الفهرس 
Chapter I: CholestaisisOnly 14 pages are availabe for public view
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Abstract
Neonatal cholestasis is a group of disorders of impaired bile
flow characterized by conjugated hyperbilirubinemia in the newborn
and young infant arising from a wide variety of disorders.
Biliary atresia is one of the most commonly identifiable
etiologies of neonatal cholestasis. Representing the most common
cause of death from liver disease in children and the most common
cause for liver transplant in pediatrics. It is a fibroinflammatory
disease, if untreated results in progressive cholestasis with hepatic
fibrosis and cirrhosis. BA prognosis relates to timely surgical
correction and therefore early diagnosis is mandatory.
Surgical intervention by KPE may restore bile drainage, but
progression of the intrahepatic disease results in complications of
portal hypertension and advanced cirrhosis in most children.
The causes of BA remain actually unknown but genetic
and immune dysregulation play a major role in the disease. Current
research focuses on the identification of blood or liver factors linked
to the pathogenesis of BA that could become therapeutic targets and
avoid the need for liver transplantation.
Genetic predisposition is one of the explored fields to
explain biliary atresia pathogenicity. It has been associated with
several inborn syndromes, chromosomal anomalies, and gene
polymorphisms in specific populations.
MicroRNAs (miRNAs) are an abundant class of small non -
coding RNAs. Accumulating evidence indicates that disruption of
miRNA expression levels plays crucial roles in all aspects of different
human diseases.
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Recent research has ascribed the role of miRNAs in all aspects
of liver disease from initiation, progression, diagnosis and treatment.
Injury to liver tissue in biliary atresia is supposed to release certain
microRNAs. High levels of these micro RNAs are found in the
intrahepatic bile ducts confirming the source of release and their
specificity.
Single nucleotide polymorphisms (SNPs) in miRNA genes are a
novel class of genetic variations in the human genome that confer the
risk of many diseases. It has been shown that SNPs in miRNA genes
could change the conformation of the secondary structure and thereby
directly affect both the binding to target mRNAs and the miRNA
maturation process, thus altering protein expression and potentially
contributing to disease susceptibility.
MiRNA-499 is a newly discovered member of miRNAs. It has
been shown to be expressed in myocardium and skeletal muscle in
mammals. It regulates the expression of the beta myosin heavy chain,
leading to enhancement of myocardial oxygen metabolism and
tolerance.
In some studies, it has been found that miRNA 499 modulate T
cell selection and receptor sensitivity and also T cell development ,
which suggests that miRNA may be associated with the development
of autoimmune diseases. Recently, functional SNP has been identified
in the miR499 gene (adenine to guanine [A/G]). This polymorphism
leads to a change from A: U pair to G: U mismatch in the stem
structure of miR 499 precursor.
Therefore, in this study we investigated the effects of the miR-
499 rs3746444 polymorphism on the risk of BA and the effect of this
polymorphism on the clinicopathologic data and whether this gene
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polymorphism affect the prognosis after Kasai operation in patient
who underwent this procedure .
The study included 300 patients selected from the inpatient and
outpatient clinic at National Liver Institute, Menoufia University.
The patients are divided into three groups:
group І 100: healthy children as control group .
group II 100: Patients with cholestatic liver disease other than biliary
atresia.
group IП 100: Patients with biliary atresia.
All individuals were subjected to; Clinical assessment, routine
laboratory investigations and miR-499 rs3746444gene polymorphism
analysis. Six months after Kasai, 86 of biliary atresia cases who
undergwent Kasai procedure were subjected to reevaluation by
laboratory investigations
The gained results showed that.
1. The genotypes distribution of miR-499 polymorphism SNP
(rs3746444) in control, non-BA and BA groups revealed a
significant difference (P= 0.019).
2. The AG genotype is the most common genotype among the
studied groups.
3. It was observed that the distribution of miR-499 SNP
(rs3746444) genotypes, alleles ,dominant, or recessive models
were not significantly associated with the disease risk in nonBA groups as compared to control groups .
4. The comparison of genotypes distribution and allele frequencies
of miR-499 SNP (rs3746444) between control and BA groups
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showed that GG genotypes were associated with a significantly
increased risk of BA.
5. The subjects with the variant G allele had a significant risk of
BA compared with wild allele A.
6. The comparison of genotypes distribution and allele frequencies
of miR-499 SNP( rs3746444 )between BA and non- BA groups
showed that GG genotypes were associated with a significantly
increased risk of BA.
7. A significant difference between different genotypes regarding
baseline ALT, AST, GGT, and total bilirubin.
8. There was no significant phenotypic difference between the
different genotypes in the BA group.
9. There was a significant difference between different genotypes
as regard the degree of fibrosis with worsening in the degree of
fibrosis with the GG genotype which signifies increase its
severity in this genotype.
10.Regarding the association between genotypes in the recessive of
miR-499 SNP (rs3746444) polymorphism with the change in
the laboratory parameters six months after Kasai in biliary
atresia group, it was found that total, direct bilirubin, and INR
levels were significantly more improved in patients carrying
AA or AG genotypes but not GG, revealing bad prognosis after
Kasai operation for patients with the GG genotype.
In summary, this study, as far as we know, is the first to
demonstrate the relationship between miR-499 polymorphism and BA
in Egyptian population. Our study showed that this polymorphism
might modify BA susceptibility and the condition after Kasai
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operation. In particular, some evidence of genotypes modifying liver
inflammation was observed in the analysis of clinicopathological
status.