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Background & Aims: We examined the diagnostic performance of plasma N‐terminal propeptide of type III procollagen (PIIINP) levels, aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis‐4 (FIB‐4) score for predicting non‐alcoholic steatohepatitis (NASH) and liver fibrosis stage in children/adolescents with non‐alcoholic fatty liver disease (NAFLD). Methods: We enrolled 204 children/adolescents with biopsy‐proven NAFLD at the "Bambino Gesù" Children's Hospital. We measured plasma PIIINP levels using a commercially available enzyme‐linked immunosorbent assay kit and calculated APRI and FIB‐4 scores using standard methods. Results: Children with NASH had higher plasma PIIINP levels, APRI and FIB‐4 scores compared with those without NASH (all P < .001). However, PIIINP levels had much better diagnostic performance and accuracy than APRI and FIB‐4 scores for predicting liver fibrosis stage. PIIINP levels correlated with the total NAFLD activity score (NAS) and its constituent components (P < .0001). The risk of either NASH or F ≥ 2 fibrosis progressively increased with increasing PIIINP levels (P < .0001), independent of age, gender, adiposity measures, insulin resistance, NAS score and the patatin‐like phospholipase domain‐containing protein‐3 rs738409 polymorphism. For every 3.6 ng/mL increase in PIIINP levels, the likelihood of having F ≥ 2 fibrosis increased by ~14‐fold (adjusted‐odds ratio 14.1, 95% CI 5.50‐35.8, P < .0001) after adjustment for the aforementioned risk factors. The area under the receiver operating characteristics curve was 0.921 (95% CI 0.87‐0.97) for F ≥ 2 fibrosis, and 0.993 (95% CI 0.98‐1.0) for F3 fibrosis respectively. Conclusions: Unlike APRI and FIB‐4 scores, plasma PIIINP levels are a promising, non‐invasive biomarker for diagnosing liver fibrosis stage in children/adolescents with biopsy‐proven NAFLD. [ABSTRACT FROM AUTHOR]

Background & Aims: It is uncertain whether non‐alcoholic steatohepatitis (NASH) is a risk factor for low bone mineral density (BMD). Our aim was to investigate: (a) associations between NASH and BMD values and (b) associations between PNPLA3 I148M genotypes and BMD, in children with histologically proven non‐alcoholic fatty liver disease (NAFLD). Methods: BMD area (g/cm2) was measured using dual‐energy X‐ray absorptiometry (DEXA). NASH was diagnosed by a Steatosis, Activity and Fibrosis (SAF) score and FLIP algorithm. Genotyping for patatin‐like phospholipase domain containing‐3 (PNPLA3) I148M genotype (rs738409) (CC, CG and GG) was undertaken using the TaqMan SNP genotyping allelic discrimination method. Logistic regression was used to test associations [OR (95% CIs)] between low BMD, and both NASH and PNPLA3 I148M genotypes. Results: Thirty‐four adolescents (mean age 13.8 ± 1.1 years) with histologically confirmed NAFLD were studied. Subjects with NASH (n = 25) had a lower BMD (means (SDs) 0.87 ± 0.06 vs 0.97 ± 0.12, P = 0.005), compared to subjects without NASH. Subjects with PNPLA3 CG+GG genotypes had a lower BMD compared with subjects with PNPLA3‐CC genotype (means (SDs) 0.79 ± 0.20 vs 0.92 ± 0.10, P = 0.009). PNPLA3 CG+GG genotypes were independently associated with NASH [OR (95% CIs 1.78, 1.24, 2.99)], and low BMD was associated with both PNPLA3 CG+GG (OR 3.62 (95% CIs 1.21, 5.53), P = 0.028) and with SAF score (OR 2.76 (95% CIs 1.12, 5.41), P = 0.045). Conclusions: Taken together the independent associations between: (a) low BMD and PNPLA3 CG+GG genotype; (b) low BMD and NASH; and (c) PNPLA3 CG+GG genotype and NASH, provide support for a causal relationship between NASH and low BMD. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: As dietary components are delivered directly to the periportal zone of the liver lobule, there is the potential for greater injury in this zone (zone 1) compared to the perivenous zone (zone 3). We investigated the associations between dietary fructose consumption and uric acid concentrations and differential zonal injury in periportal and perivenous zones. Methods: A total of 271 children's histological images were scored in 5 periportal and 5 perivenous zones for steatosis, ballooning, inflammation and fibrosis severity. Dietary fructose consumption (g/d) was assessed and uric acid measured in serum. Logistic regression was undertaken to test associations between both high fructose consumption and hyperuricaemia, and histological disease in periportal and perivenous zones. Results: Children with a mean age of 12.5 years were included in the study. Inflammation (mean ± SD) was increased in the periportal vs perivenous zones (0.78 ± 0.43 vs 0.41 ± 0.48, P = .041). There were non‐significant trends towards greater steatosis, ballooning and fibrosis in the periportal zone. In the fully adjusted models, high fructose intake was associated with disease in both zones. Example for periportal and perivenous zones, respectively, steatosis 1.56 (1.12, 2.49) and 1.21 (1.09, 2.73); inflammation 4.29 (2.31, 5.88) and 3.69 (2.14, 4.56); and fibrosis 2.72 (1.43, 3.76) and 1.96 (1.24, 2.37). Hyperuricaemia (uric acid ≥5.9 mg/dL) was associated with inflammation in the periportal zone 1.71 (1.17, 2.35); and was associated with steatosis and fibrosis in both zones; for example, for periportal and perivenous zones, respectively, steatosis 2.98 (1.65, 3.23) and 1.14 (1.05, 1.99); and fibrosis, 2.65 (1.35, 2.99) and 1.31 (1.13, 2.17). Conclusions: High fructose consumption is associated with disease severity in both lobular zones and hyperuricaemia may be associated with more severe disease in the periportal zone. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Treatment with the farnesoid X receptor (FXR) agonist obeticholic acid is ineffective in some patients with non‐alcoholic steatohepatitis (NASH) but the explanation is uncertain. We investigated hepatic FXR expression, and measurements of fibroblast growth factor 19 (FGF19) and bile acids (BAs) in children with NAFLD to investigate relationships with NASH. Methods: 33 children with NAFLD who underwent diagnostic liver biopsy were studied. Hepatic FXR protein levels and circulating FGF19 concentrations were compared with those analysed in five control subjects with proven normal liver histology. NASH was defined by the Paediatric NAFLD Histological Score (PNHS). Binary logistic regression with adjustment for covariates and potential confounders was undertaken to test factors independently associated with: a) NASH and b) hepatic FXR protein levels. Results: Mean ± SD age was 13.7 ± 1.9 years. Nineteen patients had NASH (PNHS ≥ 85) and 14 did not have NASH (PNHS < 85). Hepatic FXR level and plasma FGF19 concentration varied ~10‐fold and 5‐fold, respectively, between groups, and was highest in control subjects, intermediate in NAFLD without NASH, and lowest in NASH (between group differences P < .001 and P < .01 respectively). NASH was independently associated with both FXR protein levels (OR = 0.18, 95% CI 0.09, 0.38) and FGF19 concentration (OR = 0.55, 95% CI 0.20, 0.89). Conclusions: FXR protein levels vary markedly between normal liver, NAFLD without NASH, and NASH. Low levels of FXR are independently associated with NASH. [ABSTRACT FROM AUTHOR]

Objective Obesity in childhood is associated with an inflammatory state in adipose tissue and liver, which elevates risk for diabetes and liver disease. No prior study has examined associations between pathologies occurring in adipose tissue and liver to identify elements of tissue damage associated with type 2 diabetes risk. This study sought to determine whether inflammation and fibrosis in abdominal subcutaneous adipose tissue (SAT) in obese/overweight children (BMI- z 2.3 ± 0.76) was related to the extent of observed liver disease or type 2 diabetes risk. Methods Biopsy samples of abdominal (SAT) and liver were simultaneously collected from 33 Italian children (mean BMI 28.1 ± 5.1 kg/m2 and mean age 11.6 ± 2.2 years) with confirmed NAFLD. Histology and immunohistochemistry were conducted on biopsies to assess inflammation and fibrosis in adipose tissue and fibrosis and inflammation in liver. Results Presence vs. absence of crown-like structures (CLS) in SAT was significantly related to liver fibrosis scores (1.7 ± 0.7 vs. 1.2 ± 0.7, P = 0.04) independent of BMI. SAT fibrosis was significantly correlated with a lower disposition index ( r = −0.48, P = 0.006). No other adipose measures were associated with liver disease parameters. Conclusion Markers of subcutaneous white adipose tissue inflammation are associated with greater extent of liver fibrosis independent of obesity and SAT fibrosis may contribute to diabetes risk through reduced insulin secretion. [ABSTRACT FROM AUTHOR]

Although a rather benign course of chronic hepatitis B virus ( HBV) infection during childhood has been described, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9-24% and the incidence of cirrhosis to 2-3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer-reviewed journals from January 1980 to February 2013. The search terms used included 'Hepatitis B virus infection,' 'children,' ' HBV,' 'interferon,' 'lamivudine,' 'adefovir,' 'entecavir,' and 'tenofovir.' Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune-tolerant phase or in the inactive carrier state. For children in the immune-active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies. [ABSTRACT FROM AUTHOR]

Objective Hepatic steatosis is strongly associated with insulin resistance, but causative mechanisms that link these conditions are still largely unknown. Nowadays, it is difficult to establish whether fatty liver is the cause of insulin resistance or instead the complex metabolic derangements of insulin resistance determine hepatic steatosis and its progression to fibrosis. In patients with familial hypobetalipoproteinemia ( FHBL), hepatic steatosis is because of the genetically determined defective form of apolipoprotein B, independently of metabolic derangements. Therefore patients with FHBL represent a good in vivo model to evaluate the relationships between fatty liver and insulin sensitivity. Methods We evaluated insulin resistance through HOMA- IR in 60 children with echografic and histological features of steatosis; 30 of whom had nonalcoholic fatty liver disease ( NAFLD) and 30 had FHBL. Results All patients had histological features of hepatic steatosis. Patients with FHBL were hypolipidemic, as expected. No significant differences between two groups were observed in liver function tests. IRI and HOMA- IR were statistically higher in NAFLD subjects compared to the FHBL group. Conclusion In our study, we demonstrated that in children with FHBL, hepatic steatosis is dissociated from insulin resistance. This finding suggests that fat accumulation per se may be not a sufficient causal factor leading to insulin resistance, and that other mediators may be involved in the development of alteration in glucose metabolism and metabolic syndrome in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) is a standard treatment for children with end-stage liver disease, standing at more than 90% survival rate after one yr, and at over a 70% survival rate after five yr. The majority of transplanted children enjoy an excellent quality of life but complications can occur in the long term, and can develop subclinically in otherwise well children; there are various underestimated nutritional and metabolic aspects, including the so-called post-transplant metabolic syndrome (PTMS). During the post-transplant period, the use of immunosuppressants, corticosteroids, calcineurin inhibitors, and the presence of risk factors, including non-alcoholic fatty liver disease (NAFLD), and kidney and bone complications have been largely implicated in PTMS development. Strategies to reduce the progression of PMTS should include careful screening of patients for diabetes, dyslipidemia, and obesity, and to support weight reduction with a carefully constructed program, particularly based on diet modification and exercise. With early identification and appropriate and aggressive management, excellent long-term health outcomes and acceptable graft survival can be achieved. [ABSTRACT FROM AUTHOR]

Background Nonalcoholic fatty liver disease ( NAFLD) encompasses a spectrum of disease from simple steatosis to steatohepatitis, to fibrosis and cirrhosis. The paediatric NAFLD fibrosis index ( PNFI) and transient elastography ( TE) are potential noninvasive markers for fibrosis. To prospectively evaluate the performance of PNFI and TE in assessing clinically significant fibrosis in children with biopsy-proven NAFLD. Methods Our cohort consisted of 67 consecutive children with biopsy-proven NAFLD. The stage of fibrosis was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network. Fibrosis ≥ 2 was considered clinically significant. PNFI was calculated using age, waist circumference and triglycerides. TE was performed using the Fibroscan apparatus. Results Ten patients had fibrosis stage 2-3 and 57 patients had stage 0-1. Both PNFI and TE values were significantly higher in patients with significant fibrosis ( P < 0.05). The area under the receiver operating characteristic ( ROC) curve for predicting significant fibrosis of PNFI and TE were 0.747 and 1.00 respectively ( P = 0.005). The combined use of PNFI and TE could predict the presence or absence of clinically significant fibrosis in 98% of children with NAFLD. Conclusions In children with NAFLD, the combination of PNFI and TE can be used to accurately assess the presence of clinically significant liver fibrosis. This will help to identify patients who should undergo liver biopsy because the confirmation of advanced fibrosis would lead to closer follow-up and screening for cirrhosis-related complications. [ABSTRACT FROM AUTHOR]

Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M, Monti L, Gennari F, Torre G, de Ville de Goyet J, Bartuli A. Preemptive liver transplantation in a child with familial hypercholesterolemia. Pediatr Transplantation 2011: 15:E25-E29. © 2010 John Wiley & Sons A/S. Familial hypercholesterolemia is an autosomal codominant disorder associated with markedly elevated plasma concentration of LDL-cholesterol and increased cardiovascular risk. Homozygous patients have rapid development of atherosclerosis with death from cardiovascular disease even in childhood. Life-long recurrent apheresis to reduce plasma LDL-cholesterol is considered the gold standard for treatment. Liver transplantation can be curative for this condition, but is usually only considered after the development of cardiovascular disease. We report a 5.5-yr-old child initially misdiagnosed with heterozygous familial hypercholesterolemia and treated by low-fat diet only. In view of persistent hypercholesterolemia and development of xanthomatosis, new molecular studies indicated the presence of two different mutations in the LDL receptor gene, with one being a deletion of two exons not identifiable with standard sequencing analysis. Recurrent plasma apheresis in combination with statins lowered, but did not normalize plasma LDL-cholesterol levels. It caused progressive reduction of the size of xanthomas and prevented the development of vascular complications. After two yr, liver transplantation normalized LDL-cholesterol levels and completely resolved the skin lesions. Preemptive liver transplantation is a definitive cure of familial homozygous hypercholesterolemia and might be more effective if performed before development of vascular complications. [ABSTRACT FROM AUTHOR]

The article reflects on steatosis and fibrosis in paediatric liver transplant. It is said that post-transplant complications are the development of steatosis and fibrosis, which are observed in patients with recurrent hepatitis C infection. It is said that the pathogenesis of steatosis and fibrosis may influence the graft response to the new and different environment.

Background and Aim: Oxidative stress is an important pathophysiological mechanism in non-alcoholic steatohepatitis, where hepatocyte apoptosis is significantly increased correlating with disease severity. Protein glutathionylation occurs as a response to oxidative stress, where an increased concentration of oxidized glutathione modifies post-translational proteins by thiol disulfide exchange. In this study, we analyzed the protein glutathionylation in non-alcoholic fatty liver disease (NAFLD) and evaluated a potential association between glutathionylation, fibrosis, and vitamin E treatment. Methods: Protein glutathionylation was studied in the livers of 36 children (mean age 12.5 years, range 4–16 years) subdivided into three groups according to their NAFLD activity score (NAS) by Western blot analysis and immunohistochemistry, using a specific monoclonal antibody. In addition, we identified the hepatocyte ultrastructures involved in glutathionylation by immunogold electron microscopy. Results: Our findings showed that protein glutathionylation increases in the livers of patients with NAFLD and it is correlated with steatohepatitis and liver fibrosis. Its increase appears mainly in nuclei and cytosol of hepatocytes, and it is reversed by antioxidant therapy with reduced fibrosis. Conclusion: Protein glutathionylation significantly increases in livers with NAFLD, strongly suggesting that oxidative injury plays a crucial role in this disease. Furthermore, the marked increase of protein glutathionylation, in correlation with collagen VI immunoreactivity, suggests a link between the redox status of hepatic protein thiols and fibrosis. [ABSTRACT FROM AUTHOR]

The keratinocyte growth factor receptor (KGFR)/fibroblast growth factor receptor 2b is activated by high-affinity-specific interaction with two different ligands, keratinocyte growth factor (KGF)/fibroblast growth factor (FGF)7 and FGF10/KGF2, which are characterized by an opposite requirement of heparan sulfate proteoglycans and heparin for binding to the receptor. We investigated here the possible different endocytic trafficking of KGFR, induced by the two ligands. Immunofluorescence and immunoelectron microscopy analysis showed that KGFR internalization triggered by either KGF or FGF10 occurs through clathrin-coated pits. Immunofluorescence confocal microscopy using endocytic markers as well as tumor susceptibility gene 101 (TSG101) silencing demonstrated that KGF drives KGFR to the degradative pathway, while FGF10 targets the receptor to the recycling endosomes. Biochemical analysis showed that KGFR is ubiquitinated and degraded after KGF treatment but not after FGF10 treatment, and that the alternative fate of KGFR might depend on the different ability of the receptor to phosphorylate the fibroblast growth factor receptor substrate 2 (FRS2) substrate and to recruit the ubiquitin ligase c-Cbl. The recycling endocytic pathway followed by KGFR upon FGF10 stimulation correlates with the higher mitogenic activity exerted by this ligand on epithelial cells compared with KGF, suggesting that the two ligands may play different functional roles through the regulation of the receptor endocytic transport. [ABSTRACT FROM AUTHOR]

The article focuses on the occurrence/recurrence of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) after liver transplantation in children. It describes the difference in the causes of fatty liver disease in children and adults. Steroids are used by majority of liver transplant centers as a long-term maintenance therapy.

A letter to the editor is presented in response to the article "Fatal Fulminant Hepatitis in an Infant With Human Herpesvirus-6 Infection," by Y. Asano, T. Yoshikawa, S. Suga and colleagues in the 1990 issue.

The article focuses on Pediatric Transplantation. Topics discussed include pediatric liver transplant that provide practices in screening and managing Post‐transplant metabolic syndrome (PTMS); mentions the role of potential genetic in the post‐transplant setting; and information on the impact of genetic variants like PNPLA3 on adipose tissue and adiponectin secretion.

A letter to the editor is presented related to association between non-alcoholic fatty liver disease and survivin.

A response from the author of the article "Non-alcoholic fatty pancreas disease and Non-alcoholic fatty liver disease: more than ectopic fat" is presented.

The article reflects the opinion of the author on the significance of the measurement of advanced glycation end products (AGEs) in the changes on the management of non-alcoholic steatohepatitis. The author stressed that the discovery of nonenzygmatic AGEs and its receptors paved the way to new researches in medicine . Meanwhile, the author suggests that measurement of circulating AGEs can be a beneficial tool for discriminating patients with NASH.

A letter to the editor is presented in response to the article about the early effect of lifestyle changes on aminotransferase levels in non-alcoholic steatohepatitis (NASH) that was published in the February 2007 issue.

The author reflects on the occurrence of multiple food allergies in children with the use of tacrolimus after heart and liver transplantation. It is stated that the causes of food allergies after liver transplantation is unclear. The author suggests that there is a need to study the possible role of immunosuppressive drug therapy related allergy in children who underwent liver transplantation.

Comments on nutritional considerations in children with chronic liver disease. Indicators of protein and energy malnutrition; Mechanisms that can contribute to malnutrition; Pitfalls of malnutrition assessment.

A letter to the editor is presented in response to the article by Lucia Pacifico about magnetic resonance imaging in the clinical management of children with fatty liver that was published in the previous issue.

A letter to the editor is presented in regard to case management in children affected by non-alcoholic fatty liver disease.