الفهرس 
CholestasisOnly 14 pages are availabe for public view
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Abstract
Progressive familial intrahepatic cholestasis (PFIC) refers to heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin often present in the neonatal period or first year of life.
Three types of PFIC have been identified and related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 are caused by impaired bile salt secretion due to respectively defects in ATP8B1 (chromosome 18q21-22) encoding the FIC1 protein, and in ABCB11 (chromosome 2q24), encoding the bile salt export pump protein (BSEP).
Main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients.
Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 or PFIC2 patients, biliary diversion can also relieve pruritus and slow disease progression
Liver transplant is the most effective form of treatment for PFIC patients with progressive disease or established cirrhosis, usually within the first decade.
The aim of this study was to study the genotypic and phenotypic characteristics of children with progressive familial intrahepatic cholestasis types 1 and 2.
Our study was conducted on 42 patients who presented with direct hyperbilirubinemia, increased serum bile acid level and low GGT. They were provisionally diagnosed as PFIC 1 or 2.
The children were referred to the pediatric hepatology clinic of Dr. Yassin Abd El-Ghaffar charity Centre for Liver diseases and Research and Children′s hospital, Ain shams university where the patients were investigated, diagnosed and followed up.
The results of our study revealed that: 30 patients (71.4%) have consanguineous parents and 10 patients (23.8%) have positive family history of a similar clinical condition.
Male to female ratio was 1.1:1 which almost the same as in the normal population is. This indicates that both sexes are equally affected and confirms the autosomal recessive mode of inheritance.
The first signs of cholestasis appeared early in infancy (mean age of presentation was 4.5months with a range from 1month to 12months) or early childhood with no difference between PFIC1 and 2. The main complaints in these patients were jaundice and itching as observed by parents.
No clear-cut differences in jaundice evolution pattern were seen between PFIC1 and PFIC2 patients or in the development of pruritis. Nine patients in our study (21.4%) had a history of diarrhea and steatorrhea, (2 PFIC1 patients, 2 PFIC2 patients and 5 non-tested patients).
All patients in this study presented with jaundice due to increase serum level of direct bilirubin or pruritis which is due to high level of serum bile acids.
Portal hypertension evidenced by splenomegaly was present in 4/4 (100.0%) patients with PFIC2 compared to 11/15 (73.3%) patients with PFIC1.
During follow up portal fibrosis confirmed by liver biopsy was reported only in 7/9 (77.7%) in patients with PFIC1 who did liver biopsy. On the other hand, liver pathology showed preserved architecture in all 3 patients of PFIC2 who did liver biopsy
Gall bladder stones evidenced by abdominal ultrasound U/S were present in one PFIC1 patient (6.7%) and 2 PFIC2 patients (50.0%).
HCC was present in one patient (not tested) while hepatoblastoma in another patient with PFIC1.
Mutational analysis of ATP8B1 and ABCB11 genes was done for 22 patients of where only 19 showed mutation while 5 did not.
All patients in our study once diagnosed received UDCA at daily dose ranging from 15-30 mg / kg / day and its efficacy was evaluated in each group.
It has been suggested that UDCA therapy is efficient in the management of children with PFIC. Although this therapy is palliative, it may obviate or delay the need for liver transplantation. The results of our study showed that prolonged oral administration of UDCA is safe and apparently lead to biochemical improvement in a fair proportion of children with PFIC, as the mean value of ALT before therapy was 146 and decreased to 34.75 after therapy.
In our study 11 patients (57.9%) had homozygous mutation (8 PFIC1 patients and 3 PFIC2 patients) and 7 patients (36.8%) had only one allele mutated.
In patients with homozygous mutation, 8 patients (72.7%) have consanguineous parents and 5 patients (45.5%) had positive family history of similar clinical condition. While in patients who have only one mutation 5 patients (71.4%) have consanguineous parents and 4 patients (57.1%) have positive family history of similar clinical condition.
There was no difference between patients with homozygous and heterozygous mutation regarding onset of disease, liver function or complications.
All mutations were point mutations except 5 which were truncating mutations. There was no difference between them regarding onset of disease, liver function or complications.