Christine Carter-Kent

Nonalcoholic Steatohepatitis in Children: A Multicenter Clinicopathological Study

Nonalcoholic fatty liver disease (NAFLD) may have distinct histological features in children and adults, but to date limited data are available on the spectrum and significance of histological lesions in pediatric patients. We conducted a multicenter study of children with well‐characterized, biopsy‐proven NAFLD to (1) assess the presence and significance of a constellation of histological lesions and (2) identify clinical and laboratory predictors of disease severity. One hundred thirty children with NAFLD seen from 1995 to 2007 in five centers in the United States and Canada were studied. Clinical and laboratory data were collected. Slides stained with hematoxylin‐eosin and trichrome were evaluated by two liver pathologists. The NAFLD activity score (NAS) and the pattern of liver injury (type 1 or adult versus type 2 or pediatric nonalcoholic steatohepatitis [NASH]) were recorded. Fibrosis was staged using a published 7‐point scale. The median age was 12 years (range, 4‐18 years); 63% were boys, and 52% were Caucasian. Fibrosis was present in 87% of patients; of these, stage 3 (bridging fibrosis) was present in 20%. No patient had cirrhosis. The median NAS was 4. Overlapping features of both type 1 (adult pattern) and type 2 (pediatric pattern) NASH were found in 82% of patients. Compared with patients with no or mild fibrosis, those with significant fibrosis were more likely to have higher lobular and portal inflammation scores (P < 0.01), perisinusoidal fibrosis (P < 0.001), and NAS ≥5 (P < 0.005). Serum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003). Conclusion: Our results highlight the limitations of published proposals to classify pediatric NAFLD, and identified histological lesions associated with progressive disease. (HEPATOLOGY 2009.)

Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: implications for treatment.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a growing public health problem worldwide. NAFLD represents a wide spectrum of conditions ranging from fatty liver, that in general follows a benign nonprogressive clinical course, to nonalcoholic steatohepatitis (NASH), a serious form of NAFLD, that may progress to cirrhosis and end-stage liver disease. The mechanisms responsible for NAFLD development and disease progression remain incompletely understood, but are of great clinical interest as current therapies are limited. Future therapies will be predicted based upon the understanding of its pathogenesis. This review focuses on the growing evidence from both experimental and human studies suggesting a central role of cytokines in the pathogenesis of NAFLD. We review the role of cytokines as key regulators of insulin sensitivity and hepatic lipid overloading, liver injury and inflammation, and fibrosis and cirrhosis, with an emphasis on potential therapeutic implications.

Ultrasonographic quantitative estimation of hepatic steatosis in children With NAFLD.

Background and Aims: The diagnostic accuracy of hepatic ultrasonography (US) for detection and grading of hepatic steatosis in children with suspected nonalcoholic fatty liver disease (NAFLD) remains poorly characterized. The aim of this study was to prospectively evaluate the clinical utility of ultrasonographic quantification of hepatic steatosis. Patients and Methods: Our cohort consisted of 208 consecutive pediatric patients with biopsy-proven NAFLD. Hepatic US was performed within 1 month of the liver biopsy procedure. Steatosis identified by US was scored using a 0 to 3 scale based on echogenicity and visualization of vasculature, parenchyma, and diaphragm, and compared to histological features based on Brunts classification. Results: The median age at time of first visit was 10.8 years and 64% were boys. Sixty-nine percent had moderate to severe steatosis on histology. Ultrasonographic steatosis score (USS) had an excellent correlation with histological grade of steatosis (with a Spearmans coefficient of 0.80). The area under the receiver operating characteristic curve for ultrasonographic detection of moderate-to-severe steatosis was 0.87. The USS did not correlate significantly with inflammatory activity or fibrosis stage; however, there was significant correlation with the NAFLD activity score (NAS), albeit this was in large part the result of the strong correlation with the steatosis component of NAS. Serum alanine transaminase and aspartate transaminase were not associated with histological grade of steatosis and showed no correlation with USS. Conclusions: Our results, which represent the largest prospective pediatric study evaluating the role of hepatic US in children with biopsy-proven NAFLD, demonstrate the utility of this technique for noninvasive diagnosis and estimation of hepatic steatosis in children.

Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications

Pathological increases in cell death in the liver as well as in peripheral tissues has emerged as an important mechanism involved in the development and progression of nonalcoholic fatty liver disease (NAFLD). An increase in hepatocyte cell death by apoptosis is typically present in patients with NAFLD and in experimental models of steatohepatitis, while an increase in adipocyte cell death in visceral adipose tissue may be an important mechanism triggering insulin resistance and hepatic steatosis. The two fundamental pathways of apoptosis, the extrinsic (death receptor-mediated) and intrinsic (organelle-initiated) pathways, are both involved. This article summarizes the current knowledge related to the distinct molecular and biochemical pathways of cell death involved in NAFLD pathogenesis. In particular, it will highlight the efforts for the development of both novel diagnostic and therapeutic strategies based on this knowledge.

Hepatitis B immunity and response to booster vaccination in children with inflammatory bowel disease treated with infliximab

OBJECTIVES:Hepatitis B virus (HBV) reactivation has been described in patients treated with infliximab for inflammatory bowel disease (IBD). This has resulted in a “black box” warning. Although universal vaccination against hepatitis B was implemented in the United States in 1991, up to 10% of vaccine recipients fail to respond with adequate anti-hepatitis B surface antibodies (anti-HBs) levels after a primary series of vaccinations. In addition, anti-HBs levels are expected to decline with time. The objectives of this study were to determine HBV immunity in children with IBD on infliximab therapy and to determine response to a booster dose of the HBV vaccine in patients who were found to be non-immune.METHODS:This was a prospective cross-sectional, single-center study that included 100 pediatric IBD patients on infliximab. Serologic specimens were tested for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and anti-HBs. Patients with an anti-HBs level ≥10 mIU/ml were considered to be immune. One booster dose was given to non-immune patients and a serum sample was collected after 4 weeks to assess the presence of anamnestic response (anti-HBs level ≥10 mIU/ml after booster).RESULTS:The mean age of the patients was 17.9 (±4.0) years. None of the patients were positive for HBsAg or anti-HBc. In all, 87 patients were vaccinated against HBV and 49/87 (56%) had immunity to HBV as defined by anti-HBs level ≥10 mIU/ml. The mean concentration of anti-HBs levels in immune patients was 295.6 (±350.6) mIU/ml. Older age, lower albumin levels, and the presence of pancolitis were associated with the absence of protective antibodies; however, infliximab dose, frequency, duration, and the concurrent use of immunomodulators were not significantly different between immune and non-immune patients. Thirty-four patients received booster immunization and 26/34 (76%) had an anamnestic response. Interestingly, non-responders were given infliximab with higher frequency (every 5.9±1.2 weeks vs. every 7.1±1.8 weeks, P=0.01). Overall, 75/87 (86%) of previously immunized patients were considered immune against HBV infection.CONCLUSIONS:In pediatric IBD patients seen at a large, urban tertiary care facility in the United States, a significant minority (13%) have not been vaccinated against HBV. Nearly one-half of all patients (and 44% of previously vaccinated patients) did not have protective anti-HBs levels. Moreover, of those previously vaccinated, a significant minority (14%) appear at risk for HBV because protective anti-HBs levels were absent and could not be elicited through booster immunization. Given the high risk for severe HBV infection in this group, efforts should be made to screen for HBV immunity at the time of IBD diagnosis. Booster immunization should be considered in patients without protective antibodies.

The role of lifestyle changes in the management of chronic liver disease

The prevalence of obesity worldwide has dramatically increased during the last three decades. With obesity comes a variety of adverse health outcomes which are grouped under the umbrella of metabolic syndrome. The liver in particular seems to be significantly impacted by fat deposition in the presence of obesity. In this article we discuss several liver conditions which are directly affected by overweight and obese status, including non-alcoholic fatty liver disease, chronic infection with hepatitis C virus and post-liver transplant status. The deleterious effects of obesity on liver disease and overall health can be significantly impacted by a culture that fosters sustained nutritional improvement and regular physical activity. Here we summarize the current evidence supporting non-pharmacological, lifestyle interventions that lead to weight reduction, improved physical activity and better nutrition as part of the management and treatment of these liver conditions.

Relations of steatosis type, grade, and zonality to histological features in pediatric nonalcoholic fatty liver disease.

Background: The relations between hepatic steatosis and histological features of hepatocyte injury in children with nonalcoholic fatty liver disease have yet to be examined. The aims of the present study were to establish associations between steatosis amount, type, and distribution in a well-characterized group of children with biopsy-proven nonalcoholic fatty liver disease (NAFLD). Patients and Methods: One hundred eight children with NAFLD seen in 5 centers were studied. Clinical and laboratory data were collected. Hematoxylin-eosin and Masson trichrome stains were evaluated by 2 expert liver pathologists. Steatosis grade (0–3), type (macrovesicular, microvesicular, or mixed), and zone (1, 3, azonal, or panacinar) were determined. The NAFLD activity score and fibrosis stage were determined. Results: Median patient age was 12 years and median body mass index was 31 kg/m2. Fibrosis was present in 87%. The median NAFLD activity score was 4. Mild, moderate, and severe steatosis were present in 42%, 34%, and 24% of biopsies, respectively. Macrovesicular steatosis was present in 81% and mixed steatosis was present in 19%. Panacinar distribution of steatosis was most frequent (40%), followed by azonal (27%). Steatosis grade positively correlated with portal inflammation (P = 0.018). Azonal distribution positively correlated with presence of hepatocyte ballooning (P = 0.03). Biopsies with mixed steatosis were approximately 20 times more likely to have megamitochondria than those with macrovesicular steatosis alone (95% confidence interval 2.3–204.9). There was no relation between steatosis amount, type, or distribution to fibrosis stage. Conclusions: Specific histological patterns of steatosis in children are associated with histological markers of steatohepatitis. Ballooning and portal inflammation correlated well with features of steatosis.

Atherogenic dyslipidemia and cardiovascular risk in children with nonalcoholic fatty liver disease

Abstract Nonalcoholic fatty liver disease is now regarded as the most common form of chronic liver disease in adults and children. The close association between nonalcoholic fatty liver disease(NAFLD) and the metabolic syndrome has been extensively described. Moreover, a growing body of evidence suggest that NAFLD by itself confers a substantial cardiovascular risk independent ofthe other components of the metabolic syndrome. Given the significant potential for morbidity and mortality in these patients, and the large proportion of both pediatric and adult population affected, it is important that we clearly define the overall risk, identify early predictors for cardiovascular disease progression, and establish management strategies. In this article, we will focus on current data linking NAFLD and the severity of liver damage present in children with cardiovascular risk.

Reversal of protein-losing enteropathy after liver transplantation in a child with idiopathic familial neonatal hepatitis.

Protein-losing enteropathy (PLE) is characterized by an abnormal loss of serum proteins into the gastrointestinal tract, resulting in hypoalbuminemia, edema, and decreased immunity. Causes of protein loss from the gastrointestinal tract can be divided into 3 categories: (1) loss from intestinal lymphatics, which can be primary (primary intestinal lymphangiectasia) or secondary due to lymphatic obstruction (as seen in retroperitoneal fibrosis and lymphoma) or increased lymphatic pressure (as seen in constrictive pericarditis and portal hypertension); (2) loss from the mucosal surface after disruption of the mucosa by infectious, immunological, or vasculitic disorders; and (3) loss for metabolic reasons due to congenital disorders of glycosylation (CDGs) or heparan sulfate deficiency. The diagnosis of PLE should be suspected in patients with hypoproteinemia in whom other causes, such as proteinuria, malnutrition, and impaired protein synthesis due to liver diseases, have been excluded. The association between PLE and liver cirrhosis has been described in the literature, but there is no single mechanism to explain this association. PLE in liver disease could be due to portal hypertension and congestive gastropathy or the coexistence of primary intestinal lymphangiectasia and liver disease. The only known clear association between liver disorder and PLE is found in patients with CDG1b. Here we describe a case of PLE in a pediatric patient with cirrhosis that was completely resolved after liver transplantation. CASE REPORT

Response to hepatitis A vaccine in children with inflammatory bowel disease receiving infliximab

We read with great interest the recent article by Radzikowski et al on immunogenicity of the hepatitis A virus (HAV) vaccine in pediatric patients with inflammatory bowel disease (IBD). As outlined by the authors, there are few studies investigating the immune response to vaccinations in children with IBD. The authors specifically looked at immunogenicity of the HAV vaccine in pediatric IBD patients when compared to healthy controls. They vaccinated eligible patients with Havrix (GlakoSmithKline, Rixensart, Belgium), on a two-dose schedule of 0 and 6–12 months. They measured total anti-HAV antibodies prevaccination, at 4 and 12 weeks after the first dose, and 4 and 12 weeks after the second dose. Among the 66 IBD patients and 68 control patients, they found no significant difference in seroconversion after the second dose of the vaccine between the two groups (97% vs. 100%, P 1⁄4 0.2407). 6-Mercaptopurine (6-MP) or azathioprine (AZA) treatment with and without steroids did not affect seroconversion rates, but monotherapy with steroids reduced the rate of seroconversion at 4 weeks after the second dose. Their results were consistent with existing reports of HAV seroconversion in healthy patients and in patients with chronic liver disease. Of note, none of the patients in the study were on a biologic medication, such as infliximab. Herein we aimed to investigate the immunogenicity of the HAV vaccine in pediatric IBD patients receiving infliximab. We screened 100 patients for total anti-HAV antibodies and found that 14 patients (14%) had protective antibodies. We were able to enroll 12 patients who did not have anti-HAV antibodies to receive the full series of the vaccine. We used Havrix on a 0 and 6–12 months schedule, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units (ELU) per 0.5 mL for patients less than 19 years of age and 1440 ELU per 1 mL for patients 19 years of age and older, per the manufacturer’s recommendations. We checked the total anti-HAV prevaccination and 4 weeks after the second dose of the vaccine. The mean age at time of vaccination was 18.3 years (range 13–23 years) with a mean age at IBD diagnosis of 12.8 years. There were eight males and four females in the study. Overall, we found a seroconversion rate of 92% (11/12 patients) when the total anti-HAV was rechecked 4 weeks after the second dose. All of the patients were receiving infliximab at the time of vaccination and none of the patients were on concurrent steroids or 6-MP/AZA. Of note, two of the patients were on concurrent methotrexate, both of whom were responders to the HAV vaccine. In summary, we found a high rate of seroconversion to HAV vaccination in pediatric patients treated with infliximab for IBD. Taken together with the results of the study by Radzikowski et al, there is convincing evidence that pediatric IBD patients on a wide variety of medications for control of their disease are likely able to respond adequately to the HAV vaccine.