Summary
Liver disease in pediatrics is one of the most significant causes of morbidity and mortality in this age group and includes a broad spectrum of disorders such as infections developmental abnormalities , metabolic and neoplastic disorders that finally result in hepatic dysfunction and cirrhosis.
Detection and quantification of hepatic fibrosis represents a long standing challenge in hepatology. Currently, accurate assessment of liver fibrosis has become increasingly important in order to make therapeutic decisions, determine prognosis and to follow-up disease progression
Liver biopsy is considered as the gold standard for the evaluation of liver fibrosis .Sampling error, interobserver variability, invasiveness, and potential complications are the main limitations of liver biopsy, therefore there is a need for validation of non-invasive alternatives to liver biopsy for the evaluation of fibrosis in children with chronic liver diseases.
The serum biomarkers include both direct and indirect markers.In-direct markers can be identified in routine blood tests and indicate alterations in liver function . Such markers include the aspartate transaminase-to-platelets ratio index (APRI) and the Fibrosis-4 index (FIB-4), which have been validated to predict significant fibrosis and cirrhosis in adult patients with chronic HCV infection . Simple serum biomarkers are widely available, inexpensive, and easy to calculate and therefore provide a desirable alternative to liver biopsy.
The aim of this study was to analyze the diagnostic performance of non-invasive serum biomarkers of fibrosis (APRI and FIB-4) compared with liver biopsy for evaluation of fibrosis in children with chronic liver disease. Also, the diagnostic performance of these biomarkers when modified by BMI z-score(M-APRI, MFIB-4 , B-AST) Our study was a retrospective study carried on 100 children suffering from chronic liver diseases of different etiologies, aged from 2 months to 13 years with mean age (46.4±37.7 months). They were 46 males (46%) and 54 (54%) females. Their diagnosis based on clinical , laboratory and histopathological examination.
Methods :-
All patients were subjected to full history taking ,physical examination and laboratory investigations in form of (CBC- complete liver functions {ALT,AST, serum bilirubin total and direct ,GGT, Alkaline phosphatase , serum albumin and total protein }- hepatitis markers )
The non-invasive serum biomarker analysis included APRI and FIB-4, M-APRI, M-FIB-4 and B-AST which were calculated according to the published analytic recommendations as follow
APRI = [(AST/ (ULN) / platelets count (109/L)] ×100
FIB-4 = (age (yr) × AST) / [(platelets count (109/L) ×√ALT (U/L)]
M-APRI = APRI × BMI- z score
M-FIB-4 = FIB-4× BMI- z score
B-AST = B-AST × BMI- z score
The age used in formula was the age of the patient at the time of liver biopsy
Results:-
In the current study it is showed that viral hepatitis represents 28 % of cases (HCV 21% ,HBV 7%) , metabolic liver diseases represents 19% of cases (glycogen storage disease 15% , Wilson disease 2%, Niemann Pick disease 1%, alpha 1 antitrypsin 1%), chronic hepatitis represents 46% of cases ( autoimmune hepatitis 15%,chronic hepatitis for differential diagnosis 13%, steatohepatitis 8%, idiopathic neonatal hepatitis 10%), neonatal cholestasis disorders represents 5 % and congenital hepatic fibrosis represent 2 % in our study.
The most clinical presentation of hepatic group was abdominal distension 62% followed by jaundice 46% and pallor 41% ,LL edema was seen in 4% and ascites in 3% of cases ,and pallor 41%. M±SD of duration of liver disease was 7.1±3.2 ,m±SD of liver span was 11.7±2.6 and of spleen span was 9.4±2.3, with 64 % had hepatomegally and 16 % had splenomegally .m±SD of weight was 15.2±7.9 ,m±SD of height was 91.4±22.4 ,m±SD of BMI was 17.3±6.3 and m±SD of BMI Z score was 0.13±1.9
Liver function testes of hepatic group showed that AST was elevated by 32 fold above upper limit of normal ,ALT was elevated by 36 fold above upper limit of normal,ALP was elevated by 9 fold above normal limit of normal, GGT was elevated 15 fold above normal limit of normal , total bilirubin is elevated 21 fold above upper limit of normal, direct bilirubin elevated 35 fold above upper limit of normal , PT was elevated 2 fold above upper limit of normal ,PTT was elevated 1 fold above upper limit of normal , INR was elevated 3 fold above normal level
Hepatitis A virus antibodies were negative in 100% of cases ,Hepatitis B virus antibodies were positive in 7% of cases , Hepatitis c virus was positive in 21% of cases ,AMA and ALKI were negative in 100% of cases , ASMA were positive in 15% of cases and ANA were positive in 3% of cases
Our study showed that the most common cells were lymphocytes 75 % followed by mononuclear cells 25%, the most common change in hepatocytes was hydropic swelling 55% followed by rarified cytoplasm 15% , intracellular cholestasis 15% then macrovesicular fatty infiltration 8%,copper overload 6% and Periportal fibrosis 1%.
In the current study it is showed that 62% of hepatic group had minimal hepatitis activity index, 31% had mild hepatitis activity index, 4% had moderate hepatitis activity index and 3% had severe hepaitis index activity . the fibrosis stage was minimal in 22% of hepatic group ,mild in 41%of hepatic group , moderate in 28% of hepatic group and severe in 9% of hepatic group.
The mean±SD of five markers were APRI score(1.61±2.4),FIB-4 index(0.04±0.10),M-APRI (0.31±0.32),M-FIB-4(0.065±0.45),B- AST,(-22.5±268.6)
There was statistical significant difference between APRI score and fibrosis stages as increase in stage of fibrosis associated with increase mean ±SD of APRI score. As mean ±SD of APRI score increase from f 0 (0.47±0.50) to f 6 (8.10±50.9)
There was statistical significant difference between FIB-4 score and fibrosis stages as increase in stage of fibrosis associated with increase mean ±SD of FIB-4 score as mean±SD of FIB-4 score increase from(0.007±0.010 )in F0 cases to (0.144±0.079) in F6
there was statistical significant difference betweenM- APRI score and fibrosis stages ss increase in stage of fibrosis associated with increase mean ±SD of M- APRI score,as mean ±SD of M- APRI score increase from (-2.02±2.78) in F0 to (4.70 ±1.69) in F6
There was statistical significant difference betweenM- FIB4 score and fibrosis stages As increase in stage of fibrosis associated with increase mean ±SD of M- FIB4 score,as mean ±SD of M- FIB-4 increase from (-0.011±0.027) in f 0 to (0.55±0.070) in f 6
There was statistical significant difference between B-AST score and fibrosis stages As increase in stage of fibrosis associated with increase mean ±SD of B-AST score,as mean ±SD of B-AST increase from (-212.4±368.8) in F0 to (92.60±58.2) in F6
There was positive correlation between APRI and weight,height, bilirubin (total&direct), liver function tests (AST, ALT,ALP, GGT,PT, INR) ,HAI and fibrosis stage. However there was negative correlation between APRI and platelets.
There was positive correlation between FIB-4 and age of the patients , age of onset of liver disease ,weight ,height ,BMI, liver span ,spleen span ,liver function tests (ALP,PTT) ,HAI and fibrosis stage.However there was negative correlation between FIB-4 and WBCs and platelets .
This table shows that there was positive correlation between M APRI and age of the patients, age of onset of liver disease weight ,BMI , BMI Z score,liver span , spleen span ,bilirubin( total) ,HAI and fibrosis stage.However there was negative correlation between M APRI and platelets
There was positive correlation between M FIB-4 index and age of the patients ,age of onset of liver disease ,weight ,BMI , BMI Z score, liver span ,spleen span ,HAI and fibrosis stage.However there was negative correlation between M FIB-4 and platelets
There was positive correlation between B-AST and age of onset of liver disease ,weight ,BMI,BMI z score, liver span , spleen span ,bilirubin( total ),liver function tests (AST) ,HAI and fibrosis stage.
The best cut off values for non- invasive markers in diagnosis of any significant fibrosis stage Are > 0.97 for APRI, >0.15 for M-APRI, >0.018 for FIB-4 ,>0.004 for M-FIB-4 and >-9 for AST with the corresponding AUROCs were below 0.8 for all tests.
The best cutoff values of non-invasive markers ( APRI, M-APRI ,FIB-4 ,M-FIB-4 and B-AST ) in diagnosis of severe fibrosis were (>1.95 ,>2.1,0.046 ,>0.016 ,>91.5) with their corresponding AUC (0.839,0.968,0.833,0.894 ,0.935 ) respectively .
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