence of FVL heterozygosity and there is

no evidence for altering perioperative

management on the basis of the finding of

FVL nor is there evidence to support a role of

preoperative screening for FVL or a PC

resistance In the earlier era of our LDLT

program in NLI screening for FVL mutation

was performed in very limited number of

laboratories with high cost and long duration

So it was performed in selected high risk

cases Gradually this test become more

available with relatively less cost and

duration With the occurrence of not fully

explained thrombotic complications (which

led to graft loss) in some cases the awareness

about increased risk of thrombotic events

associated to FVL mutation became more

obvious Previously Dieter et al 2003(36)

stated that It is a matter of debate whether

potential donors with a mildly increased risk

for thrombotic events as in heterozygote

carriers of a factor V Leiden gene mutation

should be excluded from donation This

debate was stopped from 2009 in our centre

by making a decision that only FVL

homozygous individuals should be excluded

from donation but the presence of FVL

heterozygosity is accepted for donation with

precautions and that step 4 of preparation

should not start awaiting the result of FVL to

avoid late donor exclusion Liver biopsy is a

routine step in donor evaluation in a high

percentage of LDLT programs Other

methods to evaluate the fat content of the

donorrsquos liver are less sensitive and specific

than liver biopsy and these alternatives are

unable to detect any associated liver

pathology Unfortunately liver biopsy is an

invasive technique and is associated with a

certain risk of complications Recent studies

have reported an incidence of major

complications related to liver biopsy of 13

(37-39) In our centre liver biopsy which is a

mandatory part of donors evaluation was

performed routinely in step 2 of our donor

evaluation protocol There have been reports

of aborted donor hepatectomy at the time of

surgery as a result of unexpected findings

including the presence of significant hepatic

steatosis(40) We reported discontinuation of

LDLT In four cases after donor laparotomy

due to macroscopic diffuse hepatic changes

considering the liver unsuitable for donation

Subsequently any argument about the result

of liver biopsy was solved by re-evaluation by

two different expert pathologists otherwise

laparoscopic assessment for the potential

donor liver is performed The aim was to

early alleviate the controversy around the

suitability for donation and to avoid donor

exclusion after laparotomy According to

Hegab et al 2012(41) 30 potential living

donors were assessed laparoscopically in the

day of surgery to determine whether to

proceed with the abdominal incision to

harvest part of the liver for donation and they

concluded that the laparoscopic assessment of

donors in LDLT is a safe and acceptable

procedure that avoids unnecessary large

abdominal incisions and increases the chance

of achieving donor safety In our centre

laparoscopic assessment had been performed

in step 2 of evaluation for 24 donors with

debatable findings and helped to early fading

away of these debates Our observations about

late donor exclusion indicated that it affected

recipients resources and evaluation protocol

Late exclusion carried psychological effect

for recipient and family also it increased

transplantation cost and led to lose of more

resources Moreover the important issue is

the impact of these exclusions in the

evaluation protocol as each of them evoked

discussions that led to a kind of modification

in the steps of the initial evaluation protocol

Conclusion

Late pre-transplantation donor exclusion had

its impact in donors recipients and resources

Early expert well organized psychological

assessment is crucial and should be a part of

any evaluation protocol Laparoscopic

assessment of donors in LDLT is a safe and

acceptable procedure that avoids late

operative exclusions and it is useful in

debatable cases Reassessment of the donor

evaluation protocol should be a dynamic

process and it found to be greatly affected by

these late exclusions

References

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Experience after the evaluation of 700 potential

donors for living donor liver transplantation in a

single center Liver Transpl 2004 10 1087-1096

2 Pomfret EA Early and late complications in the

right-lobe adult living donor Liver Transpl 2003

9 S45-S49

3 Broering DC Sterneck M Rogiers X Living

donor liver transplantation Journal of Hepatology

2003 38(S)119ndashS135

4 Henkie PT Kusum PT and Amadeo M Adult

living donor liver transplantation Who is the ideal

donor and recipient 2005 (43) 1 13-17

5 Emond JC Renz JF Ferrell LD et al Functional

analysis of grafts from living donorsImplications

for the treatment of older recipientsAnn

Surg1996224544ndash552

6 Chen YS Chen CL Liu PP et al Preoperative

evaluation of donors for living related liver

transplantation Transplant Proc1996 282415ndash

2416

7 Trotter JF Wachs M Everson GT et al Adult-to-

adult transplantation of the right hepatic lobe from

a living donorN Engl J Med 2002 346 (14)1074ndash

82

8 Ding Y Yong-Gang W Bo L et al Evaluation

outcomes of donors in living donor liver

transplantation a single-center analysis of 132

donors Hepatobiliary amp Pancreatic Diseases

International Volume 10 Issue 5 October 2011

Pages 480ndash48

9 Erim Y Malago M Valentin-Gamazo C et al

Guidelines for the psychosomatic evaluation of

living liver donors analysis of donor exclusion

Transplant Proc 2003 35909ndash910

10 Erim Y Beckmann M Valentin-Gamazo C et al

Selection of donors for adult living-donor liver

donation results of the assessment of the first 205

donor candidates psychosomatics 2008 49143ndash

151

11 Sterneck MR Fischer L Nischwitz U et al

Selection of the living liver donor Transplantation

1995 60667ndash671

12 Schiano TD Kim-SchlugerL GondolesiG et

al Adult living donor liver transplantation the

hepatologists perspectiveHepatology 33 (2001)

pp 3ndash9

13 Pszenny C Krawczyk M Paluszkiewicz R et al

Biochemical function of the donor liver in living

related liver transplantation Transplant Proc

200234621ndash622

14 Marcos A Fisher R Ham J et al Selection and

outcome of living donors for right lobe liver

transplantation Transplantation2000

Jun1569(11)2410-5

15 Rydberg L ABO-incompatibility in solid organ

transplantation Transfus Med 200111325ndash342

16 Tanabe M Shimazu M Wakabayashi G et al

Intraportal infusion therapy as a novel approachto

adult ABO- incompatible liver transplantation

Transplantation 2002731959ndash1961

17 Bezeaud A Denninger MH Dondero F et al

Hypercoagulability after partial liver

resection Thromb Haemost 2007 981252-1256

18 Cerutti E Stratta C Romagnoli R et al

Thromboelastogram monitoring in the

perioperative period of hepatectomy for adult

living liver donation Liver Transpl 200410289-

294

19 Durand F Ettorre GM Douard R et al Donor

safety in living related liver transplantation

underestimation of the risks for deep vein

thrombosis and pulmonary embolism Liver

Transpl 20028118ndash120

20 Vandenbroucke JP Koster T Brieumlt E et al

Increased risk of venous thrombosis in

oralcontraceptive users who are carriers of factor

V Leiden mutation Lancet 19943441453-7

21 Thorogood M Mann J Murphy M et al Risk

factors for fatal venous thromboembolism in

young women a case-control study Int J

Epidemiol 19922148-52

22 WHO Venous thromboembolic disease and

combined oral contraceptives results of

international multicentre case-controlstudy World

Health Organization Collaborative Study of

Cardiovascular Disease and Steroid Hormone

Contraception Lancet 19953461575-82

23 Farmer RD Lawrenson RA Thompson CR et al

Population-based study of risk of venous

thromboembolism associated with various oral

contraceptives Lancet 199734983-8

24 Tan HP Marcos A Hepatic arterial anatomy for

right liver procurement from living donors Liver

Transpl 2004 10 134ndash135

25 Settmacher U Stange B Haase R et al Arterial

complications after liver transplantation Transpl

Int 2000 13 372

26 Taylor MC Greig PD Detsky AS et al Factors

associated with the high cost of liver

transplantation in adults Can J Surg 2002 45

425

27 Brown RS Jr Ascher NL Lake JR et al The

impact of surgical complications after liver

transplantation on resource utilization Arch Surg

1997 132 1098

28 Whiting JF Martin J Zavala E et al The

influence of clinical variables on hospital costs

after orthotopic liver transplantation Surgery

1999 125 217

29 Rees DC Cox M Clegg JB World distribution of

factor V Leiden Lancet 1995 346 1133

30 Bauer KA Rosendaal FR Heit JA

Hypercoagulability too many tests too much

conflicting data Hematology (Am Soc Hematol

Educ Program) 2002 353

31 Bertina RM Koeleman BP Koster T et al

Mutation in blood coagulation factor V associated

with resistance to activated protein C Nature

1994 369 64

32 Zoller B Hillarp A Berntorp E et al Activated

protein C resistance due to a common factor V

gene mutation is a major risk factor for venous

thrombosis Annu Rev Med 1997 48 45

33 Christella M Thomassen LG Castoldi E et al

Endogenous factor V synthesis in megakaryocytes

contributes negligibly to the platelet factor V pool

Haematologica 2003 88 1150

34 Gideon H Jane DC Karen B et al Donor Factor

V Leiden Mutation and Vascular Thrombosis

Following Liver Transplantation Liver

Transplantation and Surgery Vol 4 No 1 (

January) 1998 pp 58-61

35 Brian SD Factor V Leiden and Perioperative Risk

Anesth Analg 2004 981623ndash34

36 Dieter CB Martina S Xavier R Living donor

liver transplantationJournal of Hepatology 2003

38 S119ndashS135

37 Rinella ME Abecassis MM Liver biopsy in living

donors Liver Transpl 2002 8 1123-1125

38 Brandhagen D Fidler J Rosen C Evaluation of

the donor liver for living donor liver

transplantation Liver Transpl 2003 9 S16-S28

39 Nadalin S Malagoacute M Valentin-Gamazo C et al

Preoperative donor liver biopsy for adult living

donor liver transplantation risks and benefits

Liver Transpl 2005 11 980-986

40 El-Meteini M Fayez M Abdalaal A et al Living

related liver transplantation in Egypt an emerging

program Transplant Proc 2003 35(7)2783-2786

41 Hegab B Abdelfattah M R Azzam A et al Day-

of-surgery rejection of donors in living donor liver

transplantation World J Hepatol 2012 November

27 4(11) 299-304

Original Article

The Impact of Interleukin 28B Tumor Necrosis Factor Alpha Gene

Polymorphisms on Therapeutic Response in Chronic HCV Egyptian Patients

Hamouda S Hanno A El-Shayeb A Mansour A Elwazzan D

Department of Tropical Medicine Department of Clinical Pathologyy Alexandria UniversityEgypt

ABSTRACT

Chronic chronic hepatitis C virus (HCV) infection is a major health problem in Egypt The currently recommended

therapy of HCV infection is the combination of a pegylated interferon (PEG-IFN) alfa and ribavirin therefore reliable

markers that predict the response to therapy is of great importance from the economic point of view Objectives The

aim of this work was to find the effect of polymorphism of Interleukin 28B (IL28B) and Tumor Necrosis Factor alpha

(TNF-a) genes on the response to combination therapy (PEG-IFN and ribavirin) in chronic HCV infected Egyptian

patients Patients and methods 150 subjects divided into two groups group (I) one hundred patients with chronic

HCV who were candidates to receive combination therapy with interferon ribavirin they were subjected to all

investigations needed before IFN therapy in addition to IL28B 12979860 (using Conventional ARMS-PCR) and TNF-a

308 (using the allele specific primer conventional PCR)genotyping then received combination therapy with estimation

of HCV RNA at weeks 12 24 and six months after the end of therapy Group (II) fifty healthy subjects as a control

group also were subjected to IL28B 12979860 and TNF-a 308 genotyping Results IL28B rs12979860 and TNF-a

rs308 genotypes were observed to have a statistically significant association with the response to treatment in chronic

HCV (CHC) patients (p=000 and 0034 respectively) The IL28B C allele was higher in the responders while the T

allele was higher among the non-responders TNF-a G allele was significantly higher among the responders while the

A allele was significantly higher among the non-responders Conclusion IL28B rs12979860 and TNF-a rs308

genotyping can be used as predictors of response to combination therapy in CHC Egyptian patients

Introduction

The estimated global prevalence of HCV

infection is 3 corresponding to about 130-

210 milion HCV-positive persons worldwide

the highest prevalence (15-22) has been

reported from Egypt (12) HCV-infected people

serve as a reservoir for transmission to others

and are at risk for developing chronic liver

disease cirrhosis and primary hepatocellular

carcinoma (HCC) (3) The treatment of

hepatitis C has evolved over the years

Current treatment is combination therapy

consisting of ribavirin and IFN to which

polyethylene glycol (PEG) molecules have

been added (ie PEG-IFN) that increased the

sustained virological response (SVR

undetectability of HCV RNA 6 months after

stopping treatment) rate almost 10 fold up to

54ndash61(4) but unfortunately this combination

regimen has a number of drawbacks

Intolerable side effects necessitate prema-

turely stopping treatment in about 15 of

patients and dose reductions in another 20ndash

40 Moreover the drug regimen is very

expensive which means that most patients in

countries such as Egypt which has 10ndash12

million infected individuals cannot afford

this therapy (5) Accordingly identification of

the predictors of response to treatment is a

high priority(6) A number of viral and host

factors associated with response to interferon-

based therapy have been identified Viral

factors are limited to viral genotype HCV

RNA titer and possibly mutations in certain

regions of the viral genome In addition

several host factors are associated with

response such as patient age sex ethnicity

and cytokine polymorphisms Among these

cytokines IL28B and TNF-a (7) Genome

wide association studies (GWAS) have

identified single nucleotide polymorphisms

(SNP) near the IL28B gene Favorable variant

of the most widely studied IL28B

polymorphism rs12979860 is strongly

associated with both spontaneous and

treatment - induced viral clearance (8 9) The

IL28B genotype greatly influences response

to IFN-based therapy and so is most relevant

in the less interferon - responsive viral

genotypes (ie genotypes 1 and 4) (10) The

actual causal polymorphism at this locus

remains unknown Some studies suggested

that their IL-28B polymorphism was

associated with decreased IL-28B (and IL-

28A) expression that encodes interferon-

lambda3 (IFNλ) which may be involved in

interfering with viral replication (11 12)

Results in three possible genotypes revealed

that SVR in patients with the CC genotype is

greater than that seen in patients with a CT

genotype which is in turn greater than that

seen in patients with a TT genotype The

rs12979860 polymorphism may also explain

much of the difference in response between

different population groups in fact the C

allele which leads to better response presents

with greater frequency in European than in

African populations(13) TNF-a a potent

antiviral proinflammatory cytokine that

encoded by major histocompatibility complex

class III region on chromosome 6p21 has

been implicated as an important pathogenic

mediator in a variety of liver conditions (14)

TNF-a plays a pivotal role in host immune

response to HCV infection because cytotoxic

T lymphocytes in the liver secrete TNF-a(15)

Circulating TNF-a level increases during

HCV infection that induces TNF-a production

in human hepatocytes(16) TNF-a expression is

tightly controlled at the transcriptional and

posttranscriptional levels(17) The maximal

capacity of cytokine production varies

between individuals and may correlate with

polymorphism in cytokine gene Many

diallelic polymorphisms in the TNF-a which

are thought to affect TNF-a production have

been reported the most important is the GA

transition at position 308 (18 19) which is

thought top play a role in the pathogenesis of

acute and chronic HCV infection the

persistence of the virus (214)and the response

to IFN therapy (14)

Subjects and Methods

This study included 150 subjects divided into

two groups group (I) one hundred patients

with chronic HCV who were treatment naiumlve

for hepatitis C and appropriate candidates to

receive combination therapy with interferon

ribavirin They were collected from the

Tropical Medicine Outpatient Clinic-

Alexandria University group (II) fifty

healthy subjects of matched age and sex as a

control group An informed consent was

signed by every subject prior to start of the

research Blood samples were collected from

all patients to assess the following

parameters routine laboratory studies

complete liver profile and viral markers

including HBsAg assay HCV Ab and

quantitative HCV RNA Abdominal

ultrasonography ultrasound guided percutanous

needle liver biopsy were also done for all group

(I) patients using a Trucut liver biopsy needle

Grading and staging of chronic hepatitis were

evaluated hisologically according to the

intensity of necroinflammatory changes and

fibrosis respectively using METAVIR scoring

system All patients in group (I) received

combination therapy (pegylated IFN once

weekly injection plus ribavirin oral 1000-1200

mg per day according to body weight)

Quantitative HCV RNA was done at weeks

12 24 and 6 months after the completion of

treatment if the HCV RNA was undetectable

or if a greater than 2-log-fold reduction in

HCV RNA level was present in week 12 the

patient was considered as a responder and the

therapy was continued by the same regimen

Conversely if response was not achieved less

than 2-log-fold reduction in HCV RNA level

than baseline at week 12 or reappearance of

HCV RNA in serum while still on therapy or

after therapy is discontinued the patient was

considered as non responder and the treatment

was discontinued IL28B rs12979860 and

TNF-a rs308 genotyping Genomic DNA was

extracted from a 2 ml blood sample then

IL28B rs12979860 genotyping was done by

using a conventional ARMS-PCR (21)while

the TNF-a 308 GA SNP was determined

using the allele specific primer conventional

PCR (22)


Statistical analyses were performed using the

Statistical Package for Social Science (SPSS)

version 18 (LEAD Technology Inc) Data

were presented as means with corresponding

standard error (SE) Comparisons among

different groups were performed by one way

analysis of variance (ANOVA) Qualitative

data were described using number and percent

and association between categorical variables

was tested using Chi-square test Correlation

between variables was determined using

Pearsons or Spearmans correlation test

according to the variable In all tests the level

of significance was lt 005

Results

HCV RNA follow up According to the

results of HCV RNA (quantitative PCR)

during the course of treatment and six months

after the end of therapy those who achieved

SVR were 67 (67) patient while the non-

responders (whether during or after the end of

treatment) were 33(33) patients

Distribution of IL28B varients In group I 38

(38) patients carrying the CC genotype CT

genotype present in 48 (48) patients while

only 14 (14) patients having TT genotype

Subsequently the C allele was found in 62

of patients vs 38 for the T allele In group

II CC genotype was found in 28 (56) CT

genotype present in 18 (36) individuals

while 4 (8) individuals carrying the TT

genotype This means that the C allele present

in 74 vs 26 T allele of individuals in

group IV (table I amp figure 1)

Table (I) IL28B genotypes among different groups

CC No () CT No () TT No () CT ratio

Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426

Figure (1) Frequencies of IL28B genotypes as of total number of subjects in each group

Correlation between IL28B genotypes and response to treatment in group I patients

Among the responders to treatment (67

patients) the CC genotype was found in 34

(507) patients the CT genotype present in

31 (463) patients while TT genotype was

detected only in 2 (3) patients Within the

non-responders (33patients) the CC genotype

was found in 4 (121) patients the CT

genotype present in 17 (515) patients

while TT genotype was detected in 12

(364) patients IL28B genotypes were

observed to have a statistically significant

association with the response to treatment in

group I patients (The C allele was higher in

the responders while the T allele was higher

among the non-responders) Chi-square

(X2=264) (p=000) (Table II amp figure 2)

Table (II) IL28B genotypes among the responders and non-responders

IL28B genotypes

CC No () CT No () TT No () CT

ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000

Significant at P 005

Figure (2) Correlation between IL28 genotypes and response to treatment in group I patients

0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60

Responders Nonresponders

CC

CT

TT

TNF-a genotypes in different groups In

group I the GG genotype was found in 79

patients (79) while GA genotype was found

in 21 patients (21) This means that the G

allele present in 895 of patients vs 105

for the A allele In group II GG genotype was

found in 14 (56) patients while GA

genotype present in 11 (44) patients So the

G allele was found in 78 of patients vs 22

for the A allele

Table (III) TNF-a genotypes among different groups

GG No () GA No () GA ratio

Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964

Figure (3) Frequencies of TNF-a genotypes as of total number of subjects in each group

Correlation between TNF-a genotypes and

response to treatment in group I patients

tables (IV) amp figure (4) Among the

responders to treatment the GG genotype was

found in 57 (851) patients while the GA

genotype was detected in 10 (149) patients

Thus the G allele was found in 925 and A

allele present in 745 of patients Within the

non-responders the GG genotype was found

in 22(667) patients while GA genotype

was detected in 11 (333) patients So the G

allele was found in 834 while the A allele

was detected in 166 of patients TNF-a

genotypes were observed to have a

statistically significant association with the

response to treatment in group I patients Chi-

square (X2=451) (p=0034) The G allele was

significantly higher among the responders

while the A allele was significantly higher

among the non-responders

Table (IV) TNF-a genotypes among the responders and non-responders

TNF-a genotypes

GG No () GA No () GA ratio Total (n)

Response to therapy Responders 57 (851) 10 (149) 925 745 67

Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA

Figure (IV) Correlation between TNF-a genotypes and response to therapy

IL28B CC and CT showed PPV of 849 and

645 respectively in predicting the response

to treatment while the TT genotype showed

857 PPV in predicting the non response to

therapy Moreover the CC and CT showed

efficacy of 63 and 47 respectively in

predicting the response to treatment while the

TT genotype showed 77 efficacy in

predicting the non response to therapy

Regarding TNF-a the GG genotype showed

721 PPV in predicting the response to

treatment while the GA genotype showed


therapy furthermore both GG and GA

genotypes showed an efficacy of 68 in

predicting the response and non response to

treatment The PPV and efficacy of combined

IL28B CC genotype and TNF-a GG genotype

were 968 and 75 respectively while the

PPV and efficacy of combined IL28B TT

genotype and TNF-a GA genotype were 56

and 45 respectively

Table (V) PPV and efficacy of IL28B and TNF-a

IL28B TNF-a Combined IL28B and TNF-a

CC CT TT GG GA CC and GG TT and GA

PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

It is now proved that IL28B rs12979860

genotypes are strongly associated with HCV

infection outcomes spontaneous and

treatment induced viral clearance (8-10) Many

studies suggested that IL-28B polymorphism

is associated with decreased IL-28B (and IL-

28A) expression that encodes IFNλ 3 which

may be involved in interfering with viral

replication (11 12) In many studies it was

found that the favorable C allele of IL28B

rs12979860 was found to be more frequent in

Asian ethnicity than Caucasian and African

populations respectively(23) In the present

work it was observed that IL-28B

rs12979860 CC genotype frequency

decreased from 56 among healthy subjects

0

20

40

60

80

100

Responders Nonrespondres

GG

GA

vs 38 among CHC patients regardless of

their response to combination therapy

Furthermore the frequency of C allele was

62 in CHC patients vs 74 in healthy

subjects A comparable increase in the TT

genotype was observed in chronic HCV

patients vs healthy subjects (14 vs 8)

Regarding the heterozygote CT genotype it

was higher in chronic HCV patients compared

with the healthy subjects (48 vs 36) The

current results were in consistence with that

of El-Awady et al (24) that conducted a

research on HCV genotype 4 infected

Egyptian patients they found that there is

sharp decrease in the incidence of the

protective CC genotype and C allele

compared with the typing data of healthy

subjects 13 CC in chronic HCV patients

vs 48 CC in healthy subjects and 50 C

allele in CHC vs 67 C allele in healthy

subjects However such a decline in the CC

genotype was not reflected in a comparable

increase in the TT genotype (13 vs 14)

A two fold increase (75 vs 38) in the

heterozygous genotype CT was observed in

the CHC group compared with the healthy

subjects In a Korean study done in HCV

genotypes 1b and 2 infected patients the

prevalence of rs12979860 in healthy controls

was as follows the CC genotype was 885

the CT genotype was 115 and the TT

genotype was not found while in chronic

hepatitis C patients there was significant

decrease in the C allele and significant

increase in the T allele than that in healthy

control (25) As regards the response to

therapy to date a broad association between

favorable IL28B genotypes and SVR has been

described in patients infected with HCV

genotype 1 with a similar association

described for genotype 4 (26) although this has

been less studied However conflicting

results have been published about HCV

genotypes 23 (27) The generally reduced

association for patients with HCV genotypes

23 could be related to the high rate of SVR

present in these IFN-sensitive genotypes for

which larger sample sizes are required to find

significant differences(28) In the present

work it was noticed that IL-28B rs12979860

CC genotype incidence among the responders

and non-responders was 507 vs 121

respectively with a PPV of 849 in


reverse occurred for the TT genotype which

affected only 3 of the responders and 364

of the non-responders with a PPV of 857 in

predicting the non-response to therapy which

highlights the protective effect of the C allele

IL28B genotypes were observed to have a


response to treatment in group I patients The

C allele was higher in the responders while

the T allele was higher among the non-

responders (X2=264) (p=000) The results of

the present work were in agreement with that

of Derbala et al(29) who did a similar research

in Egypt on HCV genotype 4 they found that

the patients who did not achieve ETR (End of

therapy response) or SVR had a lower

prevalence of rs12979860 CC (174 and

233 respectively) than individuals who had

ETR or SVR (479 and 472

respectively) Moreover they observed that

carrying at least one copy of the C allele

(genotypes CT and CC) had almost 8 times

the probability of ETR compared to those

with genotype rs12979860 TT concluding

that in HCV genotype 4 patients rs12979860

is a sensitive predictor of treatment induced

viral clearance Similarly in another research

done in Egypt by Pasha HF et al (30) they

noticed that the inheritance of IL28B CT and

TT genotypes may be associated with

susceptibility to HCV infection and resistance

to combined antiviral therapy Mangia A et al (27) detected different results they claimed

that IL28B type can not be used as a predictor

of SVR in HCV genotype I infected patients

and it appeared to have limited potential for

response-guided treatment strategies In

addition Lin CY et al(17) were in agreement

with Mangia et al (27) as they found that HCV

genotype 1 infected patients younger than 40

years old had SVR rate similar to HCV

genotype 1 infected patients and the IL28B

polymorphism had no impact on the SVR rate

in these patients In the current results as

regards TNF-a gene polymorphism it was

observed that in group I patients the GG

genotype frequency was higher than GA

genotype frequency the AA genotype was

absent In comparison to control group the

GG genotype was increased from 79 in

group I patients to 92 in control group

while GA genotype was decreased from 21

in group I patients to 8 in controls The

TNF-a typing profile in group I patients

displayed a clear inversion of G to A ratios to

become 895 105 instead of 96 4

found in healthy subjects Regarding the

response to treatment among those who

achieved SVR the GG genotype frequency

was significantly higher than the GA

genotype (851 and149 respectively)

while the reverse was detected among the non

responders (the GG genotype was found in

667 and the GA genotype was detected in

333) Thus the GG genotype was found to

be correlated to the response to combination

therapy with a PPV and efficacy of 721 and

68 respectively in predicting the response to


lower PPV 523 PPV in predicting the non

response to therapy (523) The present

results were in agreement with that of Dai CH

et al (14) who demonstrated that the

distribution of TNF-a 308 promoter genotypes

in HCV genotype 1 infected patients were as

follows TNF308 GG was found in 766

TNF308 GA was found in 213 and

TNF308 AA was found in 21 of their

patients and the frequencies of the TNF308 G

allele and the TNF308 A allele were 872

and 128 respectively In the same study

after undergoing combination therapy they

found that significantly higher proportion of

TNF308 A allele non-carriers than carriers

had an SVR (981 vs 879 p=027) In

addition the carriers of the G allele were

found to have a lower fibrosis score and a

higher necro-inflammatory activity score than

did those who were A allele carriers which

was in agreement with the current results the

stage of liver fibrosis was observed to have a

statistically significant association with TNF-

a genotypes but the grade of necro-

inflammation was not associated with TNF-a

genotypes Pasha HF et al(30) documented

that the inheritance of TNF-α GA and AA

genotypes which appear to affect the cytokine

production may be associated with suscep-

tibility to HCV genotype 4 infection and

resistance to combined antiviral therapy In

disagreement to the current results Yee et

al(31) reported that there was no correlation

between TNF-a 308 polymorphisms and the

response to combination therapy in patients

with chronic HCV genotype 1infection

Moreover Abbas Z et al(31) demonstrated that

no significant differences in the degree of

necro-inflammatory activity and fibrosis were

noted among the TNF-a genotypes and they

did not modulate the response to combination

therapy for genotype 3infected patients they

attribute this to the fact that viral genotype 3

is easy to treat genotype in any case In the

current study it was found that combined

IL28B rs 12979860 CC genotype and TNF-a

rs 308 GG genotype had higher PPV and

efficacy in predicting the response to

combination therapy than testing for either

alone suggesting that testing for multiple

factors which influence the response to

treatment may be more helpful for the

physician in taking the decision for treatment

Conclusion

IL28B rs12979860 C allele and TNF-a rs308

G allele are significantly associated with

response to therapy while their T and A

alleles were found to be associated with non-

response therefore they can be used as

predictors of response to combination therapy

in CHC Egyptian patients

References

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infection World Journal of Gastroenterology

2007 13 2436ndash41

2 Frank C Mohamed MK Strickland GT et al The

role of parenteral antischistosomal therapy in the

spread of hepatitis C virus in Egypt Lancet 2000

355 887-91

3 Lavanchy D The global burden of hepatitis C

Liver Int 2009 1 74-81

4 Chen CH and Yu ML Evolution of interferon-

based therapy for chronic hepatitis C Hepat Res

Treat 2010 20101409-53

5 Samuel B Bashar A Eric D et al US

Multicenter Pilot Study of Daily Consensus

Interferon (CIFN) Plus Ribavirin for ldquoDifficult-

to-Treatrdquo HCV Genotype 1 Patients Digestive

Diseases and Siences 201156880-8

6 Samuel S and Ayman A Predicting antiviral

treatment response in chronic hepatitis C how

accurate and how soon Journal of Antimicrobial

Chemotherapy 200151487-91

7 Rau M Baur K and Geier A Host Genetic

Variants in the Pathogenesis of Hepatitis C

Viruses 2012 4 3281ndash302

8 Tanaka Y Nishida N Sugiyama M et al

Genome-wide association of IL28B with response

to pegylated interferon-alpha and ribavirin

therapy for chronic hepatitis C Nat Genet

2009411105-9

9 Thomas DL Thio CL Martin MP et al Genetic

variation in IL28B and spontaneous clearance of

hepatitis C virus Nature 2009 461798-801

10 Ge D Fellay J Thompson AJ et al Genetic

variation in IL28B predicts hepatitis C treatment-

induced viral clearance Nature 2009 461399-

401

11 Suppiah V Moldovan M Ahlenstiel G et al

IL28B is associated with response to chronic

hepatitis C interferon-a and ribavirin therapy Nat

Genet 2009 411100-4

12 Kelly C Klenerman P Barnes E Interferon

lambdas the next cytokine storm Gut 2010

54102-9

13 Cavalcante LN Abe-Sandes K Angelo A et al

Il28b polymorphisms are markers of therapy

response and are influenced by genetic ancestry in

chronic Hepatitis C patients from an admixed

population Liver Int 2012 32 476ndash86

14 Dai CY Chuang WL Chang WY et al Tumor

Necrosis Factorndasha Promoter Polymorphism at

Position -308 Predicts Response to Combination

Therapy in Hepatitis C Virus Infection JID 2006

193 98ndash101

15 Cua IH Hui JM Bandara P et al Insulin

resistance and liver injury in hepatitis C is not

associated with virus-specific changes in

adipocytokines Hepatology 2007 46 66-73

16 Juran BD Atkinson EJ Larson JJ et al Carriage

of a tumor necrosis factor polymorphism

amplifies the cytotoxic T-lymphocyte antigen 4

attributed risk of primary biliary cirrhosis

evidence for a gene-gene interaction Hepatology

2010 52 223-9

17 Nguyen-Khac E Houchi H Daoust M et al The

-308 TNF alpha gene polymorphism in severe

acute alcoholic hepatitis identification of a new

susceptibility marker Alcohol Clin Exp Res

2008 32 822-8

18 Wilson AG De Vries N Pociot F et al An allelic

polymorphism within the human tumor necrosis

factor a promoter region is strongly associated

with HLA A1 B8 and DR3 alleles J Exp Med

1993 177557ndash60

19 DrsquoAlfonso S and Richiardi PM A polymorphic

variation in a putative regulationbox of the TNFA

promoter region Immunogenetics 1994 39150ndash

4

20 Becker CM Fantini C Schramm H Lehr S Wirtz

A Nikolaev J et al TGF-suppresses tumor

progression in colon cancer by inhibition of IL-6

trans-signaling Immunity 2004 21 491-501

21 Galmozzi E Del Menico B Rametta R et al A

tetra-primer amplification refractory mutation

system polymerase chain reaction for the

evaluation of rs12979860 IL28B genotype J

Viral Hepat 2011 18628-30

22 Constantini PK Wawrzynowicz-Syczewska R

Clare M Interleukin-1 interleukin-10 and tumour

necrosis factor-alpha gene polymorphisms in

hepatitis C virus infection an investigation of the

relationships with spontaneous viral clearance and

response to alpha-interferon therapy Liver 2002

22 404-12

23 Bellanti F Vendemiale G Altomare E et al The

Impact of Interferon Lambda 3 Gene

Polymorphism on Natural Course and Treatment

of Hepatitis C Clin Dev Immunol

20122012849373-82

24 El-Awady M Mostafa L ATabll A et al

Association of IL28B SNP with Progression of

Egyptian HCV Genotype 4 Patients to End Stage

Liver Disease Hepat Mon 2012 12 271ndash7

25 Jung Y Kim J Ahn S et al Role of Interleukin

28B-related Gene Polymorphisms in Chronic

Hepatitis C and the Response to Antiviral

Therapy in Koreans J Clin Gastroenterol 2013

24 360-7

26 McCarthy J Li H Thompson A et al Replicated

association between an IL28B gene variant and a

sustained response to pegylated interferon and

ribavirin Gastroenterology 2010 38 2307-14

27 Mangia A Thompson AJ Santoro R et al

Limited use of interleukin 28B in the setting of

response-guided treatment with detailed on-

treatment virological monitoring

Hepatology 2011 54772-80

28 Mangia A Thompson AJ and Santoro R An

IL28B polymorphism determines treatment

response of hepatitis C virus genotype 2 or 3

patients who do not achieve a rapid virologic

response Gastroenterology 2010 139 821-7

29 Derbala M Rizk N Shebl F et al Interleukin-

28 and hepatitis C virus genotype-4 Treatment-

induced clearance and liver fibrosis World J

Gastroenterol 2012 187003-8

30 Pasha HF Radwan MI Hagrass HA et al

Cytokines genes polymorphisms in chronic

hepatitis C impact on susceptibility to infection

and response to therapy Cytokine 2013 61 478-

84

31 Yee LJ Tang J Gibson AW et al Interleukin 10

polymorphisms as predictors of sustained

response in antiviral therapy for chronic hepatitis

C infection Hepatology 2001 33708ndash12

C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

Original Article

Hemostatic Disorders in Egyptian Chronic Hepatitis C Patients with Liver

Cirrhosis Possible Mechanisms and Relation to Portal Vein Thrombosis


Tropical Medicine1 Clinical Pathology2 and Physiology Departments3 Faculty of Medicine Alexandria University

ABSTRACT

Liver cirrhosis is frequently accompanied by complex alterations in the hemostatic system Von Willebrand factor

(vWF) which is considered as a marker of endothelial cell activation plays an essential role in hemostasis ADAMTS13

(a distintegrin- like and metalloproteinase with thrombospondin type 1 motifs 13) which is produced exclusively in

hepatic stellate cells (HSCs) cleaves multimeric vWF Although the interaction between ADAMTS 13 and vWF could

be considered as initial step in hemostasis little information has been available on this interaction in Egyptian cirrhotic

hepatitis C virus (HCV) patients Aim of the work this study aimed at exploration of the possible relationship

between plasma level of Von Willebrand factor (vWF) and ADAMTS13 implicated in hemostatic disorders in Egyptian

cirrhotic HCV patients and its relation to portal vein thrombosis Methods The study was conducted on 40 cirrhotic

HCV patients who were further subdivided according to Child Pugh classification Moreover 20 healthy subjects were

enrolled as controls Plasma vWF and ADAMTS 13 were measured by ELISA Results Mean plasma vWF was

significantly higher in patients with liver cirrhosis than in controls (P lt 005) In patients plasma vWF was significantly

higher in those with Child C than those with Child B and A On the other hand plasma ADAMTS 13 was significantly

lower in patients than controls In patients with liver cirrhosis plasma ADAMTS 13 was significantly lower in Child C

than Child B and A ones Furthermore a significant negative correlation was observed between ADAMTS 13 and vWF

in the studied group (P lt 005)Cirrhotic patients with portal vein thrombosis had significantly lower level of

ADAMTS 13 and higher level of vWF than controls (plt 005) Conclusion Egyptian cirrhotic chronic HCV patients

may experience a hemostatic disorders which are evidenced by high levels of vWF and concomitant low levels of

ADAMTS 13 suggesting the possible role of both endothelial and liver dysfunction in those patients Moreover

further studies are needed to explore different therapeutic areas aiming at elevating levels of ADAMTS 13 particularly

in those patients with portal vein thrombosis

Introduction

Hepatitis C virus (HCV) is estimated to infect

approximately 180 million people worldwide (1) However the prevalence of HCV infection

varies through out the world Egyptian

Demographic health survey (EDHS) in 2009

reported an overall anti-HCV antibody

prevalence of 147 and the number of

Egyptians estimated to be chronically infected

was 98 (2) Cirrhosis develops in

approximately 10 to 15 of individuals

with chronic HCV infection (3) There are

external and host factors such as older age at

time of infection male gender coinfection

with hepatitis B virus (HBV) and comorbid

conditions such as schistosomiasis that can

increase the risk of progression of liver

disease (4) Normal hemostasis results from

well regulated processes that maintain blood

in a fluid clot free state in normal vessels

while inducing rapid formation of a localized

plug at the site of vascular injury(5) The liver

plays a major role in hemostasis by

synthesizing all clotting factors (except von

Willebrand factor (vWF) coagulation

inhibitors and several fibrinolytic proteins

The hepatic reticuloendothelial system clears

activated clotting factors proteolytic enzyme

inhibitor complexes and fibrin degradation



















































































Aim of Work





















































significance

Results


























T 532 677

P 0001 0000















(Table II)





T 393 292

P 0002 0001









000 0001) (Fig 4)



vWF r= -051

p= 000

r= 072

p= 000

ADAMTS 13 r= -077

p= 0001


Child Score

141210864

vW

F

600

500

400

300

200

100

0



Adamts 13

706050403020100

Ch

ild S

co

re

14

12

10

8

6

4


Discussion





































































































































































Conclusion











thrombosis

References







International 2009



physician 2010 81(11) 1351-7





Dis 2001 183(7) 1112-5








Clin Invest 2005 115(12) 3355-62





42




Hepatol 2010 2(6) 208-20







594-8


Engl J M 2002 347(8) 589-600




Hematol 2002 75(1) 25-34












Blood 2005 106(3) 922-24





313(1) 212-16




Haemostasis 2006 4(6) 1396-404



WB 1996 82-5





393- 409



552-4





84(6) 941-5




































73 601-9






Invest 1986 78 1456-61










2008 1(2) 188-96






138(4) 534-40






2005 42(3) 420-1




2730-5





29












91(1) 20-9





flow Blood 2004 104(1) 100-6





2008 6(7) 1233-5





Med 1998 339(22) 1578-84




339(22) 1585-94




FEBS Letters 2007 581(8) 1631-4











10(2) 236-48






Haemostasis 2005 93(3) 554-8












2004 40(5) 736-41








55 16-21





2006 107 3161-6

Original Article







ABSTRACT


















late exclusions

Introduction





















































































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013



















































































Aim of Work





















































significance

Results


























T 532 677

P 0001 0000















(Table II)





T 393 292

P 0002 0001









000 0001) (Fig 4)



vWF r= -051

p= 000

r= 072

p= 000

ADAMTS 13 r= -077

p= 0001


Child Score

141210864

vW

F

600

500

400

300

200

100

0



Adamts 13

706050403020100

Ch

ild S

co

re

14

12

10

8

6

4


Discussion





































































































































































Conclusion











thrombosis

References







International 2009



physician 2010 81(11) 1351-7





Dis 2001 183(7) 1112-5








Clin Invest 2005 115(12) 3355-62





42




Hepatol 2010 2(6) 208-20







594-8


Engl J M 2002 347(8) 589-600




Hematol 2002 75(1) 25-34












Blood 2005 106(3) 922-24





313(1) 212-16




Haemostasis 2006 4(6) 1396-404



WB 1996 82-5





393- 409



552-4





84(6) 941-5




































73 601-9






Invest 1986 78 1456-61










2008 1(2) 188-96






138(4) 534-40






2005 42(3) 420-1




2730-5





29












91(1) 20-9





flow Blood 2004 104(1) 100-6





2008 6(7) 1233-5





Med 1998 339(22) 1578-84




339(22) 1585-94




FEBS Letters 2007 581(8) 1631-4











10(2) 236-48






Haemostasis 2005 93(3) 554-8












2004 40(5) 736-41








55 16-21





2006 107 3161-6

Original Article







ABSTRACT


















late exclusions

Introduction





















































































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013





T 532 677

P 0001 0000















(Table II)





T 393 292

P 0002 0001









000 0001) (Fig 4)



vWF r= -051

p= 000

r= 072

p= 000

ADAMTS 13 r= -077

p= 0001


Child Score

141210864

vW

F

600

500

400

300

200

100

0



Adamts 13

706050403020100

Ch

ild S

co

re

14

12

10

8

6

4


Discussion





































































































































































Conclusion











thrombosis

References







International 2009



physician 2010 81(11) 1351-7





Dis 2001 183(7) 1112-5








Clin Invest 2005 115(12) 3355-62





42




Hepatol 2010 2(6) 208-20







594-8


Engl J M 2002 347(8) 589-600




Hematol 2002 75(1) 25-34












Blood 2005 106(3) 922-24





313(1) 212-16




Haemostasis 2006 4(6) 1396-404



WB 1996 82-5





393- 409



552-4





84(6) 941-5




































73 601-9






Invest 1986 78 1456-61










2008 1(2) 188-96






138(4) 534-40






2005 42(3) 420-1




2730-5





29












91(1) 20-9





flow Blood 2004 104(1) 100-6





2008 6(7) 1233-5





Med 1998 339(22) 1578-84




339(22) 1585-94




FEBS Letters 2007 581(8) 1631-4











10(2) 236-48






Haemostasis 2005 93(3) 554-8












2004 40(5) 736-41








55 16-21





2006 107 3161-6

Original Article







ABSTRACT


















late exclusions

Introduction





















































































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013


Child Score

141210864

vW

F

600

500

400

300

200

100

0



Adamts 13

706050403020100

Ch

ild S

co

re

14

12

10

8

6

4


Discussion





































































































































































Conclusion











thrombosis

References







International 2009



physician 2010 81(11) 1351-7





Dis 2001 183(7) 1112-5








Clin Invest 2005 115(12) 3355-62





42




Hepatol 2010 2(6) 208-20







594-8


Engl J M 2002 347(8) 589-600




Hematol 2002 75(1) 25-34












Blood 2005 106(3) 922-24





313(1) 212-16




Haemostasis 2006 4(6) 1396-404



WB 1996 82-5





393- 409



552-4





84(6) 941-5




































73 601-9






Invest 1986 78 1456-61










2008 1(2) 188-96






138(4) 534-40






2005 42(3) 420-1




2730-5





29












91(1) 20-9





flow Blood 2004 104(1) 100-6





2008 6(7) 1233-5





Med 1998 339(22) 1578-84




339(22) 1585-94




FEBS Letters 2007 581(8) 1631-4











10(2) 236-48






Haemostasis 2005 93(3) 554-8












2004 40(5) 736-41








55 16-21





2006 107 3161-6

Original Article







ABSTRACT


















late exclusions

Introduction





















































































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

Discussion





































































































































































Conclusion











thrombosis

References







International 2009



physician 2010 81(11) 1351-7





Dis 2001 183(7) 1112-5








Clin Invest 2005 115(12) 3355-62





42




Hepatol 2010 2(6) 208-20







594-8


Engl J M 2002 347(8) 589-600




Hematol 2002 75(1) 25-34












Blood 2005 106(3) 922-24





313(1) 212-16




Haemostasis 2006 4(6) 1396-404



WB 1996 82-5





393- 409



552-4





84(6) 941-5




































73 601-9






Invest 1986 78 1456-61










2008 1(2) 188-96






138(4) 534-40






2005 42(3) 420-1




2730-5





29












91(1) 20-9





flow Blood 2004 104(1) 100-6





2008 6(7) 1233-5





Med 1998 339(22) 1578-84




339(22) 1585-94




FEBS Letters 2007 581(8) 1631-4











10(2) 236-48






Haemostasis 2005 93(3) 554-8












2004 40(5) 736-41








55 16-21





2006 107 3161-6

Original Article







ABSTRACT


















late exclusions

Introduction





















































































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013




















































































Conclusion











thrombosis

References







International 2009



physician 2010 81(11) 1351-7





Dis 2001 183(7) 1112-5








Clin Invest 2005 115(12) 3355-62





42




Hepatol 2010 2(6) 208-20







594-8


Engl J M 2002 347(8) 589-600




Hematol 2002 75(1) 25-34












Blood 2005 106(3) 922-24





313(1) 212-16




Haemostasis 2006 4(6) 1396-404



WB 1996 82-5





393- 409



552-4





84(6) 941-5




































73 601-9






Invest 1986 78 1456-61










2008 1(2) 188-96






138(4) 534-40






2005 42(3) 420-1




2730-5





29












91(1) 20-9





flow Blood 2004 104(1) 100-6





2008 6(7) 1233-5





Med 1998 339(22) 1578-84




339(22) 1585-94




FEBS Letters 2007 581(8) 1631-4











10(2) 236-48






Haemostasis 2005 93(3) 554-8












2004 40(5) 736-41








55 16-21





2006 107 3161-6

Original Article







ABSTRACT


















late exclusions

Introduction





















































































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013



WB 1996 82-5





393- 409



552-4





84(6) 941-5




































73 601-9






Invest 1986 78 1456-61










2008 1(2) 188-96






138(4) 534-40






2005 42(3) 420-1




2730-5





29












91(1) 20-9





flow Blood 2004 104(1) 100-6





2008 6(7) 1233-5





Med 1998 339(22) 1578-84




339(22) 1585-94




FEBS Letters 2007 581(8) 1631-4











10(2) 236-48






Haemostasis 2005 93(3) 554-8












2004 40(5) 736-41








55 16-21





2006 107 3161-6

Original Article







ABSTRACT


















late exclusions

Introduction





















































































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013





29












91(1) 20-9





flow Blood 2004 104(1) 100-6





2008 6(7) 1233-5





Med 1998 339(22) 1578-84




339(22) 1585-94




FEBS Letters 2007 581(8) 1631-4











10(2) 236-48






Haemostasis 2005 93(3) 554-8












2004 40(5) 736-41








55 16-21





2006 107 3161-6

Original Article







ABSTRACT


















late exclusions

Introduction





















































































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

Original Article







ABSTRACT


















late exclusions

Introduction





















































































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

























































Step 1






Step 2

Liver biopsy



Step 3




antibodies

Step 4

























tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013





















tomy

Results












































of donor evaluation

Social Problem



















Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013








Substance Abuse














potential donors



















Donor Pregnancy











































exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013








exclusion


Laparotomy










































finally donated

Donor Imprisoning






Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

Step 1





HSV



Step 2





Drugs assay

Step 3





Step 4







Discussion


















































































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013










































































































































































































































Conclusion













References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

References







9 S45-S49



2003 38(S)119ndashS135











2416




82






Pages 480ndash48









151



1995 60667ndash671




pp 3ndash9




200234621ndash622




Jun1569(11)2410-5














294





























Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013


















Int 2000 13 372




425




1997 132 1098




1999 125 217










1994 369 64


















38 S119ndashS135
















27 4(11) 299-304

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

Original Article





ABSTRACT

















Introduction



























































































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

























































to IFN therapy (14)


















































PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

























PCR (22)
















Results






















Group I 38 (38) 48 (48) 14 (14) 6238

Group II 28 (56) 18 (36) 4 (8) 7426




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013




















IL28B genotypes


ratio

Total

(NO)

Response to

therapy

Responders

34 (507) 31 (463) 2 (3) 7426 67

Non-responders

4 (121) 17 (511) 12(364) 3862 33

Total (n) 38 48 14 100

X2 264

P 000



0

10

20

30

40

50

60

Group I Group II

CC

CT

TT

0

20

40

60


CC

CT

TT










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013










for the A allele



Group I 79 (79) 21 (21) 895105

Group II 46 (92) 4 (8) 964























TNF-a genotypes



Non-responders 22 (667) 11(333) 834 166 33

Total (n) 79 21 100

X2 451

P 0034


0

20

40

60

80

100

Group I Group II

GG

GA























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013























and 45 respectively




PPV 894 645 857 721 523 968 75

Efficacy 63 47 77 68 56 45

Discussion

















0

20

40

60

80

100


GG

GA
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013
















































































































































































Conclusion








References



2007 13 2436ndash41




355 887-91


Liver Int 2009 1 74-81



Treat 2010 20101409-53

















2009411105-9







401




Genet 2009 411100-4



54102-9










193 98ndash101










2010 52 223-9





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013





2008 32 822-8





1993 177557ndash60




4
















22 404-12





20122012849373-82









24 360-7























84





C1

01 August Table

02 August 2013

03 August 2013

04 August 2013

Founder Editors - ESHGIDeshgid.com/images/2018June1049PM_198080200.pdf · Khaled Madboli Ezzat Aly...

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Transcript of Founder Editors - ESHGIDeshgid.com/images/2018June1049PM_198080200.pdf · Khaled Madboli Ezzat Aly...