The clinical and the prognostic value of Insulin, Growth Hormone, TNF-R (P55) and IL-1 receptor antagonist (IL-1ra) in Chronic Hepatitis due to HCV Genotype 4 before and after combination

therapy with Pegylated Interferon α-2a and Ribavirin.

Nihal M.El Assaly1, Naema El Ashri1, Omnia El Bendary1, Shendy M.Shendy2 , Mervat Al-Damarawy3, M. Ali Saber 4 and Ehab El Dabaa4

1. Clinical Chemistry Department. Theodor Bilharz Research Institute (TBRI), 2. Gastroenterology and Hepatology Department (TBRI) 3. ICU department (TBRI). 4. Biochemistry Department (TBRI).Journal -Egyptian Medical Journal Of The National Research Center, June 2007; vol. 6 (1): 38 – 45.35401019.Abstract

Combined therapy using Interferon alfa (IFN) and Ribavirin (RIB) represents the standard treatment in

patients with chronic hepatitis C. However, the percentage of responders to this regimen is still low, while

its cost and side effects are elevated. Therefore, the possibility to predict patient's response to the above

treatment is of paramount importance. Aim of this work is to evaluate the role of IL-1ra, and TNFRI

(P55) which are receptors related to inflammatory response and, GH and Insulin which are hormones

metabolized in the liver as biochemical non invasive markers of severity of liver disease due to HCV

infection genotype 4, whether cirrhotic or non-cirrhotic. The effect of interferon alpha 2a and ribavirin

therapy on their levels and whether they could be used as parameters predicting the outcome of interferon

alpha 2a therapy in patients with chronic HCV infection . Methods 54 patients infected by HCV genotype

4 were enrolled in this study. They were classified into two groups according to the liver histology. Group

A of 42 chronic compensated HCV patients with no cirrhosis, Group B of 12 chronic HCV patients with

established cirrhosis and 12 healthy controls. Patients were treated by Pegylated INF α-2a (180 µg for

group A and 130 µg for group B) once weekly & 1200 mg Ribavirin/ day in two doses. Tested parameters

have been done by ELISA method before and after treatment for group A, group B and control group.

Results: end of treatment response (ETR) and sustained virological response (SVR) were 73.817% and

61.91% for group A, and 58.33% and 33.33% for group B respectively. Serum IL-1ra was increased after

treatment but this increase was not significant (P>0.05). There was a significant increase of serum insulin

(P<0.01) of group A after treatment compared to group A before treatment, group B and control group. On

the other hand, serum TNF-R (P55) showed significant decrease (p <0.05) in group A after treatment

compared to group A before treatment, group B and control group. TNF-R (P55) showed positive

correlation with sALT and sAST. Also, serum GH level decreased in group A after treatment compared to

the other studied groups; but, this decrease was not statistically significant Conclusion Pegylated INF α-2a

and Ribavirin are effective combination in treatment of chronic HCV genotype 4. Insulin and TNFR

(P55) correlate with HCV infection and could be used as a marker of peg - IFN α-2a and Ribavirin

response while IL-1ra and GH are of no value.

Key words: HCV, HCV patients treated with IFN and ribavirin, cytokines and receptors and hormones.

INTRODUCTION:

Chronic Hepatitis C ( HCV ) is a major public health problem in Egypt. It is caused by genotype 4 in

more than 90 % of the patients.1 Early treatment of HCV will markedly reduce the progression to cirrhosis,

decompensated disease and hepatocellular carcinoma.2

Combined therapy using Interferon alfa (IFN) and Ribavirin (RIB) represents the standard treatment

in patients with chronic hepatitis C. However, the percentage of responders to this regimen is still low,

while its cost and side effects are elevated. Therefore, the possibility to predict patient's response to the

above treatment is of paramount importance. The viral genotype, the degree of inflammation, fibrosis and

the viral load prior to treatment are considered the strongest predictors of response to antiviral therapy.3

Until recently interferon alfa (INF) and ribavirin were the combination of choice in treatment of

HCV. Response of Egyptian patients with chronic hepatitis C to standard therapy of interferon and ribavirin

combination is unsatisfactory and only less than 40 % of Egyptian patients had sustained virologic response

(SVR).4,5 Factors that influence response rate to interferon therapy are numerous and include both host and

viral factors.6

Pegylated INF has longer half life than standard INF and can be administered once weekly. So, its

combination with ribavirin resulted in SVR in 82 % of patients with genotype 2 and 3 and 42% of patients

with genotype 1.7 Good response of other genotypes (2 & 3) to Pegylated INF therapy pushed us to study

its efficacy on genotype 4.3

The number of patients with genotype 4 who were enrolled in European studies was too small to be

included in statistical analysis. Also, the response of this genotype 4 to pegylated INF with ribavirin was

not properly studied in the Middle East and north Africa.1

Interleukin-1 (IL-1) is a cytokine that plays an important role in initiating the cascade of events of

immuno-inflammatory responses through co-stimulation of T lymphocytes, B-cell proliferation and

induction of adhesion molecules and stimulation of the production of other inflammatory cytokines. The

role of IL-1 in immuno-inflammatory responses is highlighted by the presence of endogenous regulators

(IL-1 receptor antagonist, soluble receptors type 1 and II, human IL-1 accessory protein) that, when

secreted into the blood stream may serve as endogenous regulators of IL-1 action.8

Hepatitis C virus (HCV) infection is resistant to interferon alpha (IFN-Alpha) in some patients. The

mechanism of this resistance is unknown.7 It was proved that Interleukin-1 receptor antagonist (ILI-Ra) is

induced by IFN-alpha and is a good indicator of IFN activity, and this increase indicates that IFN receptors

are functioning in patients with IFN-resistant hepatitis C and that the lack of response is related to other

virologic or immunologic factors.9

Cirrhosis is characterized by high growth hormone (GH) levels which fail to decrease and often

paradoxically increase after administration of glucose or insulin.10,11 The cause of this high GH level

remains uncertain. It may be a decrease in its metabolic clearance rate or diminish in liver growth hormone

receptors.12 Insulin resistance is present in nearly all patients with liver cirrhosis, but its etiology remains

unclear. Recent studies have shown that tumor necrosis factor-a (TNF-) system is involved in the insulin

resistance of liver cirrhosis, as serum concentrations of TNF-, and soluble TNF receptors (sTNF-RI and

sTNF-RII) are increased in cirrhotic patients.13 Itoh et al4, proved that the serum levels of sTNFRs

increased in proportion to the severity of liver disease; and, that the levels of sTNFRs revealed significant

correlations with the serum levels of alanine aminotransferase and aspartate aminotransferase.14

It is presumed that resolution of hepatitis C, as evidenced by normalization of liver function tests and

disappearance of hepatitis C virus (HCV) RNA from serum reflects virus eradication.15

In this study our aim is to evaluate the role of IL-1ra, and TNFRI (P55) which are receptors

related to inflammatory response and, GH and Insulin which are hormones metabolized in the liver as

biochemical non invasive markers of severity of liver disease due to HCV infection genotype 4, whether

cirrhotic or non-cirrhotic. The effect of interferon alpha 2a and ribavirin therapy on their levels and

whether they could be used as parameters predicting the outcome of interferon alpha 2a therapy in patients

with chronic HCV infection

Patients and methods:

This study was conducted on 12 healthy control persons and 54 HCV chronic hepatitis

patients (continue with us till the end of the study out of group of patients) who had positive

anti-HCV (detected by ELISA) and detectable HCV RNA (by RT- PCR amplicor molecular

system, F Hoffmann - La roche Basel Switzerland) in their serum and did not receive antiviral

therapy for HCV before (naïve patients). All chronic hepatitis patients were of genotype 4 as

detected by the Inno Lippa HCV II assay (innogenetics inc., GA, USA). HBsAg was negative

in all patients (done by ELISA). Group A: 42 patients were highly selected from a group of

HCV patients receiving a schedule of antiviral treatment for 1 year treatment. They were

collected according to the following inclusion criteria: Genotype 4, with positive HCV-RNA,

elevated ALT more than two folds the upper limit of normal, and negative autoantibodies

including anti-ANA, anti-AMA, anti-thyroid globulin and anti LKM antibodies. exclusion

criteria: HBsAg positivity (by ELISA), diabetes, cirrhosis (by liver biopsy), disturbed thyroid

function, Hb < 11g/dl, platelets count < 100.000/cumm, and WBCs < 1500/cumm, and their

Group B: 12 patients had the same inclusion and exclusion criteria but had cirrhosis on liver

biopsy.

Study design and strategy of treatment:

The study was done over a period of 30 months. The 54 studied Egyptian patients (who

continue till the end) were classified into two groups:

Group A: 42 patients with chronic HCV hepatitis received 180 µg Pegylated INF α-2a

subcutaneously once weekly & 1200 mg Ribavirin/ day in two doses by oral route.

Group B: 12 patients with liver cirrhosis received 130 µg Pegylated INF α-2a once weekly

& 1200 mg Ribavirin/ day in two doses.

Blood samples were collected under aseptic conditions before treatment, after 12 weeks,

after 48 weeks of the combined treatment and 6 months after completion of the treatment

schedule to be assayed for our studied parameters. All subjects were fasting overnight before

sampling. Serum was separated from the other contents and stored at –70 C untill assayed.

The initial response (IR) was defined as the clearance of the virus or reduction of the viral

load by two logs after 12 weeks of treatment. Patients who failed to achieve IR discontinued

treatment Patients who achieved initial response continued treatment for 48 weeks to prevent

relapse. The end of treatment response (ETR) was defined as clearance of the virus at the end

of treatment (48 weeks).

Reassessment of ALT and HCV RNA were done 6 months after stopping therapy. Patients

who had absent HCV after these 6 months were defined to have sustained virological response

(SVR).

The dose of Pegylated INF α-2a was reduced to 130 µg in two patients from group A when

the WBCs count dropped below 1500/cmm and rose again in one of them after improvement of

the count

The dose of Ribavirin was reduced to 600 mg / day in 8 patients when the Hb level dropped

below 10 mg/dl.

I. Clinical evaluation:

- A detailed history and clinical examination was performed for all the patients with special

emphasis on the possible duration of the HCV infection, age and sex.

- Ultrasonography was done by an ultrasound machine Hitachi EUB 515 A, using a convex

linear transducer 3.5 MHz to exclude cirrhotic patients.

- Biopsy was done by a Hepafix needle 14 mm in diameter and the biopsy was done according

to the Menghini technique to confirm the diagnosis. All biopsy specimens were immersed in

10% formol and sent for histopathological analysis.

II. Laboratory tests:

The following investigations had been done to all patients at recommended times before, during and

after treatment :-

- Liver function tests (Serum albumin, direct bilirubin, AST and ALT) and CBC were done before and

every 2 weeks after starting treatment using standard laboratory methods.

- Fasting blood sugar was done using standard laboratory method to exclude diabetes.

- Hepatitis marker HCV-RNA by (PCR).

- ANA, AMA, T3, T4, TSH (By ELISA), Anti-thyroid globulin Ab, anti LKM by indirect

immunofluorescence antibody test using (the Binding site LTD, Birmingham, England).

- Serum Insulin by ELISA using (Biosource Europe S.A.)

- Serum growth hormone level by enzyme immune assay method (IBL, Hamburg, Germany, and quorum

Diagnostics Inc., Vancover, British Colombia, Canada respictevely).

- Serum Interleukin I- receptor antagonist by ELISA (Biosource IL-ra Cytoscreen Kit, Europe S.A. Rue

de L' Industrie, 8 B-1400 Nivelles Belgium.)

- Serum TNF RI by EASIA using Biosource Kit

Statistical analysis:

Medians were compared using the median test. Continuous variables were expressed as

mean SD and were compared by using paired t-test or correlated by using simple regression

done by Excel program. Differences were considered significant if P< 0.01.

RESULTS:

This study was conducted on 54 HCV patients, their ages range (20 - 70) all were Egyptian; 41 males

and 13 females. Results were presented as mean ±SD. Table (1) showing the characteristics of the studied

group and the main positive findings of the studied parameters after the combined treatment of pegylated

interferon α 2a and ribavirin.

Table (1): shows characteristics of the 54 HCV genotype 4 patients

Gender: Count %

Male 41 76.00%

Female 13 24.00%

Total 54 100.00%

Age: Total 54 100.00%

From 20 to 39 15 27.78%

From 40 to 54 34 62.96%

From 55 to 70 5 9.26%

Non- cirrhotic 42 77.7%

Cirrhotic 12 22.3%

Table 2: Clinical data of Chronic HCV patients:

Clinical Data Non-cirrhotic (n = 42) Cirrhotic (n = 12)

Presenting symptoms: Fatigue:

Dyspepsia

Upper abdominal pain

History of Jaundice

Bleeding tendency

Non (accidental)

31

23

19

8

5

5

9

7

8

6

5

0

Signs:

jaundice

Hepatomegaly

Splenomegaly

Oedema

Ascites

Foetor hepaticus/ palmar erythema

Spider Naevi/ flabbing tremors

15

28

13

0

0

0/0

0/0

6

3

7

3

0

0/3

2/0

Table 3: Endoscopic and ultrasonographic findings in patients with chronic HCV infection:

Clinical Data Non-cirrhotic (n = 42) Cirrhotic (n = 12)

Endoscopic findings:

Oesophageal varices:

1. Grade: 1/2

2. Grade: 3/4

Gastric varices

Congestive gastropathy

1. mild

2. severe

Peptic ulcer

Chronic gastritis

2/1

0/0

0

4

0

2

15

4/3

1/0

2

7

2

1

7

Ultrasonographic findings:

Liver size:

a. Average size

b. Mildly enlarged

c. Markedly enlarged

d. Shrunken

23

11

7

1

3

4

0

5

Echopattern:

Long axis of spleen

Collaterals:

Gall stones

diffuse

13+/- 1.65

3

5

coarse cirrhotic

16 +/- 3.27

7

4

Table 4: Liver function tests and viral load in HCV patients before and after treatment.

Clinical Data Non-cirrhotic Gp A (n = 42) Cirrhotic group B (n = 12)

ALT before/after treatment U/L 101.5 8.5 / 39.4 4.93* 76.3 5.92 / 45.43 4.54*

AST before/after treatment U/L 81 7.21 / 40.17 4.37* 93 4.62 / 49.94 6.73*

Bilirubin before/after treatment (mg/dl) 1.8 0.61 / 1.1 0.23 2.67 0.83 / 1.52 0.63

Serum albumin before/after treatment 3.9 0.23 / 4.05 0.31 3.1 0.41/3.31 0.47

Prothr. time before/after treatment 12.16 1.04/ 11.74 1.01 13.54 1.48 / 12.62 1.36

HCV RNA load > 2 X106 copies/ml 11/7 3/2

HCV RNA load < 2 X106 copies/ml 31/9 9/6

* Significant decrease compared to its level before treatment

Table 5: Histological findings in patients with chronic HCV infection:

Clinical Data Non-cirrhotic Group A (n = 42) Cirrhotic group B (n = 12)

Liver biopsy findings:

Activity:

1. Mild

2. Moderate

3. Severe

Grade:

1. Grade 1

2. Grade 2

3. Grade 3

4. Grade 4

5. Grade 5

(cirrhosis)

27

11

4

32

5

4

1

0

3

7

2

0

0

0

0

12

Patients with initial response (IR) in both cirrhotic and non Cirrhotic groups showed decreased end of

treatment (ETR) response that became 73.817% (31/42 patients) in non cirrhotic and 58.33% (7/12

patients) of the initial responders in cirrhotic. Sustained virological response (SVR) was 26/42 (61.91%)

and 4/12 (33.33%) in both groups. The biochemical response was also initially high then decreased in both

groups. The difference was significant between both groups concerning virological response and the

biochemical response (P <0.05).

Table 6: Virological response (disappearance of HCV RNA in serum)in both groups of chronic HCV:

Initial response (IR) End of treatment

Response (ETR)

Sustained Virological

response (SVR)

Group A 42/42 31/42 (73.817%) 26/42 (61.91%)

Group B 12/12 7/12 (58.33%) 4/12 (33.33%)

Table 7: The mean values of the studied parameters in treatment groups (before and after treatment)

and the reference group.

HCV without cirrhosis Before

treatment

HCV without cirrhosis after

treatment

Cirrhosis Before

treatment

cirrhosis after treatment

Reference group

TNF-αR (P55)mean ± SD

3.91±1.98 1.85 ±0.55**† 7.4 ±2.98**† 6.53 ±2.79** 3.23 ± 0.28

range 1.4 - 9.5 1.3 - 3.9 2.9 - 11.2 2.8 - 11.2 2.9 - 3.7

IL-1 Ra Mean ±SD

193.4±42.07** 214.7±44.04** 167.08±33.8**†166.25±44.42**

‡133.5±37.7

range 145 - 256 145 - 276 135 - 215 115 - 225 71 - 184

GHMean ±SD

7.56±1.33** 4.93±1.45† 23.15±10.9**† 22.34±10.93** 4.57±1.93

range 2.5 - 8.0 2.5 - 7 5.5 - 30.5 5.5 - 30.5 2.0 - 7.0

InsulinMean ±SD

26.72±8.27 48.8±16.07**† 51.12±16.8**† 53±19.62** 14.49±5.5

Range 14.5 - 36.5 28 - 70 14.5 - 85 32 - 80 8.5 - 28

** Statistically Significant compared to the reference group.† Statistically significant compared to the HCV without cirrhosis before treatment

NB: cirrhosis after treatment group show no significant change compared to its level before treatment.

The two HCV groups showed significantly higher basal levels of TNF-αR (P55) before

treatment compared to the reference group and a significant decrease in its level after treatment.

Its level was significantly higher in cirrhotic than non-cirrhotic patients whether before or after

treatment. IL-1ra showed significantly higher levels in the two treatment groups before

treatment compared to the reference group. Its level increased significantly in non-cirrhotic

group after treatment but didn’t show significant changes in cirrhotic patients. There were

higher levels of GH in the two treatment groups before treatment compared to the reference

group which is significant for cirrhotic group but of no significance for non-cirrhotic group and

a significant decrease of GH in non-cirrhotic patients after treatment compared to their level

before treatment. Insulin level was significantly higher in HCV patients than control group and

showed a significant increase in its level after treatment compared to its level before treatment.

The levels of both GH and insulin were significantly higher in cirrhotic than non-cirrhotic

patient.

Discussion:

Serum ALT and HCV-RNA by PCR are the standard markers to assess liver disease and to monitor

response to therapy in patients with chronic HCV infection. Other factors as viral load, genotype and

grade of fibrosis are also, used to predict the treatment outcome of such patients (8). In 1995 Martinot et

al., proved that viral genotype is a major predictor of SVR and patients with genotype 4 were considered

as “difficult to treat” by the standard interferon (9).

In this study we tried to estimate the role of IL-1ra, TNF-α R (P55) as a receptors related to

inflammatory response and, GH and insulin as a hormones metabolized in the liver in HCV infection,

cirrhotic and non-cirrhotic. Also to find their significance as non invasive biochemical markers that may

correlate with HCV infection and predict the outcome of pegylated interferon-α 2a with ribavirin therapy

in patients with chronic HCV infection genotype 4.

In our study the growth hormone levels were higher in the two studied groups before therapy

compared to the reference group. This higher level was highly significant in cirrhotic patients

while not significant in patients with early liver disease (non-cirrhotic). Also it was significantly

higher in cirrhotic than non-cirrhotic group. This means that the increases in the level of growth

hormone are related directly to the severity of the disease. After treatment its level decreased

significantly only in non-cirrhotic patients (early liver affection). It did not remarkably change

after treatment in cirrhotic patients (advanced liver disease) where treatment was not able to

correct the abnormal levels. Thus, the increase in its basal level and the return of it to normal

after treatment depends on the severity of liver disease. This was agreed by others who proved that

cirrhosis is characterized by high growth hormone (GH) levels (10, 11). The cause of this high (GH) level

remains uncertain. It may be a decrease in its metabolic clearance rate or diminish in liver growth

hormone receptors (12).

In this study also, insulin level was significantly higher in HCV patients (all are non-diabetic)

compared to control group and showed a significant increase in its level after treatment compared to its

level before treatment. The levels of insulin were significantly higher in cirrhotic than non-cirrhotic

patient. Thus, insulin also rises proportionately with the degree of liver affection, being more elevated in

cirrhotic patients. Treatment with interferon and ribavirin increased insulin levels in such patients more

and more. This was previously reported by others (17). HCV infection changes a subset of hepatic

molecules regulating glucose metabolism. A possible mechanism is that HCV core-induced suppressor of

cytokine signaling (SOCS3) promotes proteosomal degradation of insulin receptor substrates IRS1 and

IRS2 through ubiquitination. In patients with HCV infection there was increase in fasting insulin levels

and that increase was associated with the presence of serum HCV core, the severity of hepatic fibrosis

and a decrease in expression of insulin receptor substrate IRS1 and IRS2, which are central molecules of

the insulin-signaling cascade. BMI, serum levels of AST and TNF-alpha were related with HOMA-IR

(which is a measure of insulin resistance). Hepatic fibrosis and inflammation appear to play key roles in

the increase in insulin resistance and insulin level in patients with chronic HCV infection (18, 19).

Previous studies had found that impaired glucose tolerance and iron overload were frequently

demonstrated in hepatitis C virus (HCV)-related liver diseases (20).

Our study revealed a high level of IL-1ra in both groups before and after treatment in HCV patients

compared to the reference group. Its level increased significantly after treatment in patients with earlier

degree of liver affection but didn’t change in cirrhotic patients. In 1999, Gramantieri et., al (21) proved

that the increased level of IL-1Ra may contribute to the pathogenesis and the activity of chronic active

hepatitis C (21). In 2002 Cotler et al (9) proved that Serum IL-1Ra levels increased rapidly in all patients

with hepatitis C after IFN-alpha administration, irrespective of their virologic response (9). IL-1Ra levels

remained elevated at 1 week but were similar to baseline by week 2 of treatment in patients receiving

continuous therapy. The increase in IL-1Ra indicates that IFN receptors are functioning in patients with

IFN-resistant hepatitis C and that the lack of response is related to other virologic, genetic or

immunologic factors (22).

In this study, the two HCV groups showed also significantly higher basal levels of TNF-αRI (P55)

before treatment compared to the reference group and a significant decrease in its level after treatment

mainly at the non cirrhotic group, while its decrease in the cirrhotic group was not significant compared

to the reference group. Its level was significantly higher in cirrhotic than non-cirrhotic patients whether

before or after treatment, as its levels were related directly to the severity of infection. In 1999, Itoh et al

proved that in the sustained responder group, the levels of sTNF-R p55 showed a significant decrease (p <

0.0002.). He also proved that the TNF alpha-R- mediated pathway, is involved in the hepatic

inflammation-fibrosis process in chronic hepatitis C (14). More recent study revealed that hepatitis C

virus (HCV) core protein modulates multiple cellular processes, including those that inhibit tumor

necrosis factor alpha (TNF-alpha)-mediated apoptosis such as TNF-alpha R1 and that this may play

important role in the pathogenesis of HCV liver disease (23). Also, the number of TNF-alpha-producing

cells was found to be increased in the liver and the circulating levels of TNF-alpha were significantly

increased in patients with chronic hepatitis. Soluble TNF receptors, TNF-alphaRI (p55) and -alphaRII

(p75), and IL-10, act as TNF-alpha buffer. Patients with liver cirrhosis (LC) and hepatocellular carcinoma

(HCC) had significantly elevated levels for sTNF-alphaRII compared with the other patient groups and

controls (24). In another study, correlation was found between the two soluble TNFRs (P < 0.0001) and

between the soluble TNFRs and ALT levels (P < 0.003). It was suggested that these sTNF-alphaR closely

correlated with disease progression and may reflect the degree of inflammation in the liver and even may

be related to the development of HCC (25). Other study revealed that treatment with interferon did not

affect serum levels of sTNF-alphaRs and, that the lower levels of soluble TNFR-p75 were present from

day 3 in patients who had significant virus decay at day 30 (26). In one study, it was found that both

tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) TRAIL-R1 and -R2 showed

coefficient correlation with caspase-3 activity, and were strongly associated with apoptosis in human

HCC (27). Thus, it was found that activation of the tumour necrosis factor (TNF)-alpha system has a

pivotal role in the inflammatory process of chronic hepatitis C, and TNF-alpha levels correlate with the

degree of inflammation. Also, TNF-alpha is known to cause insulin resistance, with similar defects in the

insulin signalling pathway to those described in HCV infection and HCV patients have significantly high

levels of soluble TNF-alpha receptors particularly in those with diabetes (28).

It is concluded from this study that pegylated INF-α combined with ribavirin therapy is the regimen of

choice in treating chronic HCV infection of genotype 4 especially in non cirrhotic patients for at least 48

weeks. The increase in the basal levels of GH and TNF-αRI (P55) and the reduction of these levels after

treatment depends on the severity of liver disease, thus it can be used successfully as a sensitive, non-

invasive and cheap liver function tests related to both the severity of the disease and to the response to

medical treatment. P55 can be used successfully as a liver function test denoting improvement of

patients by this treatment with or without HCV RNA denoting regression of the viremia and viral

affection of liver cells. P55 and IL-1ra could be also used on selecting the patients to be treated

successfully. GH and Insulin could be used for the follow up.

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و النمو وهرمون األنسولين من لكل االكليكينية األهمية دراسة

مضاداتمستقبالت و ألفا الورمى التآكل عامل مستقبالت

ج ١االنترلوكين- المزمن الكبدى مرضااللتهاب تطور فى داللتها و

الوراثى ألفا ٤النوع باالنترفيرون العالج وبعد قبل أ ۲وذلك

والريبافيرين

** * * * ، شندى محمد شندى ، البندارى أمنية ، العشرى نعيمة ، العسالى ميرفت نهال**** **** الدباغ*** ايهاب و علىصابر ،محمد الدمراوى

* الهضمى الجهاز قسم و و األكلينيكية الكيمياء قسم لألبحاث، بلهارس تيودور معهد **** *** الحيوية الكيمياء قسم و المركزة الرعاية قسم و واألمراضالمتوطنة والكبد

: ملخصالبحث

ألفا باالنترفيرون العالج لمرض ۲ان عليه المتعارف العالج يمثل والريبافيرين أوالتكلفة الجانبية واألعراض قليلة االستجابة نسبة ولكن ج المزمن الكبدى االلتهاب

لهذا المرضى استجابة خاللها من نتوقع عوامل عن البحث امكانية فان ولذلك عالية . عادية غير أهمية ذات لهو العالج

تطور فى والداللة االكلينيكية األهمية تقييم هو البحث هذا من الهدف كان ولذلكمستقبالت مضادات و ألفا الورمى التآكل عامل مستقبالت من لكل المرض

األنسولين ١االنترلوكين- وكذلك لاللتهابات المسببة بالسيتوكينات والمرتبطةااللتهاب مرضى فى ذلك و الكبد طريق عن منها التخلص يتم والتى النمو وهرمون

الوراثى النوع ج المزمن هذه ٤الكبدى أهمية عن والبحث متليف، والغير المتليفالمرض استجابة وتوقع العدوى مراحل لتقييم نافذة غير كيميائية كدالالت العوامل

للعالج.الدراسة شملت الوراثى مريضا ٥٤وقد النوع ج المزمن الكبدى ٤بااللتهاب

: وتشمل األولى مجموعتين ال عندهم ٤۲مقسمين يوجد ال و مستقرة حالتهم مريضاوتشمل الثانية والمجموعة كبدى يوجد ١۲تليف لكن و أيضا مستقرة حالتهم مريضا

الى باإلضافة كبدى تليف . ١۲عندهم المرضى عالج تم وقد سليمة مقارنة حالةألفا ( ۲باالنترفيرون و ١٨٠أ األولى المجموعة فى اسبوعيا مريض لكل ميكروجرام

والريبافيرين ) ١٣٠ الثانية المجموعة فى اسبوعيا مريض لكل مجم ١۲٠٠ ميكروجرام . وبعد قبل المرضى لتقييم الالزمة الفحوص تمعمل وقد يوميا جرعتين على مقسمة

التآكل عامل مستقبالت و النمو وهرمون األنسولين الفيروسو تحاليل شاملة العالج- االنترلوكين مضاداتمستقبالت و ألفا .١الورمى

فى استجابة النتائج أظهرت قد ٨۲,و و% ٧٣ العالج نهاية ٩١,عند استجابة% ٦١وفى األولى المجموعة فى ٣٣,مستديمة و% ٥٨ العالج نهاية ٣٣,عند استجابة % ٣٣

- . االنترلوكين مستقبالت مضادات مستوى ازداد وقد الثانية المجموعة فى ١مستديمةفى األنسولين مستوى ازداد كما إحصائية، داللة بدون المجموعتين فى العالج بعد

الثانية المجموعة فى وعنه العالج قبل عنه إحصائية داللة ذو زيادة األولى المجموعةانخفاضا ألفا الورمى التآكل عامل مستقبالت انخفضمستوى وقد المقارنة، وحاالت

والذى المقارنة وحاالت الثانية المجموعة فى وعنه العالج قبل عنه إحصائية داللة ذو . النمو هرمون مستوى انخفض كما الكبد إنزيمات مع طرديا تناسبا متناسبا أيضا كان

الثانية المجموعة فى وعنه العالج قبل عنه إحصائية داللة ذى غير انخفاضا ولكنه. المقارنة وحاالت

ألفا باالنترفيرون العالج أن البحث هذا من فعال ۲يستنتج عالج هو والريبافيرين أالوراثى النوع ج المزمن الكبدى االلتهاب حاالت و ٤فى األنسولين مستوى أن و

وتطوره العدوى بوجود مرتبط و داللة له ألفا الورمى التآكل عامل مستقبالت

مستقبالت مضادات و النمو هرمون على ذلك ينطبق وال للعالج، واستجابته. ١االنترلوكين-