Liver Fibrosis In Children Research Articles

Cytokeratin-18 and hyaluronic acid levels predict liver fibrosis in children with non-alcoholic fatty liver disease.

There is a need to replace liver biopsy with non-invasive markers that predict the degree of liver fibrosis in fatty liver disease related to obesity. Therefore, we studied four potential serum markers of liver fibrosis and compared them with histopathological findings in liver biopsy in children with non-alcoholic fatty liver disease (NAFLD). We determined fasting serum level of hyaluronic acid (HA), laminin, YKL-40 and cytokeratin-18 M30 in 52 children (age range 4-19, mean 12 years, 80 % of them were overweight or obese) with biopsy-verified NAFLD. Viral hepatitis, autoimmune and metabolic liver diseases (Wilson's disease, alpha-1-antitrypsin deficiency, cystic fibrosis) were excluded. Fibrosis stage was assessed in a blinded fashion by one pathologist according to Kleiner. Receiver operating characteristics (ROC) analysis was used to calculate the power of the assays to detect liver fibrosis (AccuROC, Canada). Liver fibrosis was diagnosed in 19 children (37 %). The levels of HA and CK18M30 were significantly higher in children with fibrosis compared to children without fibrosis (p=0.04 and 0.05 respectively). The ability of serum HA (cut-off 19.1 ng/ml, Se=84 %, Sp=55 %, PPV=52 %, NPV=86 %) and CK18M30 (cut-off 210 u/l, Se=79 %, Sp=60 %, PPV=56 %, NPV=82 %) to differentiate children with fibrosis from those without fibrosis was significant (AUC=0.672 and 0.666, respectively). The combination of both markers was superior (AUC=0.73, p=0.002). Laminin and YKL-40 levels did not allow a useful prediction. Cytokeratin-18 and hyaluronic acid are suitable serum markers predicting liver fibrosis in children with NAFLD. Studying these markers may identify patients at risk of disease progression.

Acoustic radiation force impulse-imaging in the assessment of liver fibrosis in children

Acoustic radiation force impulse-imaging (ARFI) uses sound waves to interrogate the mechanical stiffness of a tissue. To determine the usefulness of ARFI for estimating liver fibrosis in children. A prospective masked study of children with chronic liver disease (CLD) and/or before liver transplant (LT) comparing ARFI with histopathological analysis. Children with no history of liver disease served as a control group. ARFI was performed with Virtual Touch software using ACUSON S2000. Share wave velocities (SWV) of several regions within the liver were measured. Fifty-two children were studied (mean age 8 years; range 1-16 years). The abnormal group included 10 children (31%) with CLD and 22 (69%) planned for LT. There were 20 normal controls. Mean SWV was 1.42 m/s in the abnormal group and 1.11 m/s [corrected] in the controls. For diagnosis of fibrosis stage ≥ F1, ≥F2 and F4, the areas under the receiver-operator characteristics curves were 0.834, 0.818 and 0.983, respectively. SWV is related to the degree of liver fibrosis in children, and may be a non-invasive alternative to biopsy.

M1988 Noninvasive Markers of Liver Fibrosis in Children With Nonalcoholic Fatty Liver Disease (NAFLD)

M1988 Noninvasive Markers of Liver Fibrosis in Children With Nonalcoholic Fatty Liver Disease (NAFLD)

Antiviral treatment with interferon alpha and ribavirin influences serum markers of liver fibrosis in children with chronic hepatitis C

Antiviral treatment with interferon alpha and ribavirin influences serum markers of liver fibrosis in children with chronic hepatitis C

Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis

Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis

Prognostic value of computerized quantification of liver fibrosis in children with biliary atresia

Biliary atresia (BA) is the leading indication for liver transplantation (LTx) during childhood. Predictive markers for progression are lacking. We investigated the correlation between quantified fibrosis of the liver at the time of Kasai hepatic portoenterostomy (KPE) and the clinical course. Liver tissue was obtained at the time of KPE in 53 children and stained with Picrosirius red. The mean volume of fibrosis per number of periportal fields (Vfib) and the Ishak score were calculated. Vfib was 3.9%. Transplant-free survival was significantly higher in those patients with Vfib < 2.5% (P < 0.05, Kaplan-Meier analysis). Vfib < 2.5% predicted transplant-free survival with a sensitivity of 100% and a specificity of 48% (positive predictive value: 100%, negative predictive value: 17%). Vfib was correlated with bilirubin 6 months after KPE (Bili6m). The negative predictive value could be enhanced to 23% if Vfib < 2.5% was combined with Bili6m < 20 micromol/L. The Ishak score showed no correlation with transplant-free survival or Vfib. Detection of Vfib at the time of KPE is a valid marker in predicting transplant-free survival in children with BA. This method should be considered an integral part of scoring systems predicting the indication for LTx. Liver Transpl 15:876-882, 2009. (c) 2009 AASLD.

The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease

BackgroundLiver fibrosis is a stage of non-alcoholic fatty liver disease (NAFLD) which is responsible for liver-related morbidity and mortality in adults. Accordingly, the search for non-invasive markers of liver fibrosis has been the subject of intensive efforts in adults with NAFLD. Here, we developed a simple algorithm for the prediction of liver fibrosis in children with NAFLD followed at a tertiary care center.MethodsThe study included 136 male and 67 female children with NAFLD aged 3.3 to 18.0 years; 141 (69%) of them had fibrosis at liver biopsy. On the basis of biological plausibility, readily availability and evidence from adult studies, we evaluated the following potential predictors of liver fibrosis at bootstrapped stepwise logistic regression: gender, age, body mass index, waist circumference, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase, albumin, prothrombin time, glucose, insulin, triglycerides and cholesterol. A final model was developed using bootstrapped logistic regression with bias-correction. We used this model to develop the 'pediatric NAFLD fibrosis index' (PNFI), which varies between 0 and 10.ResultsThe final model was based on age, waist circumference and triglycerides and had a area under the receiver operating characteristic curve of 0.85 (95% bootstrapped confidence interval (CI) with bias correction 0.80 to 0.90) for the prediction of liver fibrosis. A PNFI ≥ 9 (positive likelihood ratio = 28.6, 95% CI 4.0 to 201.0; positive predictive value = 98.5, 95% CI 91.8 to 100.0) could be used to rule in liver fibrosis without performing liver biopsy.ConclusionPNFI may help clinicians to predict liver fibrosis in children with NAFLD, but external validation is needed before it can be employed for this purpose.

Performance of ELF Serum Markers in Predicting Fibrosis Stage in Pediatric Non-Alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in children and adolescents in industrialized countries. It is important to accurately determine the stage of fibrosis in these patients. The enhanced liver fibrosis (ELF) test has been validated for staging liver fibrosis in adult patients with chronic liver diseases, including NAFLD. We investigated the performance of this test in assessing liver fibrosis in children and adolescents with NAFLD, identified by biopsy. The ELF test was performed on a panel of serum samples collected from 112 consecutive subjects that were likely to have NAFLD (64 male, mean age of 13.8+/-3.3). A previously described and validated algorithm was used to analyze the data on hyaluronic acid (HA), amino-terminal propeptide of type III collagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels. In pediatric patients with NAFLD, the ELF test predicted liver fibrosis stage with a high degree of sensitivity and specificity; results were superior to those reported for adults. The area under receiver operating characteristic curves/best possible ELF test cut-off values for the prediction of "any" (>or= stage 1), moderate-perisinusoidal (>or= stage 1b), moderate-portal/periportal (>or= stage 1c), significant (>or= stage 2), or advanced (>or= stage 3) fibrosis were 0.92/9.28, 0.92/9.33, 0.90/9.54, 0.98/10.18 and 0.99/10.51, respectively. The ELF test can be used to accurately assess the level of liver fibrosis in pediatric patients with NAFLD. This information is important for identifying patients with progressive fibrosis that require further histopathological analysis or therapeutic follow-up.

Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis

Objective:Waist circumference is widely accepted as a risk factor for cardiovascular disease and metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) is a feature of the metabolic syndrome. A contribution of...

Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease

Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children. In 72 biopsy-proven NAFLD children (aged 9-18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R; IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp); glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients. Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 +/- 1.39 and 4.4 +/- 2. NASH was diagnosed in 38 and simple steatosis in 25 children; diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 41 patients. Median NAFLD activity (NAS) score was 3.42 +/- 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 +/- 6.3 in score 1 to 17.4 +/- 6.9 in score 2 (P = 0.01) and 22.2 +/- 6.8 ng/ml in score 3 (P < 0.001); FLI 2.56 +/- 1.40, 3.57 +/- 0.34, 4.45 +/- 0.64 respectively (P = 0.05)); ballooning (from 13.7 +/- 6.7 in score 1 to 17 +/- 7.5 in score 2 (P = 0.001) and 22.1 +/- 7.1 ng/ml in score 3 (P = 0.01); FLI 2.81 +/- 1.50, 3.40 +/- 1.65, 4.57 +/- 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 +/- 7 to18.3 +/- 6.9; P = 0.03; FLI 3.03 +/- 1.57 vs 3.92 +/- 077; P < 0.05) and NAS score (score 1-2: 12.9 +/- 6.9; score 3-4: 17 +/- 6.9 (P = 0.01); score 5-7: 22.9 +/- 7.5 ng/ml (P = 0.03); FLI 2.70 +/- 1.53, 3.12 +/- 1.53, 4.58 +/- 1.57 P = 0.01 and P = 0.05 between 1-2 vs 3-4 and 3-4 vs 5-7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r(0) = 0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r(0) = 0.4, P < 0.0001), steatosis (r(0) = 0.5, P < 0.0001) and NAS score (r(0) = 0.5, P < 0.0001). Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.

Matrix-derived serum markers in monitoring liver fibrosis in children with chronic hepatitis B treated with interferon alpha

To evaluate prospectively 4 selected serum fibrosis markers (tenascin, hyaluronan, collagen VI, TIMP-1) before, during and 12 mo after IFN treatment of children with chronic hepatitis B. Forty-seven consecutive patients with chronic hepatitis B (range 4-16 years, mean 8 years) underwent IFN treatment (3 MU tiw for 20 wk). Fibrosis stage and inflammation grade were assessed in a blinded fashion before and 12 mo after end of treatment. Serum fibrosis markers were determined using automated assays. IFN treatment improved histological inflammation but did not change fibrosis in the whole group or in subgroups. Only hyaluronan correlated significantly with histological fibrosis(r = 0.3383, P = 0.021). Basal fibrosis markers did not differ between responders (42.5%) and nonresponders(57.5%). During IFN treatment only serum tenascin decreased significantly in the whole group and in nonresponders. When pretreatment values were compared to values 12 mo after therapy, TIMP-1 increased in all patients and in nonresponders, and hyaluronan decreased in all patients and in responders. Tenascin reflects hepatic fibrogenesis and inflammation which decreases during IFN treatment of children with chronic hepatitis B. TIMP-1 correlates with nonresponse and hyaluronan with histological fibrosis.

Serum fibrosis markers as predictors of an antifibrotic effect of interferon alfa in children with chronic hepatitis B

Interferon alfa (IFN-alpha) may retard hepatic fibrogenesis in adults with chronic hepatitis C. We evaluated prospectively four selected serum fibrosis markers before, immediately after and 12 months after IFN treatment of children with chronic hepatitis B (CHB). Forty-seven children (mean age 8 years, range 4-16) with CHB underwent IFN-alpha treatment (3 MU t.i.w.) for 5 months. Fibrosis and inflammation were assessed blindly before and 12 months after the end of treatment. Serum laminin-2, collagen IV, MMP-2 and MMP-9/TIMP-1 complex were determined using automated assays. Twelve months after treatment had been discontinued levels of laminin-2, collagen IV and MMP-2 were decreased, and serum MMP-9/TIMP-1 complex was increased. Levels did not differ between sustained responders (42.5%) and non-responders. Similarly, fibrosis did not progress in both groups, whereas histological inflammation improved only in responders. A 5 month IFN-alpha treatment has no marked effect on histological liver fibrosis in children with CHB, irrespective of virological response. The evolution of serum fibrosis markers suggests they may be more sensitive to detect minor antifibrotic effects than semiquantitative follow-up histology.

A simple noninvasive index (APRI) predicts advanced liver fibrosis in children with chronic hepatitis B†

A simple noninvasive index (APRI) predicts advanced liver fibrosis in children with chronic hepatitis B†

Diagnostic accuracy of serum biochemical fibrosis markers in children with chronic hepatitis B evaluated by receiver operating characteristics analysis

To investigate the diagnostic accuracy of potent serum biochemical fibrosis markers in children with chronic hepatitis B evaluated by receiver operating characteristics (ROC) analysis. We determined the serum level of apolipoprotein A-I (APO A-I), haptoglobin (HPT) and a-2 macroglobulin (A2M) with an automatic nephelometer in 63 children (age range 4-17 years, mean 10 years) with biopsy-verified chronic HBeAg-positive hepatitis B. Fibrosis stage and inflammation grade were assessed in a blinded fashion according to Batts and Ludwig. We defined mild liver fibrosis as a score < or =2 and advanced fibrosis as a score equal to 3. ROC analysis was used to calculate the power of the assays to detect advanced liver fibrosis (AccuROC, Canada). Serum concentrations of APO A-I, HPT and A2M were not significantly different in patients with chronic hepatitis B compared to controls. However, APO A-I level of 1.19 ng/L had a sensitivity of 85.7% and a specificity of 60.7% (AUC = 0.7117, P = 0.035) to predict advanced fibrosis. All other serum biochemical markers and their combination did not allow a useful prediction. None of these markers was a good predictor of histologic inflammation. Apolipoprotein A-I may be a suitable serum marker to predict advanced liver fibrosis in children with chronic hepatitis B.

Serum laminin-2 and hyaluronan predict advanced liver fibrosis in children with chronic hepatitis B

Serum laminin-2 and hyaluronan predict advanced liver fibrosis in children with chronic hepatitis B

SERUM PROCOLLAGEN III PEPTIDE IS ELEVATED IN ADOLESCENTS WITH CHRONIC HEPATITIS C COMPARED TO HEALTHY CONTROLS

106 Serum procollagen III peptide (sPIIIP) is a precursor of collagen III, one of the main components of connective tissue in the liver. Increased sPIIIP has been found in adults with liver fibrosis, cirrhosis and chronic viral hepatitis. However, previous studies in healthy children showed that collagen III and sPIIIP are normally elevated due to active somatic growth, which renders the marker non-helpful in the detection of active liver disease in children. The purpose of the study was to examine whether sPIIIP may be used as noninvasive marker of liver fibrosis in children with hepatitis C virus (HCV) infection. Methods: 39 anti-HCV+ (EIA-2) patients (ages 10.8± 0.9, range 0.5-23y) had sPIIIP (RIA-gnost®, Boehring, Germany), alanine aminotransferase (ALT) and histology activity index (HAI) scores according to Knodell criteria. Sera of healthy patients with ages (1-30y) were analyzed for sPIIIP and ALT. Both groups were stratified for age as follows: (Table) Eventhough patients >16 years had increased sPIIIP, there was no correlation between sPIIIP, HAI, fibrosis or ALT. However, sPIIIP was elevated in 3 patients with liver fibrosis and near normal ALT. Conclusions: In HCV+ adolescents > 16 years, sPIIIP was significantly elevated compared to controls. In 3/8 adolescents sPIIIP predicted liver injury better than ALT. Therefore, sPIIIP may be useful as a number of liver fibrosis in children if age-related controls are used.TABLE

Mechanisms of hepatic fibrosis.

Mechanisms of hepatic fibrosis.