Diagnostic and Therapeutic Challenges in Pediatric Primary Sclerosing Cholangitis

Transcription

1 LIVER TRANSPLANTATION 18: , 2012 REVIEW Diagnostic and Therapeutic Challenges in Pediatric Primary Sclerosing Cholangitis Benjamin L. Shneider Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children s Hospital of Pittsburgh of UPMC, Pittsburgh, PA Sclerosing cholangitis, an uncommon disorder in children, is progressive and is, therefore, an important indication for pediatric liver transplantation. This review summarizes current challenges in the diagnosis and treatment of this rare form of pediatric liver disease. Liver Transpl 18: , VC 2011 AASLD. Received November 16, 2011; accepted November 22, Primary sclerosing cholangitis (PSC) is relatively infrequent in children with a likely incidence less than 20% of that reported for adults (ie, approximately 0.2 cases per 100,000 patient years). 1,2 Despite this, PSC remains an important cause of morbidity and mortality in children and accounted for approximately 2% to 3% of the liver transplants performed in children in the United States between 1988 and The 5 largest pediatric PSC series include only 214 cases in all, and these cases were referred to the centers over an average period of 16 years (ie, 2-3 cases per year). 4-8 These single-center reports all derive from transplant-affiliated programs, so we must assume a bias toward more severe cases. This is especially relevant when we are considering issues related to the prognosis. The development of an evidence-based approach to the diagnosis and management of PSC in children is especially problematic because of the relatively limited and anecdotal published data. There are no controlled therapeutic trials for pediatric PSC, and the published data often include varying treatment regimens applied to heterogeneous patient populations over long periods of time As a result, paradigms designed for the care of adults have been used for children. This reliance on adult-derived clinical approaches presumes that PSC in children is similar to PSC in adults. However, evidence suggests that PSC in children is different and is not simply an earlier disease stage. Some inherited diseases and immunological defects may produce a clinical picture similar to PSC. These entities usually present clinically during childhood and may have an expanded spectrum of disease including milder variants that are labeled as PSC when they are unrecognized. For example, mild to moderate defects in the adenosine triphosphate binding cassette B4 (ABCB4) gene (multidrug resistance protein 3) are a likely cause of a number of cases of small-duct PSC in children. 12,13 The overlap syndrome of autoimmune hepatitis (AIH) and PSC appears to be significantly more common in children. Many reports have shown that children with PSC have higher serum alanine aminotransferase/aspartate aminotransferase and gamma-glutamyl transpeptidase levels than their adult counterparts. This has been interpreted as evidence of a distinct disease process. Finally, many of the important and potentially life-threatening sequelae of PSC, such as cholangiocarcinoma, are rarely observed in childhood; a Abbreviations: ABCB4, adenosine triphosphate binding cassette B4; AIH, autoimmune hepatitis; PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid. This review was presented in part at an American Association for the Study of Liver Diseases/North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition pediatric symposium (Update on Pediatric Autoimmune Diseases), which was held in San Francisco, CA on November 4, Address reprint requests to Benjamin L. Shneider, M.D., Pediatric Gastroenterology, Hepatology, and Nutrition, Children s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA Telephone: FAX: ; benjamin.shneider@chp.edu DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2011 American Association for the Study of Liver Diseases.

2 278 SHNEIDER LIVER TRANSPLANTATION, March year-old was the youngest pediatric patient with PSC to develop cholangiocarcinoma. 14,15 Thus, many of the clinical approaches used in the care of adults may not be applicable to children. The focus of this summary is the diagnosis and treatment of pediatric PSC. DIAGNOSIS Figure 1. High-power view of a portal tract from a child with PSC. The portal tract has been expanded with a mixed inflammatory infiltrate. The bile duct structures are highlighted by cytokeratin 19 staining. Bile duct proliferation and injury are evident. The limiting plate of the portal tract is not completely intact because there is minimal encroachment of inflammatory cells into the lobule. It is not clear that this biopsy sample should be considered indicative of autoimmune overlap. When we consider diagnostic criteria for PSC, we need to be cognizant of the question that we are trying to answer by making a specific diagnosis. Some are seeking an academic/research answer, some are seeking a prognosis, and others are seeking insight into therapeutic approaches. The rigor of a diagnostic investigation is influenced to some extent by the question being asked. This presumes that PSC is a single disease with a single prognosis and treatment regimen. Consider these 2 relatively common scenarios. First, a teenager with inflammatory bowel disease who is screened for liver disease is found to have minor elevations in his liver enzyme levels; his magnetic resonance cholangiopancreatography findings are normal, and a biopsy sample reveals chronic biliary injury. Second, a teenager who presents with gastrointestinal bleeding from varices is found to have biliary cirrhosis and marked abnormalities in the intrahepatic and extrahepatic biliary tree. One could go on and on. It is certainly plausible and is in fact likely that pediatric PSC is the clinicopathological picture of many different disease processes. The diagnosis of PSC often requires a high index of suspicion. The measurement of gamma-glutamyl transpeptidase levels is important for identifying potential biliary disease in children because elevated levels of alkaline phosphatase are associated with bone growth. Unfortunately, gamma-glutamyl transpeptidase is not part of most standard panels of hepatic function testing, so clinicians must consider requesting this test for the assessment of all children with chronic liver disease. Serum transaminases may be more significantly elevated in children versus adults. 16 During the process of diagnosing PSC in children, a variety of causes of chronic liver disease, including cystic fibrosis and ABCB4 disease (which can mimic PSC), need to be excluded. 12,13,17 Standard serological testing for autoimmune diseases, including immunoglobulin G subtypes, may be useful but perhaps not specific. Many clinicians suggest that PSC and PSC-AIH overlap are distinct in terms of both the prognosis and the treatment. This important issue is not completely clear (as discussed later). Blood testing often suggests PSC, but its ultimate diagnosis requires further substantiation, usually with cholangiography, liver biopsy, or both. Magnetic resonance cholangiography is an appropriate first biliary imaging approach in children and often circumvents the need for endoscopic approaches. 18,19 Careful attention to the technical details of the approach is required to generate optimal and potentially diagnostic images. 20 Stricturing or diffuse irregularities/ beading of the extrahepatic biliary system (or both) are diagnostic in the appropriate clinical setting. It is less clear whether these lesions in the intrahepatic system or more subtle findings such as pruning and parallelism are diagnostic (Fig. 1). Other findings of unclear significance are smooth dilation of the common bile duct and enlargement of the gallbladder. In select circumstances, a more invasive endoscopic approach, endoscopic retrograde cholangiography, may be required to support a diagnosis of PSC. An alternative invasive approach to diagnosis is liver biopsy. Liver biopsy may have great relevance for children, especially for the diagnosis of small-duct PSC and the identification of histological features of autoimmune or immune-mediated disease. 21 The pathognomonic finding of concentric periductular fibrosis (also known as onion skinning) is unfortunately not commonly observed in needle biopsy samples of the liver. Often, more subtle markers of biliary injury (eg, ductular proliferation or periductular inflammation) with variable degrees and types of portal infiltration are seen (Fig. 2). These findings are often reported as being consistent with PSC, although they are not diagnostic in their own right. Fibrosis is also staged via liver biopsy, although the prognostic significance of the staging is not clear. A potential key finding is the presence or absence of features of immune-mediated hepatitis. These features include interface hepatitis and a lymphoplasmacytic portal infiltrate. Caution is advised in differentiating biliary hepatitis from lymphocytic interface hepatitis. It is presumed that features of immune-mediated hepatitis indicate a somewhat different pathophysiology, and this may be accompanied by a different prognosis and/or response to immunosuppressive therapy. This

3 LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 SHNEIDER 279 Figure 2. Magnetic resonance cholangiography image from a child with PSC. The intrahepatic bile ducts appear to be slightly irregular and somewhat pruned. The extrahepatic duct is not well visualized on this image. The gallbladder is large. The findings are potentially consistent with a diagnosis of PSC, although they are not the classical findings. presumption has not been formally proven, nor have the features of immune-mediated hepatitis in PSC been subjected to a rigorous analysis of reliability. In many circumstances, blood work, cholangiography, and liver biopsy are all required to provide support for a diagnosis of PSC. Many of the features may be suggestive but not diagnostic, and this can make clinical decision making more difficult. It is not clear, however, that liver biopsy is required in all cases, especially when laboratory findings suggest biliary disease and cholangiographic findings are characteristic. The added value in terms of the therapeutic approach and prognostic certainty should be considered in the decision to perform liver biopsy. MANAGEMENT OF PSC IN CHILDREN Dominant strictures are uncommon in children but can cause significant morbidity in select circumstances. Their management should be similar to that recommended for adults, although the risk of cholangiocarcinoma is probably less. Ursodeoxycholic acid (UDCA), bile acid binding resins, and rifampin have been used in the management of pruritus related to cholestatic liver disease in children, and they may be useful in children with PSC. 22 Evidence-based approaches to the management of portal hypertension in children are limited, although extrapolations have been made from consensus opinions for adults. 23 Hepatic osteodystrophy can occur in children with chronic cholestasis, although approaches to its monitoring and management are unclear. Bone disease can certainly be exacerbated by the chronic use of corticosteroids. Periodic measurements of serum calcium, magnesium, phosphorus, 25-hydroxyvitamin D, and parathyroid hormone levels in children with clinical or biochemical evidence of cholestasis are warranted. Calcium and vitamin D supplementation should be instituted for documented deficiencies. The vitamin E and vitamin A status should also be monitored in children with chronic cholestasis with the provision of appropriate supplementation. Bisphosphonate therapy in children remains controversial, so there is no current rationale for the routine monitoring of bone mineral density in children with PSC. Pharmacological therapy that is specifically directed at the treatment of PSC has unclear value for the prevention of the long-term progression of liver disease. Published data that have been derived from pediatric studies are uncontrolled, often lack hard endpoints, and are too heterogeneous to permit meaningful conclusions. Some negative conclusions, however, may also not be supported by existing data. For instance, the following conclusion was drawn from a retrospective analysis that included only 11 untreated children with PSC: Although pharmacological therapy may improve symptoms and liver tests initially, it does not seem to impact long-term outcomes. 7 At present, clinicians are forced to make judgments about the potential risks and benefits of PSC-specific pharmacological therapies. UDCA has a long history of use in the treatment of various pediatric cholestatic liver diseases despite an absence of firm data demonstrating its efficacy and a lack of regulatory approval in the United States for this indication. UDCA has generally been thought to be potentially helpful and at worst harmless, so clinicians have been comfortable in using it in pediatric patients with PSC. 6-9 Dramatic improvements in the biochemical evidence of liver disease have been observed in many children treated with UDCA. 8 A recent study calls into question the safety of UDCA for PSC. 24 In this randomized placebo-controlled trial, subjects receiving high-dose UDCA (28-30 mg/kg/ day) had a greater likelihood of reaching a clinically relevant negative endpoint in comparison with those receiving a placebo (eg, 15 of 76 UDCA subjects developed varices, whereas only 5 of 74 placebo subjects did). Clinicians now face a difficult decision about the continued use of UDCA in children with PSC. Are the findings of Lindor et al. s study 24 related to the dosing or to UDCA independently of the dosing? Is a lower dose safe? Anecdotal experience with adolescents who have not adhered to their medical regimens indicates that liver biochemistries may worsen in children who are withdrawn from UDCA therapy. What do we do when a patient s alanine aminotransferase and gamma-glutamyl transpeptidase levels go from 12 and 25 to 140 and 360 IU/L, respectively, in the context of UDCA withdrawal? A prospective investigation of UDCA withdrawal in children with PSC is underway and is beginning to address this issue (NCT ). At present, caution should be exercised in using UDCA at a dose greater than 20 mg/kg/day. Full disclosure

4 280 SHNEIDER LIVER TRANSPLANTATION, March 2012 of adult experiences with UDCA to the families of children with PSC is recommended before this therapy is employed. Immunosuppressive therapy, typically in the form of corticosteroids and azathioprine/6-mercaptopurine, is an accepted therapy for PSC with an AIH overlap. 6-8 The rationale for the presumed efficacy of the approach primarily stems from the experience of treating AIH. There is no question that these medications have potential toxicity. One critical question is what constitutes overlap. It is not certain that meeting the International Autoimmune Hepatitis Working Group criteria is sufficient. 25 The biochemical response to UDCA alone in children with positive autoimmune markers and histological findings inconsistent with AIH was significant. 8 This calls into question which children with PSC require immunosuppressive therapy. At present, a clear answer is not available. According to current evidence, a trial of corticosteroids with or without azathioprine is reasonable if the liver histology examination shows interface hepatitis, the immunoglobulin G levels are elevated, and autoimmune markers are present. A careful stepwise introduction of therapies with careful monitoring of the responses may be required. One wonders whether these patients would respond to UDCA alone and what the histological response would be. A rigorous prospective and multicenter analysis of histological findings for pediatric PSC with respect to responses to therapy is essential. Oral vancomycin has been used in a limited number of individuals with PSC as a novel therapeutic approach. Preliminary studies have shown a significant biochemical response that is reversed with the withdrawal of the medication but that can be reinduced with the reinstitution of vancomycin. 10 The exact mechanisms of the effects of oral vancomycin are not known. Ongoing investigations may shed more light on the utility of this novel approach (NCT and NCT ). Just as with the aforementioned therapies, the effects on long-term outcomes are unknown. Liver transplantation is a successful treatment modality for advanced liver disease; the 1-year survival rates in children may be higher than the rates for other pediatric liver diseases. 3 Decompensated cirrhosis is a clear indication for transplantation, whereas dominant stricture formation with or without recurrent cholangitis is a more complicated indication. In a US study, the mean Pediatric End-Stage Liver Disease score at the time of liver transplantation for children with PSC was 6. 3 These children often had complications of portal hypertension (eg, ascites or gastrointestinal bleeding), although their mean platelet count was /ll. On average, they had relatively compensated disease, which manifested with an average international normalized ratio of 1.5 and an average albumin level of 3.2 g/dl. Recurrent PSC occurred in up to 10% of the recipients at an average of 18 months after transplantation. Thus, a careful assessment of the timing of transplantation in children with PSC is essential. In summary, PSC in children likely represents a clinicopathological picture resulting from several different pathologies. The diagnosis relies on the judicious use of biochemical and serological testing, cholangiography, and liver biopsy. A number of drug treatments have been shown to alter the biochemical evidence of liver disease in pediatric patients with PSC. The efficacy of these pharmacotherapies in influencing the long-term prognosis of children with PSC is unknown, so clinicians must make judgments about the risks and benefits of existing treatment regimens. Liver transplantation is a very successful treatment modality for PSC, although the ideal timing for its utilization in children is not well understood. REFERENCES 1. Card TR, Solaymani-Dodaran M, West J. Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study. J Hepatol 2008;48: Kaplan GG, Laupland KB, Butzner D, Urbanski SJ, Lee SS. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol 2007;102: Miloh T, Anand R, Yin W, Vos M, Kerkar N, Alonso E; for Studies of Pediatric Liver Transplantation Research Group. Pediatric liver transplantation for primary sclerosing cholangitis. Liver Transpl 2011;17: Debray D, Pariente D, Urvoas E, Hadchouel M, Bernard O. Sclerosing cholangitis in children. J Pediatr 1994; 124: Wilschanski M, Chait P, Wade JA, Davis L, Corey M, St Louis P, et al. Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis. Hepatology 1995;22: Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, Mieli-Vergani G. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33: Feldstein AE, Perrault J, El-Youssif M, Lindor KD, Freese DK, Angulo P. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology 2003;38: Miloh T, Arnon R, Shneider B, Suchy F, Kerkar N. A retrospective single-center review of primary sclerosing cholangitis in children. Clin Gastroenterol Hepatol 2009; 7: Gilger MA, Gann ME, Opekun AR, Gleason WA Jr. Efficacy of ursodeoxycholic acid in the treatment of primary sclerosing cholangitis in children. J Pediatr Gastroenterol Nutr 2000;31: Davies YK, Cox KM, Abdullah BA, Safta A, Terry AB, Cox KL. Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic. J Pediatr Gastroenterol Nutr 2008;47: Ibrahim SH, Lindor KD. Current management of primary sclerosing cholangitis in pediatric patients. Paediatr Drugs 2011;13: Jacquemin E, De Vree JM, Cresteil D, Sokal EM, Sturm E, Dumont M, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001;120: Ziol M, Barbu V, Rosmorduc O, Frassati-Biaggi A, Barget N, Hermelin B, et al. ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults. Gastroenterology 2008;135:

5 LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 SHNEIDER Björnsson E, Angulo P. Cholangiocarcinoma in young individuals with and without primary sclerosing cholangitis. Am J Gastroenterol 2007;102: Deneau M, Adler DG, Schwartz JJ, Hutson W, Sorensen J, Book L, et al. Cholangiocarcinoma in a 17-year-old boy with primary sclerosing cholangitis and inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011; 52: Floreani A, Zancan L, Melis A, Baragiotta A, Chiaramonte M. Primary sclerosing cholangitis (PSC): clinical, laboratory and survival analysis in children and adults. Liver 1999;19: Sinha J, Morotti RA, Norton KI, Gold D, Shneider BL. Cystic fibrosis in an adolescent being evaluated for primary sclerosing cholangitis. Semin Liver Dis 2006;26: Chavhan GB, Roberts E, Moineddin R, Babyn PS, Manson DE. Primary sclerosing cholangitis in children: utility of magnetic resonance cholangiopancreatography. Pediatr Radiol 2008;38: Ferrara C, Valeri G, Salvolini L, Giovagnoni A. Magnetic resonance cholangiopancreatography in primary sclerosing cholangitis in children. Pediatr Radiol 2002;32: Chavhan GB, Babyn PS, Manson D, Vidarsson L. Pediatric MR cholangiopancreatography: principles, technique, and clinical applications. Radiographics 2008;28: Batres LA, Russo P, Mathews M, Piccoli DA, Chuang E, Ruchelli E. Primary sclerosing cholangitis in children: a histologic follow-up study. Pediatr Dev Pathol 2005;8: Yerushalmi B, Sokol RJ, Narkewicz MR, Smith D, Karrer FM. Use of rifampin for severe pruritus in children with chronic cholestasis. J Pediatr Gastroenterol Nutr 1999; 29: Shneider B, Emre S, Groszmann R, Karani J, McKiernan P, Sarin S, et al. Expert pediatric opinion on the report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. Pediatr Transplant 2006;10: Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50: Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E; for International Autoimmune Hepatitis Group. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011;54: