Emer Fitzpatrick

Human hepatocyte transplantation: state of the art

Hepatocyte transplantation is making its transition from bench to bedside for liver‐based metabolic disorders and acute liver failure. Over eighty patients have now been transplanted world wide and the safety of the procedure together with medium‐term success has been established. A major limiting factor in the field is the availability of good quality cells as hepatocytes are derived from grafts that are deemed unsuitable for transplantation. Alternative sources of cell, including stem cells may provide a sustainable equivalent to primary hepatocytes. There is also a need to develop techniques that will improve the engraftment, survival and function of transplanted hepatocytes. Such developments may allow hepatocyte transplantation to become an accepted and practical alternative to liver transplantation in the near future.

Serum levels of CK18 M30 and leptin are useful predictors of steatohepatitis and fibrosis in paediatric NAFLD.

Background: With the alarming growth in prevalence of paediatric nonalcoholic fatty liver disease (NAFLD), there is a need for noninvasive methods of stratifying disease severity. Our aim was to evaluate a combination of serum biomarkers as a measure of disease activity in paediatric NAFLD. Patients and Methods: Forty-five children with biopsy-proven NAFLD were enrolled. Caspase-cleaved CK18 fragments (CK18 M30), hyaluronic acid, leptin, and adiponectin were measured in serum using enzyme-linked immunosorbent assays and high-sensitivity C-reactive protein using a colorimetric assay. Results: Median age was 12.7 years (55% boys). Median body mass index z score was 1.7. CK18 M30 levels were significantly higher in patients with NAFLD versus controls, median 288 IU/L versus 172 IU/L (P < 0.001), and in those with steatohepatitis, median 347 IU/L versus simple steatosis (NAFLD activity score < 3), median 191 IU/L (P = 0.006). Significant fibrosis (≥F2) could be differentiated from no/minimal fibrosis (<F2), median 393 IU/L versus 243 IU/L (P = 0.03). Leptin could distinguish <F2 from ≥F2; 28.9 ng/mL versus 70.1 ng/mL (P = 0.037). Adiponectin, hyaluronic acid, and high-sensitivity C-reactive protein did not achieve significance in predicting steatohepatitis nor significant fibrosis. Conclusions: The present study combines use of markers for different processes in the development of steatohepatitis. Serum biomarkers, especially CK18 M30, are useful in stratifying disease severity in paediatric NAFLD.

Nonalcoholic Fatty Liver Disease: A Challenge for Pediatricians

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is considered the most common form of chronic liver disease in children. Several factors contribute to NAFLD development, including race/ethnicity, genetic factors, environmental exposures, and alterations in the gut microbiome. The histologic spectrum of NAFLD ranges from simple steatosis to the more aggressive nonalcoholic steatohepatitis (NASH). Fibrosis and eventually cirrhosis can develop from NAFLD during childhood. Diagnosing advanced disease is challenging and may require a liver biopsy, highlighting the urgent need for reliable, noninvasive markers of disease severity. The mainstay of treatment for NAFLD remains lifestyle modifications and weight loss. Probiotics and ω-3 fatty acids may ameliorate disease progression. Recent data have suggested that vitamin E may be considered as a NASH-specific therapy in children, and there are several ongoing human studies evaluating different therapeutic targets for NAFLD. We provide an up-to-date review of the risk factors, diagnosis, and treatment to manage this common disease in children.

Noninvasive biomarkers in non-alcoholic fatty liver disease: Current status and a glimpse of the future

The development of non invasive biomarkers of disease has become a major focus of interest in nonalcoholic fatty liver disease (NAFLD). The large prevalence of the disease and the invasive nature of the investigation means that screening with liver biopsy is impractical. In addition to screening, the differentiation of those with simple steatosis vs steatohepatitis and fibrosis is clinically important as the prognosis of each differs. Serum biomarkers may be a combination of simple markers derived from large data sets or direct markers of disease activity. Serum markers of inflammation, apoptosis and oxidative stress in addition to fibrosis have been extensively studied in patients with NAFLD. Other techniques such as transient elastography, magnetic resonance elastography and acoustic radiation force imaging are becoming more established as noninvasive methods of detecting fibrosis in a variety of chronic liver conditions in addition to NAFLD. Newer high throughput methods such as proteomics and glycomics allow the nonhypothesis-driven identification of novel markers and may also potentially contribute to our understanding of the pathogenesis of the condition. This review addresses some of the methodological issues which need to be considered in the search for the ideal biomarker. It is likely that a combination of serum biomarkers and techniques such as transient elastography may provide the optimal diagnostic discrimination however this remains to be proven in large studies.

Transient elastography is a useful noninvasive tool for the evaluation of fibrosis in paediatric chronic liver disease

Background: Outcome of liver disease in children is mainly determined by severity and progression of liver fibrosis. Liver biopsy is the accepted standard for evaluating fibrosis but is limited by the need for sedation in children, sampling error, and risks including bleeding. The aim of the present study was to compare tools for noninvasive assessment of liver fibrosis in a paediatric cohort. Methods: Children undergoing liver biopsy for chronic liver disease were recruited and underwent transient elastography (TE). Liver biopsies were scored by a hepatohistopathologist from F0 (no fibrosis) to F4 (cirrhosis). TE was compared with biopsy score. Results: During the study period, 104 children (62 boys) were enrolled (median age 13.6 years). Diagnosis was autoimmune liver disease in 27; nonalcoholic fatty liver disease in 37; posttransplant in 16; hepatitis B/C in 8; Wilson disease in 5; and the remainder, miscellaneous. TE was successful in all but 7 patients and was a good discriminator of significant fibrosis (≥F2) (P < 0.001), severe fibrosis (≥F3) (P < 0.001), and cirrhosis (F4) (P = 0.003). The area under the receiver operating characteristic curve for the prediction of ≥F2, ≥F3, and F4 using TE was 0.78, 0.79, and 0.96, respectively. TE performed best in children with autoimmune liver disease and in those posttransplant. Conclusions: The present study demonstrates that TE is a reliable tool in distinguishing different stages of liver fibrosis in paediatric patients. Thus, TE may serve as a useful adjunct to liver biopsy for diagnostic purposes providing a reliable method of noninvasively monitoring liver disease progression in children.

The incidence of cyclic vomiting syndrome in children: population-based study.

OBJECTIVE:Cyclic vomiting syndrome (CVS) is characterized by severe recurrent episodes of vomiting in an otherwise healthy child. Currently, there is no population data on the incidence of CVS. The aim of this study was to determine the incidence of CVS and to define the clinical characteristics of the condition at diagnosis.METHODS:Each pediatrician on the island of Ireland was surveyed on a monthly basis from January 1, 2005 to December 31, 2005 by the Irish Pediatric Surveillance Unit (IPSU) and was asked to report any incident cases of CVS according to the criteria outlined by the First International Symposium on CVS. Subsequently, data on demographics and clinical features were collected anonymously from the reporting pediatricians.RESULTS:Eighty-nine percent (1,647 of 1,848) of the surveillance cards were returned, reporting 41 valid cases of CVS. The incidence of CVS in Ireland was 3.15/100,000 children per annum for 2005 (95% confidence interval [CI] 2.19–4.11). The median age at diagnosis of CVS was 7.42 yr (range 1.8–15 yr). The median age at onset of CVS was 4 yr (range 0.5–14 yr) with 46% (19 of 41) of children having an onset at or before the age of 3 yr. The median number of episodes of CVS per child per year was eight (range 3–52); the median duration of an episode was 24 h (range 1 h to 5 days). Of school-age children, 85% (22 of 26) had missed school in the previous year due to CVS and 44% (18 of 41) were admitted to hospital for supportive treatment or investigation of CVS.CONCLUSION:CVS is a relatively common condition in pediatric patients, with an incidence comparable to other major gastrointestinal diseases of childhood, such as Crohns disease. The onset of pediatric CVS is generally early in childhood and this disease causes significant morbidity in the majority of those affected.

Management of cholestatic pruritus in paediatric patients with alagille syndrome: the King's College Hospital experience.

Objectives: The aims of the study were to perform a retrospective observational review of the present management and outcome of cholestatic pruritus in children with Alagille syndrome (AGS) at Kings College Hospital and to use results to inform appropriate guidelines. Methods: A retrospective review of 62 patients diagnosed as having AGS from January 1995 to November 2010 treated at Kings College Hospital was performed. The departmental database of the Paediatric Liver Centre was searched to identify all patients and the clinical records were then analysed. Results: Fifty-one (82.3%) patients experienced pruritus and 50 (80.6%) received antipruritic medication. Ursodeoxycholic acid was the most prescribed drug (n = 40). Other drugs prescribed were rifampicin (n = 39), cholestyramine (n = 18), naltrexone (n = 14), alimemazine (n = 13), nonsedating antihistamine agents (n = 7), ondansetron (n = 5), and phenobarbitone (n = 1). Albumin dialysis using the molecular adsorbent recirculation system was used in 1 patient. Sixteen patients (25.8%) were listed for liver transplantation, and 11 had undergone transplantation by November 2010. Patient survival was high at 95.2%. Pruritus resolved permanently in 39.2% (n = 20) of patients. Fifty-five percent (n = 11) of such patients had undergone liver transplantation. Pruritus was controlled by medication in 41.2% (n = 21). Itching remained a significant problem, affecting quality of life in 19.6% of patients (n = 10). Conclusions: The management of cholestatic pruritus in AGS is difficult and often suboptimal. Pruritus may remain intractable even with combination medical treatment, and at this stage, surgery or liver transplantation is indicated. At our centre, pruritus was successfully treated in 80.4% of patients with medical and surgical management.

Analysis of adipokine concentrations in paediatric non-alcoholic fatty liver disease.

What is already known on this subject Non‐alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and the rising prevalence is closely associated with the rise in obesity. Adipokines, inflammatory mediators which arise from adipocytes or inflammatory cells infiltrating fatty tissue, are likely to be involved in the evolution of steatohepatitis from simple steatosis in nonalcoholic fatty liver disease.

Fatty liver disease in children: eat now pay later.

IntroductionWith the recent epidemic in childhood obesity, nonalcoholic fatty liver disease (NAFLD) has become an emerging problem and a common cause of chronic liver disease in children.MethodsIn this review, the most recent insights on the pathogenesis, diagnosis, natural history, and treatment of NAFLD in children are discussed.

Hepatopathy of Mauriac syndrome: a retrospective review from a tertiary liver centre

Background Mauriac syndrome is characterised by growth failure, cushingoid appearance and hepatomegaly which occurs in patients with insulin dependent diabetes and was first described shortly after the introduction of insulin as a treatment for the condition. Objective To describe the clinical features, histological findings and outcome of young people with glycogenic hepatopathy, the hepatic manifestation of Mauriac syndrome (MS). Design Retrospective cohort study. Patients Young people with glycogenic hepatopathy. Setting Tertiary paediatric hepatology unit. Results Thirty-one young people (16 M), median age of 15.1 years (IQR 14–16.2) presented within the study period. Median age of diagnosis of diabetes was 10 years (IQR 8–11). Median insulin requirement was 1.33 units/kg/day; median HbA1c was 96.7 mmol/mol (IQR 84.7–112.0). Growth was impaired: median height z-score was −1.01 (−1.73 to 0.4) and median body mass index (BMI) z-score was 0.28 (−0.12 to 0.67). Hepatomegaly was universal with splenomegaly in 16%. Transaminases were abnormal with a median aspartate aminotransferase (AST) of 76 IU/L and gamma glutamyltransferase of 71 IU/L. Liver biopsy was undertaken in 19 (61%). All showed enlarged hepatocytes with clear cytoplasm with glycogenated nuclei in 17. Steatosis was present in the majority. Inflammation was present in 8 (42%). Fibrosis was seen in 14 (73%) and was generally mild though 2 had bridging fibrosis. Megamitochondria were described in 7. Presence of megamitochondria correlated with AST elevation (p=0.026) and fibrosis on biopsy (p=0.007). At follow-up 17 children had normal or improved transaminases, in 13 there was no change. Transaminases followed the trend of the childs HbA1c. Conclusions Despite modern insulin regimens and monitoring in children with type 1 diabetes, MS still exists. Significant steatosis, inflammation and fibrosis were all seen in liver biopsies.