Pediatricians' practices and knowledge of metabolic dysfunction-associated steatotic liver disease: An international survey.

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease in children. It is associated with significant intra- and extrahepatic comorbidity. Current guidelines lack consensus, potentially resulting in variation in screening, diagnosis and treatment practices, which may lead to underdiagnosing and/or insufficient treatment. The increasing prevalence of MASLD and associated long-term health risks demand adequate clinical management and consensus in guidelines. This study aims to evaluate the daily practices of pediatricians in screening, diagnosis and treatment of MASLD in children. METHODS: An online survey with 41 questions (single/multiple response options) was sent to pediatricians (with/without subspecialty) in Europe and Israel, via members of the ESPGHAN Fatty Liver Special Interest Group, between June and November 2022. The 454 pediatricians were included in this study. RESULTS: 51% of pediatricians indicated using any guideline for diagnosis and treatment of MASLD, with 68% reporting to follow recommendations only partially. 63% is of the opinion that guidelines need revision. The majority of pediatricians screen for MASLD with liver function tests and/or abdominal ultrasound. A large variety of treatment options is utilized, including lifestyle management, supplements and probiotics, with a notable 34% of pediatricians prescribing pharmacotherapy. When asked how often pediatricians request a liver biopsy in children with MASLD, 17% indicates they request a liver biopsy in more than 10% of cases. CONCLUSIONS: There is limited awareness and considerable variation in screening, diagnosis and treatment practices among European pediatricians, and a clear demand for new, uniform guidelines for MASLD in children.

Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. METHODS: The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). RESULTS: Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut-off. CONCLUSIONS: Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.

Prevalence and Significance of Autoantibody Seropositivity in Children with Wilson's Disease.

Autoantibodies occur in healthy subjects as well as in children with Wilson's disease (WD), but their prevalence and significance are unknown. Thus, we aimed to assess the prevalence of autoantibodies and autoimmune markers, and their relationship to liver injury in WD children. The study included 74 WD and 75 healthy children as a control group. Patients with WD underwent transient elastography (TE) examinations, as well as determination of liver function tests, copper metabolism markers, and serum immunoglobulins (Ig). In the sera of the WD patients and controls, anti-nuclear (ANA), anti-smooth muscle, anti-mitochondrial, anti-parietal cell, anti-liver/kidney microsomal, anti-neutrophil cytoplasmic autoantibodies, and specific celiac antibodies were determined. Among the autoantibodies, only the prevalence of ANA in children with WD was higher than in the controls. There was no significant relationship between the presence of autoantibodies and liver steatosis or stiffness after TE. However, advanced liver stiffness (E > 8.2 kPa) was related to IgA, IgG, and gamma globulin production. The type of treatment did not influence the prevalence of autoantibodies. Our results suggest that autoimmune disturbances in WD might not be directly related to liver damage as expressed by steatosis and/or liver stiffness after TE.

Wilson's disease- management and long term outcomes.

Wilson's disease (WD) is an autosomal recessive genetic disorder of copper metabolism leading to liver or brain injury due to accumulation of copper. Diagnosis is based on: clinical features, biochemical tests including plasma ceruloplasmin concentration, 24h urinary copper excretion, copper content in the liver, and molecular analysis. Pharmacological therapy comprises chelating agents (penicillamine, trientine) and zinc salts which seem to be very effective. Still, poor compliance is a major problem. Adolescents and patients with psychiatric disorders usually have problems with adherence to treatment. As transition is a vulnerable period transition ''training'' should start before the planned transfer, preferably already in early adolescence in cooperation between adult and pediatric clinics. Response to treatment is assessed based on physical examination, normal liver function tests and monitoring of copper metabolism markers. Liver transplantation has a well-defined role in Wilsonian acute hepatic failure according to the prognostic score. The long-term survival in WD patients seems to be very similar as for the general population if disease is early diagnosed and correctly treated. WD patients with a longer delay from diagnosis to therapy and who present with neurological and psychiatric symptoms have worse quality of life.

Fatty Acid-Binding Protein 1 as a Potential New Serological Marker of Liver Status in Children With Wilson Disease.

OBJECTIVES: Wilson disease (WD) is a copper metabolism disorder with toxic copper accumulation in the liver leading to liver steatosis or fibrosis. In vitro studies suggest that fatty acid-binding protein 1 (L-FABP) and lipid droplet-associated protein 5 (PLIN5) may have an impact on both processes, but knowledge about these potential biomarkers is insufficient in the case of WD. Thus, the aim of this study was to determine L-FABP and PLIN5 levels in sera of WD patients in relation to liver steatosis/fibrosis. METHODS: The final study involved 74 WD children in whom liver steatosis (WD1 subgroup, n = 28) and fibrosis (WD2 subgroup, n = 13) were assessed with the use of transient elastography. Control groups included WD children without steatosis and fibrosis (WD0 subgroup, n = 33) and healthy children (n = 75). L-FABP and PLIN5 measurements were performed in sera with the use of the immunoenzymatic method. RESULTS: L-FABP was significantly higher in the WD2 subgroup, and the correlation between L-FABP concentration and liver fibrosis was confirmed statistically by regression analysis (P = 0.04) with Pearson's coefficient r = 0.24. L-FABP was significantly correlated with alanine aminotransferase (r = 0.42) and aspartate aminotransferase (r = 0.37) activity. PLIN5 concentration was similar in all groups and was not related to steatosis and fibrosis. CONCLUSIONS: Our results suggest that serum L-FABP could be a novel biomarker of liver fibrosis in WD children.

Expression of Matrix Metalloproteinases and Their Tissue Inhibitors in Peripheral Blood Leukocytes and Plasma of Children with Nonalcoholic Fatty Liver Disease.

Gene expression profiles of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) were evaluated in peripheral blood leukocytes of children with nonalcoholic fatty liver disease (NAFLD). Gene expression patterns were correlated with their plasma protein counterparts, systemic parameters of liver injury, and selected markers of inflammation. The MMP-2, MMP-9, MMP-12, MMP-14, TIMP-1, TIMP-2, TGF-ß, and IL-6 transcripts levels were tested by the real-time PCR. Plasma concentrations of MMP-9, TIMP-1, MMP-9/TIMP-1 ratio, MMP-2/TIMP-2 ratio, sCD14, leptin, resistin, IL-1 beta, and IL-6 and serum markers of liver injury were estimated by ELISA. The MMP-9, TIMP-2 expression levels, plasma amounts of MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio were increased in children with NAFLD. Concentrations of AST, ALT, GGT, and leptin were elevated in serum patients with NAFLD, while concentration of other inflammatory or liver injury markers was unchanged. The MMP-2 and MMP-9 levels correlated with serum liver injury parameters (ALT and GGT concentrations, respectively); there were no other correlations between MMP/TIMP gene expression profiles, their plasma counterparts, and serum inflammatory markers. Association of MMP-2 and MMP-9 expression with serum liver injury parameters (ALT, GGT) may suggest leukocyte engagement in the early stages of NAFLD development which possibly precedes subsequent systemic inflammatory responses.

Tryptophan-kynurenine profile in pediatric autoimmune hepatitis.

The impairment of regulatory T cells (Tregs) is a characteristic feature of autoimmune hepatitis (AIH), and the degradation of tryptophan (Trp) to kynurenine (Kyn), by gamma interferon-induced indoleamine-2,3-dioxygenase-1 (IDO-1), is a central metabolomics check point in the differentiation of Tregs. For this reason, we investigate whether or not Kyn and IDO activity is potentially useful biomarkers in pediatric AIH.Between January 2016 and January 2017, children of AIH type-1 (AIH-1, n = 37), AIH type-2 with liver kidney microsome-1 autoantibodies (AIH-2-LKM-1, n = 8), and autoantibody-negative Wilsons Disease (WD, n = 8) and alpha-1 anti-trypsin deficiency (AATD, n = 10), were enrolled in a cross-sectional survey of Kyn and Trp levels and Kyn/Trp ratios (IDO activity) by HPLC, and neopterin levels by ELISA.The mean Kyn and mean Kyn/Trp ratios of AIH-1 with smooth muscle antigen (SMA) 1.85 µM and 27 µmole/mmole, and AIH-2-LKM-1; 1.7 µM and 28.6 µmole/mmole were lower than that of the WD; 2.2 µM p = 0.03 and 33 µmole/mmole p = 0.02 and of AATD; 2.3 µM, p = 0.02 and 55 µM, p = 0.001. Kyn/Trp ratios of AIH relapse; 23.6 µmole/mmole were lower than Kyn/Trp ratios of AIH remission; 27.6 µmole/mmole (p < 0.05). The stage of liver disease and grade of liver biopsies in AIH-1 patients negatively correlated with the Kyn/Trp ratios.The serum Kyn levels and Kyn/Trp ratio of AIH patients, within or below the normal range, indicate a trend of IDO activity lower than non-autoimmune WD or AATD. Prospective monitoring of serum tryptophan metabolomics in larger cohorts of pediatric AIH patients is required to confirm the apparent paradigm of weak IDO activity contributing to the Treg deficit and pathogenesis of pediatric AIH.

European paediatric non-alcoholic fatty liver disease registry (EU-PNAFLD): Design and rationale.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in children and has the potential to progress to advanced fibrosis/cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, the natural history of the condition is poorly understood and there are no approved treatments. The European Paediatric Non-Alcoholic Fatty Liver Disease Registry (EU-PNAFLD) is a multi-centre registry of paediatric NAFLD that will serve as a prospective, observational, natural history study and provide a tractable back-bone to support recruitment into subsequent interventional trials. Collection of samples into a bio-repository will facilitate translational studies, including genome sequencing and metabolomics. EU-PNAFLD will work closely alongside the existing adult European NAFLD Registry to obtain data on clinical outcomes after 20-30 years. Through an international, well-characterised large-scale cohort, EU-PNAFLD will address the key questions in paediatric NAFLD and benefit patients with the condition.

Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND: Clinical presentations of Wilson's disease (WD) in childhood ranges from asymptomatic liver disease to cirrhosis or acute liver failure, whereas neurological and psychiatric symptoms are rare. The basic diagnostic approach includes serum ceruloplasmin and 24-hour urinary copper excretion. Final diagnosis of WD can be established using a diagnostic scoring system based on symptoms, biochemical tests assessing copper metabolism, and molecular analysis of mutations in the ATP7B gene. Pharmacological treatment is life-long and aims at removal of copper excess by chelating agents as D-penicillamine, trientine, or inhibition of intestinal copper absorption with zinc salts. Acute liver failure often requires liver transplantation. This publication aims to provide recommendations for diagnosis, treatment, and follow-up of WD in children. METHODS: Questions addressing the diagnosis, treatment, and follow-up of WD in children were formulated by a core group of ESPGHAN members. A systematic literature search on WD using MEDLINE, EMBASE, Cochrane Database from 1990 to 2016 was performed focusing on prospective and retrospective studies in children. Quality of evidence was assessed according to the GRADE system. Expert opinion supported recommendations where the evidence was regarded as weak. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using the nominal voting technique.

Transient Elastography for Detection of Liver Fibrosis in Children With Autosomal Recessive Polycystic Kidney Disease.

Introduction: Congenital hepatic fibrosis (CHF) is invariably present in all patients with autosomal recessive polycystic kidney disease (ARPKD) but is usually clinically asymptomatic. The portal hypertension in the course of CHF develops and progresses over time, so an early detection of liver fibrosis remains crucial. Aim: The aim of the study was to evaluate a predictive value of transient elastography for evaluating liver disease progress in pediatric ARPKD patients. Material and Methods: The study group encompassed 21 pediatric patients with ARPKD and 20 healthy children (control group) from The Children's Memorial Health Institute in Warsaw, Poland. Liver fibrosis was determined by assessing the liver stiffness (LS) with transient elastography (FibroScan®, FS) using size-appropriate probes. In ARPKD group the laboratory findings, results of an abdominal ultrasound examination, and an endoscopic gastroduodenoscopy were also analyzed. Results: Compared with healthy controls, patients with ARPKD had significantly increased median LS values (22 vs. 4.25 kPa, p < 0.0001). Based on FS results, ARPKD group was divided into two subgroups: patients (n = 5) with LS results suggestive of no fibrosis or minimal fibrosis (LS < 6.9 kPa, METAVIR fibrosis stage 0-1) and patients (n = 16) with LS results suggestive of at least significant liver fibrosis (LS ≥ 6.9 kPa, METAVIR fibrosis stage 2-4). In the first subgroup (no fibrosis or minimal fibrosis), all patients had no signs of portal hypertension. In the subgroup with at least significant liver fibrosis, splenomegaly was observed in 87.5% of patients and thrombocytopenia in 69% of patients. An endoscopic gastroduodenoscopy was performed in 15 out of 21 ARPKD patients, nine patients (60%) had esophageal varices. All of these patients had LS results suggestive of at least significant liver fibrosis. Conclusions: TE by FibroScan can be used as an additional method for evaluating liver disease progress in pediatric ARPKD patients.

A heterozygous mutation in GOT1 is associated with familial macro-aspartate aminotransferase.

BACKGROUND & AIMS: Macro-aspartate aminotransferase (macro-AST) manifests as a persistent elevation of AST levels, because of association of the protein with immunoglobulins in the circulation. Macro-AST is a rare, benign condition without a previously confirmed genetic basis. METHODS: Whole exome sequencing (WES)-based screening was performed on 32 participants with suspected familial macro-AST, while validation of variants was performed on an extended cohort of 92 probands and 1,644 healthy controls using Taqman genotyping. RESULTS: A missense variant (p.Gln208Glu, rs374966349) in glutamate oxaloacetate transaminase 1 (GOT1) was found, as a putative causal variant predisposing to familial macro-AST. The GOT1 p.Gln208Glu mutation was detected in 50 (54.3%) of 92 probands from 20 of 29 (69%) families, while its prevalence in healthy controls was only 0.18%. In silico analysis demonstrated that the amino acid at this position is not conserved among different species and that, functionally, a negatively charged glutamate on the GOT1 surface could strongly anchor serum immunoglobulins. CONCLUSIONS: Our data highlight that testing for the p.Gln208Glu genetic variant may be useful in diagnosis of macro-AST. LAY SUMMARY: Higher than normal levels of aspartate aminotransferase (AST) in the bloodstream may be a sign of a health problem. Individuals with macro-AST have elevated blood AST levels, without ongoing disease and often undergo unnecessary medical tests before the diagnosis of macro-AST is established. We found a genetic variant in the GOT1 gene associated with macro-AST. Genetic testing for this variant may aid diagnosis of macro-AST.

Early Onset of Wilson Disease: Diagnostic Challenges.

OBJECTIVES: The aim of the study was to analyze the clinical presentations, diagnosis, and treatment of patients ages ≤5 years with early onset Wilson disease (WD). METHODS: Data from 143 pediatric patients with WD treated at our center between January 1996 and November 2015 were retrospectively analyzed. RESULTS: A review of the 143 pediatric patients with WD identified 21 (10 girls, 11 boys) with first symptoms or abnormal liver function test results at age ≤5 years. The diagnosis of WD was confirmed in 8 patients younger than 5 years. At baseline the mean serum alanine aminotransferase level was 222 U/L and the mean serum aspartate aminotransferase level was 130 U/L. The mean serum ceruloplasmin concentration in 16 tested patients was <20 mg/dL. Of the 15 patients who underwent urinary copper excretion testing, 8 had levels between 40 and 100 µg/day, with only 4 having levels >100 µg/day. Liver copper quantification was >250 µg/g dry weight in 16 patients. The most common mutation was p.H1069Q, with compound heterozygosity in 5 patients and homozygosity in 9. Sixteen patients were treated with zinc salts and 5 with D-penicillamine. Both treatments were effective, with no serious side effects observed after 3 to 24 months. CONCLUSIONS: WD can present as early as 2 years of age. Because biochemical tests may be less sensitive in very young children, diagnoses may require a combination of tests. If molecular tests are inconclusive, liver copper content should be measured.

Diagnostic and therapeutic management of children with lysosomal acid lipase deficiency (LAL-D). Review of the literature and own experience.

Lysosomal acid lipase deficiency may present at any age (in infants, children and adults). Its presenting features commonly include elevated serum transaminase activity levels, hypercholesterolemia, fatty liver, progressive liver fibrosis, and cirrhosis. Nonspecific clinical manifestations can lead to a delay in the diagnosis of both children and adults. The early development of fibrosis and cirrhosis suggests that the lysosomal accumulation of cholesterol esters and triglycerides in the liver is a potent inducer of fibrosis. Elevated levels of low-density lipoprotein-cholesterol or low levels of high-density lipoprotein-cholesterol with elevated transaminase activity should raise the suspicion of lysosomal acid lipase deficiency in the diagnostic workup. Still, some patients may not present with abnormal triglyceride and cholesterol concentrations. Early onset LAL-D has a different clinical presentation, with acute symptoms, including liver failure, and can be confused with many other metabolic conditions or with lymphohistiocytosis. The dried blood spot test enables rapid diagnosis and should be widely applied when the cause of liver disease remains unknown.

Clinical presentations of Wilson disease among Polish children.

INTRODUCTION: Wilson disease (WD) may present from early childhood up to the eighth decade, presenting with variable hepatic and neuropsychiatric symptoms. Establishing the diagnosis is straightforward if the major clinical and laboratory features are present. However, clinical phenotypes are highly varied and early, proper diagnosis can be challenging. AIM: The aim of our study was to analyze clinical presentations and diagnostic tests of Polish pediatric patients with WD. METHODS: We retrospectively analyzed medical history of 156 patients with confirmed diagnosis of WD treated at our Institute from 1996 till March 2016. RESULTS: The mean age at onset of symptoms was 10.15±4.23 years of age. Hepatic presentation was the most common one (94.23%) with either liver failure (16.03%) or more frequently increased transaminases (78.2%). In 90.26% cases ceruloplasmin serum concentration was ≤0,2 g/l, in 51.93% patients basal urinary copper excretion was >100 µg/24 h. Mutation analysis was performed in 155 (99.36%) cases. The most common mutation was p.H1069Q. CONCLUSIONS: Wilson disease can present with only significantly increased transaminases activity and hepatomegaly or liver failure, but neurological symptoms are very rare in children. Diagnostic approach is challenging due to wide spectrum of clinical presentations in a high variable degree of severity. Genetic screening is supportive, ceruloplasmin and urinary copper excretion are valuable tests in the majority of patients but do not allow to exclude WD.

Coeliac disease not responding to a gluten-free diet in children: case studies and literature review.

We presented the cases of three children with coeliac disease who despite good adherence to a glutenfree diet remained non-responsive to treatment. Two patients, one of them with IgA deficiency, were successfully treated by complete gluten exclusion with enteral nutrition. However the third child with a severe coeliac disease did not achieve clinical and histologic improvement, even on immunosuppressive treatment. If no hidden sources of gluten can be identified, other causes of persistent villous atrophy, dierent from coeliac disease, have to be considered. They include e.g. inflammatory, immune and endocrine diseases of the digestive tract. In severe cases of childhood coeliac disease not responding to a gluten free diet, autoimmune enteropathy and refractory coeliac disease must be taken into account.

Omega-3 Fatty acids therapy in children with nonalcoholic Fatty liver disease: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of omega-3 fatty acid supplementation in children with nonalcoholic fatty liver disease (NAFLD). STUDY DESIGN: Overweight/obese children with NAFLD (n = 76; median age, 13 years; IQR, 11.1-15.2 years) were eligible to participate in the study. The diagnosis of NAFLD was based on elevated alanine aminotransferase (ALT) to ≥ 30% of the upper limit of normal (ULN) and liver hyperechogenicity on ultrasound. Patients were randomized to receive omega-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid, 450-1300 mg/day) or placebo (omega-6 sunflower oil). The primary outcome was the number of patients who demonstrated decreased ALT activity by ≥ 0.3 times the ULN. Secondary outcomes included alterations in liver function tests, liver hyperechogenicity, insulin resistance, and other metabolic markers after 6 months of intervention. RESULTS: Out of 76 enrolled patients, 64 completed the trial and were analyzed. After 6 months, we found no significant differences between the omega-3 and placebo groups in the number of patients with decreased ALT by ≥ 0.3 times the ULN (24 vs 23) or in median (IQR) ALT activity (48.5 [31-62] U/L vs 39 [27-55] U/L), liver hyperechogenicity, insulin resistance, or serum lipid levels. However, patients in the omega-3 group had lower levels of aspartate aminotransferase (28 [25-36] U/L vs 39 [27-55] U/L; P = .04) and gamma-glutamyl transpeptidase (26 [17.5-36.5] U/L vs 35 [22-52] U/L; P = .04), and significantly higher levels of adiponectin. CONCLUSION: Omega-3 fatty acid supplementation did not increase the number of patients with decreased ALT levels and it did not affect liver steatosis on ultrasound, but it improved aspartate aminotransferase and gamma-glutamyl transpeptidase levels in children with NAFLD compared with placebo. TRIAL REGISTRATION: Registered with ClinicalTrials.gov: NCT01547910.

Gastrointestinal side effects in children with Wilson's disease treated with zinc sulphate.

AIM: To investigate the side effects of a zinc sulphate therapy in a cohort of Polish pediatric patients with Wilson's disease. METHODS: We retrospectively analyzed a cohort of 53 pediatric patients with Wilson's disease treated at the Children's Memorial Health Institute in Warsaw, Poland between the years 1996 and 2011 with zinc sulphate. Patients were diagnosed with Wilson's disease according to the scoring system of Ferenci, with 49 cases confirmed by mutation analysis. Data about the dosage scheme of zinc sulphate, side effects and efficacy and toxicity of the treatment were collected and recorded in the patient's medical chart at each visit to the hospital. RESULTS: Mean age of diagnosis for the entire cohort was 10 years (range, 2.5-17 years). Duration of treatment with zinc sulfate was 83.3 wk (range, 8-344 wk). Side effects, all of gastrointestinal origin, were observed in 21 patients (40%--9 males and 12 females), irrespective of the duration of therapy. Thirteen out of 21 patients were over the age of 10 years. The most common ATP7B mutation was p.H1069Q. Esophagogastroduodenoscopy, performed in 7 patients (33.3%) suffering from persistent and severe abdominal pain, revealed gastrointestinal ulcerations or erosions with negative Helicobacter pylori tests in all subjects investigated. The above mentioned 7 patients were treated with proton pump inhibitors. Three of those experienced resolution of symptoms, whereas proton-pump inhibitors failed to alleviate symptoms of the remaining four children and conversion of therapy to D-penicillamine was needed. CONCLUSION: Zinc sulphate appears to cause significant gastrointestinal side effects, which children on therapy for Wilson's disease should be closely monitored for.

Omega-3 fatty acids for treatment of non-alcoholic fatty liver disease: design and rationale of randomized controlled trial.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome since obesity and insulin resistance are the main pathogenic contributors for both conditions. NAFLD carries increased risk of atherosclerosis and cardiovascular diseases. There is an urgent need to find effective and safe therapy for children and adults with NAFLD. Data from research and clinical studies suggest that omega-3 fatty acids may be beneficial in metabolic syndrome-related conditions and can reduce the risk of cardiovascular disease. METHODS/DESIGN: We are conducting a randomized, multicenter, double-blind, placebo-controlled trial of treatment with omega-3 fatty acids in children with NAFLD. Patients are randomized to receive either omega-3 fatty acids containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or placebo for 24 weeks. The dose of omega-3 (DHA+ EPA) ranges from 450 to 1300 mg daily. Low calorie diet and increased physical activity are advised and monitored using validated questionnaires. The primary outcome of the trial is the number of patients who decreased ALT activity by ≥ 0,3 of upper limit of normal. The main secondary outcomes are improvement in the laboratory liver tests, liver steatosis on ultrasound, markers of insulin resistance and difference in fat/lean body mass composition after 6 months of intervention. DISCUSSION: Potential efficacy of omega-3 fatty acids in the treatment of NAFLD will provide needed rationale for use of this safe diet supplement together with weight reduction therapy in the growing population of children with NAFLD. TRIAL REGISTRATION: NCT01547910.

Non-alcoholic fatty liver disease in children.

Non-alcoholic fatty liver disease is increasingly prevalent in children, together with obesity. Transaminases, tests for insulin resistance, ultrasonography and MRI are variably used as surrogates markers of steatosis. Other liver diseases, such as Wilson disease, should be excluded. A liver biopsy is performed in selected cases: young children, familial history of severe disease, inconclusive tests for other pathologies, suspected advanced fibrosis, hypertransaminasemia despite weight loss and in clinical trials. Weight reduction, and changes in lifestyle, are the front-line treatment. Drug therapy is under evaluation.