الفهرس 
Chronic Liver Diseases in ChildrenOnly 14 pages are availabe for public view
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Abstract
Most forms of chronic liver disease are associated with the development of liver fibrosis, where the rate of degradation of extracellular matrix proteins may be low relative to the increased rate of synthesis.
Liver injury and regeneration have both been linked to complex extracellular matrix (ECM) related pathways. While normal degradation of ECM components is an important feature of tissue repair and remodeling, irregular ECM turnover contributes to a variety of liver diseases. Matrix metalloproteinases (MMPs) are the main enzymes implicated in ECM degradation. MMPs not only remodel the ECM, but also regulate immune responses.
This study aimed to evaluate diagnostic value of MMP-1 in children with chronic liver diseases.
This case-control study was carried out on 120 children suffering from chronic liver diseases of different etiologies, and 60 healthy children matched age and sex were taken as a control group.
All children were subjected to full history taking, complete clinical examination, abdominal US, and laboratory investigations as complete blood count (CBC), and liver function tests (Alt, AST, Albumin, PT, PTT, INR, Total and direct bilirubin), Liver biopsy was performed for all cases, and Serum MMP-1 antigen levels were measured using human enzyme-linked immunosorbent assay (ELISA).
Results:
• The mean age of the hepatic group was 11.1±5.3 years, and included 70 males and 50 females. The mean age in the control group was 10.3±4.4 years, and included 29 males and 31 females. There was no statistical difference between hepatic and control groups regarding age, or sex.
• The most frequent diagnosis was autoimmune hepatitis in 29 patients (24.2%), metabolic liver diseases in 31 patients (25.8%) {21 patients (17.5%) had glycogen storage disease, 5 patients (4.1%) had Wilson disease, 3 patients (2.5%) had Neiman pick disease, 2 patients (1.7%) had tyrosinemia}, 23 patients (19.1%) had viral hepatitis { 18 patients (15%) had HCV, and 5 patients (4.1%) had HBV}, 17 patients (14.1%) had cholestasis {14 patients (11.7%) had biliary atresia, and 3 patients (2.5%) had familial intrahepatic cholestasis }, 9 patients (7.5%) had congenital hepatic fibrosis, and 11 patients (9.2%) had chronic hepatitis for differential diagnosis.
• There was statistical significant difference between studied groups regarding anthropometric measures, as weight, height and BMI were statistically lower in hepatic group than control group (p<0.001, for each).
• There was statistical significant difference between studied groups regarding Hb and PLT as they were lower in hepatic group, while liver function tests (ALT, AST, PT, PTT, INR, Total and direct bilirubin) were higher in hepatic group. However there was no statistical difference between studied groups regarding WBCs and albumin.
• Regarding to histological parameters, the degree of fibrosis was 67 patients (55.8%) had F1, 27 patients (22.5%) had F2, 10 patients (8.3%) had F3 and 16 patients (13.3%) had F4.
• Regards histological activity index (HAI); most cases 62 patients, (51.7%) had A1 score, 31 patients (25.8%) had A2 score, and 27 patients (22.5%) had A3 score.
• Biopsy showed that; 30 patients (25%) had mosaic like appearance, 29 patients (24.1%) had interface hepatitis, 19 patients (15.9%) had apoptotic cells in liver biopsy, 19 patients (15.9%) had hydropic swelling no steatosis, 6 patients (5%) had regular hepatocytes, 6 patients (5%) had distended mononuclear phagocytic cells, 6 patients (5%) had hepatocytes showed diffuse hydropic and ballooning degeneration, and 5 patients (4.1%) had mononuclear inflammatory cells.
• Regarding to different causes of liver disease and the degree of fibrosis; as most cases of autoimmune hepatitis (25/29), HBV (4/5), HCV (15/18), and glycogen storage disease (16/21) was F1 degree. In contrast to patients with Wilson disease, Tyrosenemia, Neiman pick, and cases with chronic hepatitis for differential diagnosis; most cases was F3 and F4 degree. Regarding patients with biliary atresia (n=14); 2 patients had F1 degree, 6 patients had F2 degree, 4 patients had F3 degree, and 2 patients had F4 degree. Regarding patients with congenital hepatic fibrosis (n=9); 3 patients had F1 degree, 3 patients had F2 degree, and 3 patients had F3 degree.
• Regarding Child-Pugh score;most patients (104 patients, 56.7%) had score A, 11 patients (9.2%) had score B, and 5 patients (4.2%) had score C. The mean PELD Score was 13.9±9.3, and the mean MELD Score was 12±3.1.
• AST to Platelet Ratio Index (APRI) score, and Fibrosis-4 (FIB-4 score), where used as a non-invasive biomarkers for assessment of liver fibrosis in hepatic group the mean APRI score was 1.1±0.85, and the mean FIB4 score was 0.53±0.54in hepatic group.
• There was statistical difference between different degrees of fibrosis as regarding to APRI score and FIB-4 score; as both scores increased gradually with the increasing degree of fibrosis.
• The mean MMP-1 was 15.2±5.1ng/ml in hepatic group, and 64.7±27.4ng/ml in control group. MMP-1 was statistically lower in the hepatic group that controls.
• There was a significant positive correlation between MMP-1and (hemoglobin, WBCs, and platelets), while there was a significant negative correlation between MMP-1 and (ALT, AST, PT, PTT, INR, albumin, PELD score,MELD score, APRI score, FIB-4 score, and CHILD-PUGH score), while there was no statistical significant correlation between MMP-1 and age, anthropometric measures, or US parameters.
• MMP-1 level was significantly lower in patients who had hepatomegaly, splenomegaly, or ascites than who didn’t (p=0.031, p=0.018, and p<0.001, respectively).
• MMP-1 level decreased significantly with increasing the degree of fibrosis, the mean MMP-1 in F1 was 19.2±1.5, in F2= 13.1±0.7, in F3= 8.8±0.4, and in F4=6.2±0.5 ng/ml, p<0.001.MMP-1 level decreased significantly with increasing HAI, the mean MMP-1 in A1 score was 18.3±2, in A2 score = 14.4±5.3, and in A3 score =9±3.5 ng/ml, p<0.001.
• MMP-1 level decreased significantly with increasing the degree of severity of liver disease, the mean MMP-1 in score A was 16.3±4.4, in score B= 8.8±3.5, and in score C=7±0.8 ng/ml, p<0.001.
• ROC analysis was done to assess the performance of MMP-1 to detect liver fibrosis (>F1); AUC was 0.972 (95% confidence interval: 0.909-0.987), p<0.001. At a cutoff point < 21.3 ng/ml, the sensitivity was 95% and specificity was 95%. ROC analysis was done to assess the performance of MMP-1 to detect sever liver fibrosis (>F3); AUC was 1, p<0.001. At a cutoff point < 10.5 ng/ml, the sensitivity was 100% and specificity was 100%.
• ROC analysis was done to assess the performance of APRI and FIB-4 to detect liver fibrosis (>F1); Regarding APRI score; AUC was 0.945 (95% confidence interval: 0.908-0.982), p<0.001. At a cutoff point > 0.37, the sensitivity was 95.8% and specificity was 95%. Regarding FIB-4 score; AUC was 0.911 (95% confidence interval: 0.867-0.956), p<0.001. At a cutoff point > 0.125, the sensitivity was 90.1% and specificity was 91.7%. Then ROC analysis was done to assess the performance of APRI and FIB-4 to detect sever liver fibrosis (>F3); regarding APR; AUC was 0.975 (95% confidence interval: 0.952-0.998), p<0.001. At a cutoff point > 1.44, the sensitivity was 100% and specificity was 89.7%. Regarding FIB-4; AUC was 0.939 (95% confidence interval: 0.890-0.981), p<0.001. At a cutoff point > 0.44, the sensitivity was 100% and specificity was 75.6%.
• Logistic regression analysis was conducted for prediction of liver fibrosis, using age, gender, BMI, CBC, liver function tests and MMP-1 as covariates. Higher ALT, AST, PT, PTT, INR and lower platelets and MMP-1 were associated with risk of liver fibrosis occurrence in univariable analysis. However, taking significant covariates into multivariable analysis revealed that only higher levels of PT and INR, and lower levels of platelets and MMP-1 was considered as predictor for liver fibrosis development.
Conclusion:
Our study findings demonstrate that MMP-1 would be useful for detection of fibrosis in children with chronic liver diseases. MMP-1 was statistically lower in the hepatic group that controls, p<0.001.
Recommendation:
MMP-1 could be used as a noninvasive marker of fibrosis pediatric patients. Which could help to guide clinicians in whom to treat, and serve as a longitudinal marker of treatment efficacy without the need for repeated liver biopsies.