Controversies in the management of pediatric liver disease: Hepatitis B, C and NAFLD: Summary of a single topic conference

The AASLD Hepatitis Single Topic Conference (STC) entitled "Controversies in the Management of Pediatric Liver Disease: Hepatitis B,C and NAFLD," was held at the Emory Conference Center on March 3 and 4, 2006. The conference was organized to juxtapose the current state-of-the-art in the management of pediatric liver disease with evidenced-based approaches that exist for the same problems in adults. The principal goal of the conference was to assess critically current management of hepatitis B and C, and NAFLD in children, since evidence-based approaches are generally lacking. The conference included formal didactic presentations by experts (Table 1A-C) and informal active discussions between faculty and conference participants. The informal discussions were very animated and educational including both question and answer sessions and case discussions. Herein, we synthesize some of the information presented during the proceedings. Our aim with this summary is to highlight salient issues that were discussed in the STC rather than present a comprehensive review of the topics or formulate consensus statements. Individual sections have been reviewed by the faculty for that particular section, although they are not co-authors per se. The success of the conference was due in large part to the active exchange of information that took place between faculty and the participants. The complex biology and natural history of hepatitis B virus (HBV) coupled with recent advances in therapeutic approaches makes clinical decision-making in this common infection very problematic. A relatively limited published dataset related to HBV in children has left the clinician without clear-cut clinical guidelines for nearly all aspects of the care of children with chronic HBV infection. The presentations (Table 1A), case discussions and question and answer sessions at the STC highlighted marked differences in approaches to HBV infection in children by clinicians who have longstanding expertise in the management of childhood liver disease. In addition, it was also notable that the application of adult HBV guidelines to children is problematic and potentially not appropriate, since children are typically in a different stage of HBV infection and are at lower near-term risk of developing significant morbidity and mortality.1 Currently, there are National Institutes of Health (NIH)-funded multi-center studies of hepatitis C virus (HCV) and nonalcoholic fatty liver disease (NAFLD) in children and adults but there is a notable absence of similar investigations of HBV infection in children or adults. A careful and critical understanding of the natural history of HBV infection in children is essential in making informed decisions regarding monitoring and treatment. One needs to be cognizant of the effects of HBV genotype and potential environmental effects in different regions of the world when analyzing the natural history of HBV. Thus, longitudinal data from Southeast Asia may not necessarily be applicable to Western Europe or North America. It is useful to subdivide chronic HBV infection in children into perinatal versus other modes of transmission. Perinatal transmission of HBV is typically characterized by an immunotolerant state that is presumed to be fostered by prenatal transplacental fetal exposure to the HBeAg. Children who have perinatally acquired HBV infection usually have normal or near normal serum aminotransferases, very high serum HBV DNA levels and persistent HBsAg and HBeAg positivity (Fig. 1, Box A). They typically maintain this pattern of laboratory test results for most of childhood and often into adulthood. Spontaneous HBeAg seroconversion may occur during the immunotolerant HBV phase, although the rates during early childhood are low.2 Seroconversion rates are generally less than 2% before the age of 3 years and then HBeAg seroconversion occurs at a rate of approximately 4% to 5% per year. HBeAg seroconversion rates are higher for individuals with elevated aminotransferase levels. In the United States, immunotolerant perinatally acquired HBV infection represents approximately 50% of children with chronic HBV infection. Childhood acquired HBV infection is usually characterized by somewhat lower circulating levels of HBV, more biochemical evidence of hepatitis and higher rates of spontaneous eAg seroconversion. Seroconversion rates are higher for genotype B relative to C.3 It is not widely appreciated that spontaneous HBeAg seroconversion may be associated with significant elevation of aminotransferases, generally ascribed to immune mediated cytolysis. This stage may persist for months to years during which substantial liver damage can be accrued before HBeAg seroconversion (Fig. 1, Box B).4 Thus, it can be very difficult to assess the stage of disease in a child with chronic HBV infection from a single set of laboratory values. In some children HBV precore mutants that prevent HBeAg production are selected. These children may have persistent elevation in aminotransferases and relatively high levels of HBV DNA in serum after HBeAg seroconversion.5 Most children who undergo HBeAg seroconversion will be in the inactive carrier state for years to decades. Natural History of HBV Infection and Potential Interventions. (Modified from DS Chen. From hepatitis to hepatoma : Lessons from type B viral hepatitis. Science 1993;262:369-370. Part or all of this figure originally modified from D-S Chen, J. Gastroenterol. Hepatol. 8 470 (1993), Blackwell Scientific Publications. Reprinted with permission. With the implementation of universal newborn immunization against HBV in 1984 in Taiwan, the HBsAg seroprevalence rate was dramatically reduced.6 The incidence of hepatocellular carcinoma (HCC) in children aged 6 to 14 dropped more than 50% from 263 cases/48,764,799 (0.54 cases/100,000) to 35 cases/17,817,510 (0.20 cases/100,000). It is worth noting that even in the pre-vaccination era the incidence of HCC in childhood was less than 0.01% (assuming a 10% prevalence of HBVsAg). Annual mortality from HBV-related fulminant hepatitis decreased 3-fold after vaccination was implemented.7 Similar results have been described as a result of routine immunization efforts in Alaska.8 Routine immunization initially resulted in an increase in the percentage of infected children with HBV surface gene "a" determinant mutants, although the total number of children with HBV surface mutants has dropped in recent years due to the marked reduction in the number of HBV positive children.9 This should not be construed as an argument against immunization, which has led to remarkable improvements in HBV related morbidity and mortality. It is clear that routine HBV vaccination programs result in decreased disease burden and should be considered where financially feasible (Fig. 1, Box C). There are only a limited number of long-term studies of HBV starting in childhood. One of the most common questions that arises relates to the prognosis for children with chronic HBV. The answer to that question is often derived based upon cross-sectional data from adult cohorts followed in tertiary care centers. A 25% lifetime risk of developing HCC is often given, although this risk estimate does not emanate from longitudinal analysis of HBV infection first diagnosed in childhood. In addition, these estimates are based upon cohorts from Southeast Asia and it is not certain whether they can be extrapolated to other patient populations. Since current screening and treatment approaches are based upon these estimates, accurate assessment of risk is of critical importance. In Taiwan, Chang prospectively analyzed the course of 415 children with chronic HBV for an average of nearly 8 years. In this cohort only two children developed cirrhosis, one of whom developed HCC.2 Long-term follow up of 174 children in Montreal revealed one child with cirrhosis and no cases of HCC.10 Tenyear follow up of 73 children in the United Kingdom revealed no cases of cirrhosis or HCC.11 Eighteen-year follow up of a cohort of children in Italy identified 3 children who had HCC, although it was identified at presentation in all three cases.12 Unfortunately, at present there are inadequate numbers of patients with sufficiently long follow-up to give an accurate assessment of the lifelong risk and/or predictors of serious morbidity and mortality in children with chronic HBV. Hepatocellular carcinoma has been reported in children with chronic HBV.8, 13, 14 The case series typically are collected from a cross-sectional or retrospective analysis in a single center and are not typically the result of prospective analyses. There are biases toward the publication of series with larger numbers of cases. Although anecdotal cases of HCC in the first years of life exist.15, 16 when liver cancer occurs in childhood, it occurs much more commonly in the second decade of life. Since denominators are not available in most of the series published, it is nearly impossible to assess an accurate risk of development of HCC before the age of 20 years in children with HBV infection acquired early in life. Informal discussions in the STC revealed that in light of the reported cases of HCC in children, significant and costly efforts are often undertaken in both screening and treatment. Many clinicians obtain serum alpha fetoprotein levels biannually and surveillance abdominal ultrasonography on an annual basis. Interestingly, typical screening efforts in adults are not recommended until the age of 40 or 50 except for those with cirrhosis or a family history of HCC (Fig. 1, Box D).17 Thus children who transition to adult practices may have their surveillance discontinued for 20 or 30 years. It must be acknowledged that much of this screening in children stems from medicolegal concerns. There are no data to suggest that screening for HCC in children with HBV is cost-effective, nor is there evidence that it alters the natural history of the disease in childhood. Thus, it can be concluded that there is no standard of care that requires screening for HCC in children with chronic HBV, although one might consider it in children with advanced fibrosis or cirrhosis of a family history of HCC. The STC highlighted significant controversies revolving around the issue of the indications for and methods of treatment of chronic HBV in children. There was general agreement that the ultimate goal of therapy is to reduce the morbidity and mortality related to the development of cirrhosis and HCC. Prevention of spread of HBV and social concerns have become less pronounced reasons for treatment due to effective active and passive immunization strategies. Although there is some data in selected adults that treatment may reduce the risk of development of HCC, no data in children show statistically and clinically relevant reductions in morbidity and mortality as a result of current treatments applied during childhood. This issue is further complicated by spontaneous HBeAg seroconversion that often occurs during childhood.4 Current trends of using nucleoside analogs in treating adults to reduce HBV viral loads are of limited relevance to the child with immunotolerant HBV infection.18 A major concern is long-term safety and efficacy of nucleoside analogs. Approved nucleoside analogs except for lamivudine have limited safety record even among adults, and resistance has been reported in association with all nucleoside analogs. There was active debate regarding the indications for treatment in children. If there was a general consensus it was that treatment might be considered for children with biochemically and histologically active disease who may be at higher risk to develop cirrhosis during childhood. Identifying these patients may be difficult since these findings are common in children undergoing spontaneous HBeAg seroconversion. Active disease in this setting for more than six months may be an indication to consider treatment both in HBV infected children and adults. Interferon (IFN) and lamivudine are both approved as single agents by the Food and Drug Administration for the treatment of HBV in children, based in part upon randomized clinical trials.19, 20 When therapy is indicated, the preferred choice of therapeutic agent is not clear. Durable response rates seem to be higher with IFN, although its use is associated with significant toxicity. By contrast, lamivudine is significantly safer than IFN but prolonged use of lamivudine is often associated with the emergence of resistant viral strains, which may limit its future use as part of combination therapy. This issue may be particularly problematic given the long expected lifespan for children. Rapid and on-going advances in understanding the biology and treatment of HBV makes the future very bright for children with this infection. New approaches to the management of HBV in children are clearly indicated. Ultimately it would be most useful to interrupt this chronic infection at a time before there is irreversible progression to an increased risk of HCC (Fig. 1, Box E). Unfortunately, the timing of this stage is not well understood. A novel approach to the treatment of immunotolerant HBV was presented by Dr. Giorgina Mieli-Vergani.21 That approach, which was evaluated in only a limited number of children, utilized sequential and combination therapy with lamivudine and IFN. Significant numbers of patients underwent both HBeAg and HBsAg seroconversion, which is very different than previous experience with combination therapy in adults. If confirmed in subsequent studies, this could represent a tremendous advance in the approach to the management of HBV in children. Ultimately, if these findings can be replicated and/or improved in prospective multi-center studies, this approach may yield the greatest long-term reduction in the risk of development of HCC. As new therapeutic agents become available it will be critically important to reassess the end-points utilized in determining the effectiveness of specific therapies in children. Identification of predictors of future risk of cirrhosis and/or HCC is another priority in pediatrics. It is hoped that a future conference might focus on this important issue. Ideally this discussion should include active input from the Food and Drug Administration, the NIH, the pharmaceutical industry, the lay public and clinicians actively participating in research related to and care of children with HBV. STC, single topic conference; HBV, hepatitis B virus; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NIH, National Institutes of Health; Ag, antigen; Ab, antibody; HCC, hepatocellular carcinoma; PCR, polymerase chain reaction; RNA, ribonucleic acid; SVR, sustained virologic response; NASH, nonalcoholic steatohepatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; IFN, interferon; Peg, pegylated; AT, aminotransferase. Hepatitis C virus infection is a major global health problem. In the United States, there are approximately 7 million adults and 70-100,000 children infected with HCV.22-24 The financial burden of this viral infection is staggering with projected medical costs of $10.7 billion in adults in the years 2010-2019 and $199—426 million over the next 10 years in children.23, 25 While the incidence of HCV infection has significantly decreased since the implementation of reliable blood-bank screening strategies, maternal-infant transmission remains an important route of transmission.26 By contrast to HBV, there is no reliable strategy to prevent maternal-infant HCV transmission and screening all pregnant women for HCV infection does not appear to be cost-effective.27 Although young infants may not be suitable candidates to receive currently available antiviral therapies, they are at some risk of developing chronic liver disease. Therefore, early detection of HCV infection in young infants may be useful in selecting a unique group who would benefit from judicious medical monitoring. To screen infants born to mothers with HCV infection one reasonable approach is to test for the presence of anti-HCV in serum at 12-18 months of age, when maternally derived antibodies have disappeared. Advocates of this approach highlight its economical advantage as this strategy relies on relatively inexpensive and that is by HCV infection at an as during the STC, may be useful in selected cases where the potential of an infection results in significant the risk of transmission.26 In this setting HCV infection with is and may be worth the infants with HCV in should be as spontaneous viral may occur during childhood. A recent large that spontaneous viral was more common with HCV genotype 3 than other and after 3 years of reliable management guidelines on the of accurate information its natural the STC there was a clear that data is regarding the long-term of infected with HCV during childhood and in this This of data may to potentially application of adult data to children infected with available information on retrospective that HCV infection is generally a in children but significant liver disease including chronic cirrhosis and HCC can As in adults, children with liver are more to have disease than those with normal liver but advanced liver disease may be even in those without biochemical Liver disease does not appear to with specific HCV or circulating levels of HCV in There are no specific guidelines to care for children with chronic HCV infection. Conference that these young individuals should be for disease The clinical should include a careful assessment for liver including liver and of viral potential of liver disease should be in children with liver issue which animated debate was related to the to the of chronic HCV infection to programs or other similar Although the to may between some that the social associated with an disease the potential of particularly in the current era of universal for liver cancer in children with chronic HCV infection is particularly problematic there are only reported cases of HCC in and young adults with infection and all had It that HCC is a in children with HCV infection but those with significant fibrosis or cirrhosis should undergo data is monitoring children with significant fibrosis or cirrhosis with serum of and abdominal as in adults seem The for and timing of a liver is another issue that led to debate during the significant may be even in children with normal liver some that a liver should be as part of the since this information was critically important to assess the of By contrast, this approach the potential associated with this and the in most infected children. methods to assess liver fibrosis including and appear in but they have not been evaluated in children. In the STC that a liver as for other should be considered only if the results will medical A liver may be useful in children who are considered for antiviral treatment. in that the for assessment is particularly for those infected with HCV or 3 who have a high of a sustained virologic response with currently available treatments (Table Although clearly very is the of HCV infection in children. evidence in adults that a in liver have understanding of the disease and may to new therapies and strategies. there are differences in both and between children and adults may the to children should on a risk to develop liver disease. Children liver disease would be more to would be those expected to have a course would be treatment and as the natural history of chronic HCV infection in children is and risk associated with disease progression in this are if and when to children is currently a and (Table children should not be antiviral treatment on the of their The use of treatment in clinical of IFN for childhood HCV makes it difficult to but appear in children than in adults of the in adults, have IFN in in 73 of children with IFN in these randomized clinical in adults virologic response rates with the use of particularly when with To only two published have evaluated IFN in children with chronic In one of children with HCV genotype of given In the other of children with with an SVR, virologic response was in only of of those with HCV genotype associated with a response to IFN or in combination with in children are similar to those in adults and include infection with HCV or 3 and HCV levels. In one children than years of age to As in adults, children had response rates to combination treatment than but the number of patients limited the virologic response rates are similar between children with normal and serum that may response early in the course of treatment and in therapy in adults, as early virologic response and of have not been in are common in children during treatment with IFN or in combination with and include and In contrast to adults, the rates of appear to be similar between children with IFN or with the pediatric data from and studies, which currently to therapeutic The results of the a or with will treatment for children with HCV infection. In a relatively of significant have been in understanding of HCV particularly in adults. It is clear from the discussion that there is a critical for studies to the natural and of HCV infection in children to formulate evidence-based management for this unique The of multi-center as and the Pediatric Hepatitis C will the of this By contrast to the with chronic hepatitis B and even chronic hepatitis C in childhood in is the and natural history of nonalcoholic fatty liver disease (NAFLD) in for this is only at the of comprehensive and With to childhood NAFLD the at this conference was to the current of this in children and the for future research to treatment (Table was first described in adults in the on the of Since has been identified as part of a of chronic liver disease associated with on the liver and most often with or NAFLD as a of liver disease in without in associated with and and cirrhosis, which in adults often was reported in children in the early and NAFLD has to be in both adults and children (Table This is due to increased of the but the in and and in children, in the 20 years has to its increased Currently, the prevalence of fatty liver in children is at to A comprehensive review of clinical studies in pediatric NAFLD has been presented As in adults, represents the of NAFLD in the incidence of cirrhosis in childhood NAFLD is very but cirrhosis A of individuals developing HCC in after NAFLD as children have been NAFLD in adults is associated with and type and is considered to be the of the adult with NAFLD has of disease from to to be in most adult estimates suggest that over years of patients with will develop chronic with approximately one of these will on to develop and approximately of the cohort will develop who develop cirrhosis have a prognosis and a high risk of HCC. NAFLD in the after liver and of NAFLD after for cirrhosis a argument for regarding these patients as NAFLD in the first The the rate of disease progression in adult NAFLD are not They may include the of the the if is and as in adult NAFLD is levels of fatty appear to the important in the of the liver disease as they are the of the and including those and is also an important of the disease by is and and are which may development of when levels are decreased levels of Although the disease in NAFLD in children is not resistance a The of resistance in childhood is than that with Children with NAFLD are often of although present with abdominal which may to the children are identified with liver or a liver NAFLD occurs more in than in and the average age for is approximately although NAFLD may be diagnosed at age except in but not children are has been can be problematic since significant may be difficult to is present in in childhood NAFLD critical Children with are expected to have normal serum aminotransferases, but those with may also have normal serum When aminotransferases are the is higher than the AST, usually as may be a of in is with in serum although serum is elevated as levels are significantly elevated in children with NAFLD, but is is essential for the of is a although it may not be in the of is a specific pattern of liver it is not the of and in the absence of a disease In adults the findings include which may or or other of can include and and may be identified around This hepatocellular occurs in 3 of the is initially around and toward of may be as cirrhosis In children the of from that in adult and fibrosis to be and are typically of hepatocellular and are not are with fibrosis and fibrosis between may be The of may also toward and the is not in The for this between adults and children is not Current typically a clinical of NAFLD based on studies to biochemical of liver of and assessment of or or both are the acknowledged currently liver does not figure into the for or even to liver in the is as was in discussions at the The critical for to or to this was but there was also a consensus that liver should be early in the in children with significantly elevated of currently on determining the and it based on the age and of the child using for and Prevention or other of and data to and also for children. of or of remains a research at the present is at the reduction of clinical are available in children to show that is the treatment strategy for childhood Since resistance to in both and and most children with NAFLD are or a strategy for treatment should aim to and and with the of a The may be an effective and and it has been effective in or may be programs have not been evaluated in childhood NAFLD, and is by for in combination with the it and normal generally due to is associated with increased Drug treatment for childhood NAFLD has not been and are currently in an prospective multi-center at reduction in the child have not been in childhood NAFLD to These treatment include which of by of and and a They have been in with although issues to both safety and efficacy of these in this the of in children and has not been although it effective in some adults with important from experience with the treatment of is that all those with an important when for treating NAFLD in adults may have relevance to childhood NAFLD in the might include agents as or the and If have a in the disease of NAFLD, then of this by may be a novel approach to treatment. disease critical clinical and of NAFLD in children, and the natural history of the disease in children is critical for effective of clinical research to this disease. with developing therapy of this requires randomized research should on these issues in childhood The of a in needs children with a should NAFLD in most of This requires of normal for infants and children, as for by the Health and research to the of While these seem somewhat from the of they have relevance to this new important liver disease. The faculty for careful review of the and conference the

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