A Retrospective Single-Center Review of Primary Sclerosing Cholangitis in Children

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7: A Retrospective Single-Center Review of Primary Sclerosing Cholangitis in Children TAMIR MILOH,* RONEN ARNON,* BENJAMIN SHNEIDER, FREDERICK SUCHY,* and NANDA KERKAR* *Department of Pediatrics, Department of Surgery, and Recanati/Miller Transplant Institute, Mount Sinai Hospital, New York, New York; Department of Pediatric Gastroenterology, Children s Hospital of Pittsburgh, Pittsburgh, Pennsylvania Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and progressive bile duct fibrosis. There are limited data on pediatric PSC. Methods: We performed a retrospective chart review of 47 pediatric patients with PSC. Results: The mean age at was years. Symptoms occurred before presentation in 81% of patients; inflammatory bowel disease was found in 59% and autoimmune hepatitis (overlap syndrome) in 25% of patients. Magnetic resonance cholangiography revealed both extrahepatic and intrahepatic, isolated intrahepatic, isolated extrahepatic, and no biliary involvement (small-duct PSC) in 40%, 14%, 10%, and 36%, respectively. Advanced fibrosis (stage >II) was present in 65%. Colonoscopy revealed pancolitis, rectal sparing, and normal findings in 24%, 24%, and 18%, respectively. All patients were treated with ursodeoxycholic acid (UDCA); 9 with overlap syndrome also received immunosuppressants. Fifteen patients without overlap syndrome had positive autoimmune markers and responded to UDCA monotherapy. Liver transplantation was performed in 9 patients (3 with overlap syndrome and 2 with small-duct PSC) at a median time of 7 years after. The 10-year posttransplant survival rate was 89%. Conclusions: In one of the largest single-center studies of children with PSC, we found that most children with PSC had inflammatory bowel disease or autoimmune overlap and advanced fibrosis at. Levels of alanine aminotransferase and -glutamyl transferase were highest in patients with overlap syndrome and lowest in those with small-duct PSC. Levels of serum liver enzymes normalized after therapy with UDCA, including patients with positive autoimmune markers without histologic features of autoimmune hepatitis. Primary sclerosing cholangitis (PSC) is a chronic, insidious cholestatic liver disease of uncertain etiology, characterized by inflammation and progressive obliterative intrahepatic and/or extrahepatic bile duct fibrosis. 1 It may lead to cirrhosis, end-stage liver disease, cholangiocarcinoma, and the need for liver transplantation. In children, the incidence of PSC was reported as 0.23 cases per 100,000 person-years compared with 1.11 cases per 100,000 person-years in adults. 2 PSC is associated with inflammatory bowel disease (IBD) (without correlation between the severity and onset of PSC and IBD) and autoimmune hepatitis (overlap syndrome). 1 Recently, immunoglobulin G (Ig)4 was reported to be associated with a steroid-responsive cholangitis and may represent a distinct subtype of PSC. 3 Diagnosis of small-duct disease is made when the characteristic liver histology of PSC is accompanied by radiologically normal bile ducts. 4,5 Several series of children with PSC have been reported in the literature Most pediatric cases of PSC involve the intrahepatic bile ducts 7,9 with an apparent higher incidence of overlap syndrome with autoimmune hepatitis (AIH) in comparison with adults. 10 Ursodeoxycholic acid (UDCA) is conventionally recommended for patients with PSC. UDCA leads to biochemical improvement, decreases pruritus, and may lower the risk of colon cancer and cholangiocarcinoma. 4,12,13 However, it has not been shown to slow the course of disease or prolong survival Immunosuppressants may be beneficial in cases of overlap syndrome. 1 Most therapies are supportive and directed at managing complications (dominant stricture, pruritus, nutritional deficiencies, and cholangitis) rather than the underlying cause of PSC. Liver transplantation remains the only life-extending alternative for patients with end-stage PSC with a 1% to 33% recurrence rate. 4 In children, the median survival with native liver was reported to be 12.7 years. 10 The aim of this study was to characterize the pediatric population diagnosed with PSC in our center, adding to a relatively limited pediatric-specific published experience. Methods This retrospective chart review of 47 patients with PSC, who were seen in the pediatric liver program at the Mount Sinai Medical Center in NY between January 1995 and January 2007, was approved by the Mount Sinai Institutional Review Board. The of PSC was based on biochemical, histologic, and/or radiologic findings characteristic of PSC. Secondary causes including surgery, trauma, ischemia, tumors, and infections were excluded. The biochemical findings included a biliary profile ( 50% increase of alkaline phosphatase [ALP] or -glutamyl transferase [GGT] levels than the upper limit of normal for age). Liver biopsy specimens were reviewed in routine clinical practice at our institution by experienced pathologists. The Abbreviations used in this paper: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CD, Crohn s disease; ERCP, endoscopic retrograde cholangiopancreatography; GGT, gamma glutamyl transferase; IBD, inflammatory bowel disease; Ig, immunoglobulin; MRCP, magnetic resonance cholangiography; panca, perinuclear antineutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis; UC, ulcerative colitis; UDCA, ursodeoxycholic acid by the AGA Institute /09/$36.00 doi: /j.cgh

2 240 MILOH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 2 Table 1. Patient Demographics and Clinical Presentation Age at, y Mean, Median, 12 (range, 2 20) Sex, male/female 29/18 (62% male) Signs and symptoms at presentation Hepatomegaly 19 (40%) Abdominal pain 17 (36%) Diarrhea 13 (28%) Splenomegaly 11 (23%) Fatigue 11 (23%) Pruritus 9 (19%) Weight loss/delayed growth 9 (19%) Jaundice 8 (17%) Fever 6 (13%) Asymptomatic 9 (19%) IBD 28 (59%) UC 20 (42%) Crohn s colitis 8 (17%) Overlap 12 (25%) Overlap with IBD 6 (13%) Other conditions 8 (17%) Family history of autoimmune disease 7 (15%) specimens were stained with H&E and Masson s trichrome. The biopsy specimens were evaluated for histologic features of PSC and autoimmune hepatitis including bile duct injury, periductal fibrosis (onion-skinning) or inflammation, portal edema or fibrosis, fibro-obliterative cholangitis, ductopenia, ductular proliferation, cholestasis, and interface hepatitis. The stage of fibrosis was determined as follows: stage 1, portal fibrosis; stage 2, periportal fibrosis; stage 3, bridging fibrosis; and stage 4, cirrhosis. Autoimmune overlap was diagnosed based on PSC concomitant with histologic features of autoimmune hepatitis, namely interface hepatitis and lymphoplasmacytic infiltration. The international criteria for of autoimmune hepatitis were applied retrospectively to all children diagnosed with autoimmune overlap. 17 The radiologic features included multifocal strictures, focal dilatation, or beading of the biliary tree as assessed by either magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). The images were reviewed in routine clinical practice by a radiologist with experience in hepatobiliary imaging for involvement of the extrahepatic and intrahepatic bile ducts. Small-duct PSC was diagnosed in the setting of biochemical and histologic features consistent with PSC with a normal biliary tree on imaging. 4,10 All patients were followed up at our institution. When the was made before referral to Mount Sinai, the history and laboratory tests, imaging, and histology were reviewed by our hepatologists, radiologists, and pathologists, respectively. Laboratory blood tests obtained from all patients included complete blood counts, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALP, GGT, total and direct bilirubin and albumin levels, and prothrombin time. Serologic testing included total IgG, antinuclear antibody, anti smooth muscle antibody, antibody to the liver/kidney microsome type 1 and perinuclear antineutrophil cytoplasmic antibody (panca). Other liver diseases such as viral hepatitis, Wilson s disease, and -1 antitrypsin deficiency were ruled out by specific blood and/or urine tests. Colonoscopy to investigate for IBD was performed in all patients with gastrointestinal symptoms and, in a few asymptomatic patients, as screening for IBD. The of IBD was confirmed on histology in conjunction with the endoscopic findings reported by the endoscopist. Results Patient Population and Clinical Presentation The main demographic and clinical data are summarized in Table 1. The patients who were asymptomatic at presentation were diagnosed based on abnormal liver test results detected during an unrelated medical evaluation or routine check-up screening patients with IBD. IBD was diagnosed concurrently with PSC in 59%, IBD was diagnosed first in 26%, and PSC was diagnosed first in 15% of patients. Twenty-five percent were diagnosed with autoimmune overlap. Two patients who underwent liver transplantation for PSC with overlap syndrome developed ulcerative colitis (UC) posttransplant. In 6 patients overlap syndrome was associated with IBD (5 UC and 1 Crohn s disease [CD]). Other comorbid conditions were 2 patients with mental retardation, 1 patient with celiac disease, 1 patient with malignant lymphoma, 1 patient with hypereosinophilia, 1 patient with hearing loss and nephropathy, 1 patient with spherocytosis, and 1 patient with cardiomyopathy who was a cardiac transplant recipient. Primary Sclerosing Cholangitis Diagnosis All 47 patients had biochemical evidence of biliary disease (increased serum GGT and/or ALP levels) with histologic and/or radiologic findings typical for PSC. The mode of is summarized in Table 2. Laboratory Features at Diagnosis The laboratory data at the time of is summarized in Tables 3 and 4. Ten patients had a total serum bilirubin level between 1 and 5 mg/dl and 2 patients had a bilirubin level greater than 5 mg/dl. The mean ALP level was within normal range in 9 patients. The mean GGT level was 9 times the upper limit of normal and was increased in all patients including those with normal ALP levels. The mean serum levels of ALT and AST were within normal range in 3 patients. Seven of 10 patients with positive panca also were diagnosed with IBD, and 50% of all patients who were diagnosed with concomitant IBD had positive panca. Fifteen patients (32%) had at least one positive autoimmune marker without histologic evidence of AIH. This group presented with a median IgG level of 1835 mg/dl (range, mg/dl) and lower ALT, AST, and GGT levels in comparison with the overlap group (Table 4). Table 2. Mode of Diagnosis Diagnostic studies Number of patients Percentage Liver biopsy Biopsy MRCP Biopsy ERCP 4 9 Biopsy MRCP ERCP 8 17 MRCP ERCP 14 30

3 February 2009 PSC IN CHILDREN 241 Table 3. Laboratory Data at Presentation Laboratory results at Mean SD median (range) Cholangiographic Features MRCP was performed in 39 patients. Cholangiographic involvement of both intrahepatic and extrahepatic bile ducts was found in 16 patients (40%), whereas 6 patients (14%) showed only intrahepatic and 4 (10%) had only extrahepatic PSC. Sixteen patients (36%) had normal MRCP or ERCP findings and were diagnosed with small-duct PSC. ERCP was performed on 14 patients and in 8 patients in conjunction with MRCP. Diagnostic ERCP after MRCP did not reveal new findings. The ERCP was normal in 2 patients, the latter 2 also had a normal MRCP. ERCP was used for papillotomy in the setting of gallstones and sludge in 5 patients. A stent was placed for a dominant stricture in 2 patients and a balloon dilatation was performed once in a patient presenting with an acute obstructive cholangiopathy. Six patients benefited from the intervention with a decline in bilirubin levels, and 2 patients had refractory jaundice ultimately requiring liver transplantation. Histologic Features Liver biopsies were performed on 45 patients (96%). All patients had histologic features of PSC. Stage 1 to 2 fibrosis was diagnosed in 16 patients (35%), bridging fibrosis in 25 patients (56%), and cirrhosis in 4 patients (9%). Twelve patients (25%) also showed interface hepatitis along with other histologic characteristics of AIH and were diagnosed with overlap syndrome. Of the 9 patients who were asymptomatic at presentation, 7 had fibrosis stages 3 to 4 on biopsy. Colonoscopic Features Normal range % abnormal Hemoglobin, g/dl (8 15) White blood cell count, /ul 8 (3 14.2) Platelets, 10 3 /ul (40 947) Total bilirubin level, mg/dl 0.6 (0.2 10) Direct bilirubin level, mg/dl 0.2 ( ) Albumin level, g/dl (2.6 5) IgG level, mg/dl ( ) Colonoscopy was performed on 33 patients and the biopsy reports were available in 28 patients (some endoscopies were performed locally). Eight patients (24%) had pancolitis and a similar number had colitis with rectal sparing. Three patients had left-sided colitis and 5 patients were diagnosed with CD. Five patients had a normal colonoscopy. Seven asymptomatic patients underwent a colonoscopy for IBD screening, of whom 3 were diagnosed with UC (2 with rectal sparing) and 2 were diagnosed with CD. Table 4. Laboratory Data at Diagnosis and 1 Year into Ursodeoxycholic Acid Therapy Small-duct PSC (n 16) Nonoverlap positive autoimmune markers (n 15) Overlap syndrome (n 12) All patients (n 47) 1 y into UDCA therapy 1 y into UDCA therapy 1 y into UDCA and immunosuppression therapy 1 year into UDCA therapy Test ALT AST ALP GGT NOTE. The transaminases are expressed as mean standard deviation.

4 242 MILOH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 2 Overlap of Primary Sclerosing Cholangitis and Autoimmune Hepatitis Twelve patients (25%) were diagnosed with overlap syndrome based on liver histology. The median age at was 13.5 years (range, 4 18 y) and 9 patients (75%) were male. In 9 patients AIH was diagnosed simultaneously with PSC and in 3 patients AIH preceded PSC. GGT and ALT levels at presentation were higher than in the non-aih PSC patients (Table 4). All patients had positive autoimmune markers (either increased IgG, antinuclear antibody, and/or anti smooth muscle antibody levels). The average IgG level was mg/dl compared with mg/dl in the nonoverlap group (P.04). Anti smooth muscle antibody, total IgG, and antinuclear antibody were positive in 7, 6, and 5 patients, respectively. Seven patients had 1 marker increased, 4 had 2 markers increased, and 1 patient had 3 markers increased. Antibodies to the liver/kidney microsome were not detected in any of the patients. Four patients had definite AIH based on the international criteria for of AIH and 8 had probable AIH. However, when 3 points were not deducted for biliary changes, 9 patients fulfilled the criteria for definite AIH. Six patients had concomitant IBD. Seven patients (58%) had advanced fibrosis (stages 3 4) on liver biopsy. Five of 12 patients with overlap syndrome were diagnosed with small-duct PSC. Small-Duct Primary Sclerosing Cholangitis Sixteen patients were diagnosed with small-duct PSC based on normal biliary imaging findings and biochemical and histologic evidence of PSC. The median age at was 10.5 years (range, 2 18 y). Eleven patients (69%) were male. The mean GGT and ALT levels are presented in Table 4. Nine patients had positive autoimmune markers, however, only 5 had histologic overlap. Seven patients (44%) had advanced fibrosis (stages 3 4) on liver biopsy. Eight patients had IBD (4 UC and 4 CD). None progressed to large-duct PSC. Follow-Up Evaluation and Therapy Children with PSC were followed up for a median of 78 months (range, mo). Seven patients developed bacterial cholangitis, of whom 5 had recurrent cholangitis and 6 had intrahepatic and extrahepatic involvement. Five patients developed cholecystitis in the setting of cholelithiasis. Interventional ERCP was performed on 8 patients (5 papillotomies, 2 stent placements, and 1 balloon dilatation) and cholecystectomy was performed in 2 patients. Four patients had pancreatitis (not ERCP associated), and all patients had intrahepatic and extrahepatic bile duct abnormalities and IBD (2 CD and 2 UC). Two patients developed ascites and 1 patient had variceal bleeding. One patient with overlap and UC was diagnosed with large T-cell lymphoma and underwent a diagnostic/therapeutic splenectomy and received chemotherapy. No patient developed intestinal or hepatobiliary malignancy during follow-up evaluation. All 47 children were treated with UDCA at doses of 20 to 30 mg/kg/d. As summarized in Table 4, serum ALP, GGT, ALT, and AST levels significantly improved with therapy in all patients, including those children with overlap and small-duct disease. Nine patients with autoimmune overlap also received steroids and/or azathioprine and 2 received methotrexate (both with IBD); all responded biochemically with a reduction in transaminase levels. A group of patients (15 of 47) with positive autoimmune markers but lacking histologic features of AIH responded biochemically to administration of UDCA without corticosteroids or immunosuppressants. Liver transplantation was performed in 9 patients (19%) at a mean of 7 years (range, 4 19 y) after the of PSC. Six patients had intrahepatic and extrahepatic disease, 3 had overlap syndrome, 2 had small-duct PSC (of whom 1 had overlap syndrome as well), and 2 were asymptomatic at presentation. Indications for transplantation were as follows: recurrent cholangitis and decompensated cirrhosis in 5 patients, decompensated cirrhosis in 3 patients, and recurrent cholangitis in 1 patient. Five (56%) patients were female and 8 of 9 had fibrosis stages 3 to 4 at. The median follow-up evaluation after liver transplantation was 6 years (range, 2 15 y). The 1- and 5-year patient and graft survival after liver transplantation was 100%. One patient had PSC recurrence and underwent retransplantation 10 years after the initial transplant. That patient developed hepatic artery thrombosis, intra-abdominal abscess, and sepsis, and died from multiorgan failure a year after the second transplant. Two patients transplanted with overlap syndrome developed UC after transplant. Kaplan Meier curves of patient graftfree survival for the total PSC population, small-duct PSC, and overlap is presented in Figure 1. Carbohydrate antigen 19-9 level was examined in 7 patients (normal level, 35 U/mL). One patient had a level of 438 U/mL and was found to have a dominant stricture in the right hepatic duct. After ERCP, sphincterotomy, and balloon dilatation, the carbohydrate antigen 19-9 level subsided to 48 U/mL. The patient eventually underwent liver transplantation because of recurrent cholangitis and decompensated cirrhosis, but had no evidence of cholangiocarcinoma. A second patient was found to have a carbohydrate antigen 19-9 level of 82 U/mL and subsequently was diagnosed with lymphoma. The remaining 5 patients had levels less than 50 U/mL. Carcinoembryonic antigen and -fetoprotein levels were within normal range in all 7 patients. Figure 1. Transplant-free survival curves of pediatric patients at Mount Sinai Medical Center with small-duct, large-duct, and autoimmune overlap PSC.

5 February 2009 PSC IN CHILDREN 243 Discussion This study is one of the largest single-center series of children with PSC reported, analyzing subpopulations with overlap syndrome with AIH and small-duct PSC. Similar to other reports, 6 10 most of our patients were male, diagnosed during the second decade of life, and presented with signs and/or symptoms of chronic liver disease. Most patients had intact hepatic synthetic function and normal bilirubin levels, suggesting that the majority had compensated disease. Asymptomatic patients at presentation had a high prevalence of advanced fibrosis and could progress to end-stage liver disease requiring transplantation, as previously reported. 18 The mean serum GGT/ALP level was 9.3/2 times the upper limit of normal and 19% had age-appropriate ALP levels. GGT level is a reliable marker for PSC and we advocate that it be tested whenever PSC is suspected and in all children with chronic hepatitis. The serum AST/ALT levels at (236/233) were higher than those reported in adults with PSC (48/83), and highest in patients with overlap syndrome (464/421), suggesting that children, especially those with overlap syndrome, have a stronger hepatocellular disease component than adults who have a cholestatic predominance. 19 In our series, we found that 25% of patients met criteria for overlap syndrome, reported to occur in 8% to 10% of adults with AIH, 20,21 and as high as 50% of children with PSC. 11 It is therefore important to carefully assess histologic features and check serum IgG levels and autoimmune antibodies in children diagnosed with PSC. The International Autoimmune Hepatitis scoring system 17 was developed primarily as a research tool, although it has been applied in clinical practice to diagnose AIH, especially in complicated cases. The system deducts points for high ALP/AST or ALT ratios and for biliary changes, which are important features for a of PSC. On the other hand, it adds points for female sex (most PSC patients are male) and for alcohol abstinence (not relevant in children). Therefore, the role of the International Autoimmune Hepatitis scoring system in its present form in the of PSC/AIH overlap, especially in children, is debatable. Alvarez et al 17 stated that there are no universally agreed on definitions or classifications of overlap syndrome and that there is a need for a new working party to clarify this definition. Younger age and higher ALP and bilirubin levels at baseline were associated with higher autoimmune overlap risk. 21 Anti smooth muscle antibody was the most common positive autoimmune marker (58%). Liver/kidney microsome type 1 was not found in any child with autoimmune overlap. panca antibodies did not prove to be specific. All patients with overlap syndrome had a favorable biochemical response to immunosuppression and UDCA treatment. Because AIH may precede PSC, a high index of suspicion needs to be exercised to rule out underlying PSC, especially in male patients and those with IBD. Progression to liver transplantation occurred in 25% of patients with overlap syndrome and in 17% with nonoverlap syndrome. Patients with positive autoimmune markers, who do not have histologic findings consistent with overlap syndrome, may respond biochemically to UDCA without commencing immunosuppressants. Small-duct PSC was observed in 34% of our patients, as opposed to 6% to 11% reported in adults. 22 The serum ALT level was higher (214/143 U/L) and the GGT level was lower (320/553 U/L) when compared with patients with large-duct PSC. Advanced fibrosis was less prominent in small-duct patients compared with large-duct PSC patients (44% vs 65%). Two patients with small-duct disease, one of whom had overlap syndrome, underwent liver transplantation. None progressed to large-duct PSC, as reported in the adult literature, 23 suggesting that small-duct PSC is a distinct clinical entity rather than an early form of classic PSC. Small-duct PSC has a more benign course, as previously described. 1,22 Half of the patients had IBD, of whom half had CD in comparison with 17% of the non small-duct PSC patients. It has been reported that patients with small-duct PSC have a higher prevalence of CD than UC. 22 Liver biopsy was the most common diagnostic modality in our cohort. Although it is not necessarily needed for, except in those with small-duct PSC, 24 it was useful in excluding other diseases. It also was useful in assessing the presence of features of AIH and overlap syndrome. Most of the children had bridging fibrosis at, perhaps secondary to the fact that our institution is a tertiary referral care center. The classic onion skinning was reported in only 12 patients, all with advanced fibrosis (stages 3 4), suggesting it is a late finding. The significance of early and its prognostic implications are unclear and may not necessarily be predictive of disease progression. 25 MRCP has the advantage of being noninvasive, without the risks of radiation and ERCP-associated pancreatitis, and is able to provide images of the bile ducts proximal to strictures and the extraluminal abdomen. MRCP was well tolerated by our patients and when performed in conjunction with ERCP had equal diagnostic accuracy, as previously reported. 26 The majority of our patients had combined intrahepatic and extrahepatic involvement, as opposed to mostly intrahepatic disease reported in other pediatric series. 7,9 MRCP can be used for screening patients with AIH or IBD to rule out PSC. Therapeutic interventions with ERCP were performed successfully in 17% of patients. Endoscopic screening of children with PSC who did not have gastrointestinal symptoms for IBD revealed that 5 of 7 patients had IBD (3 UC and 2 CD), and therefore is recommended. Children with PSC have a significantly shorter survival time than the expected survival for the age- and sex-matched general population. 10 All of our patients were treated with UDCA and have shown significant improvement in serum ALP, GGT, ALT, and AST levels. Two patients who were nonadherent with UDCA had an increase in liver enzyme levels, which was reversible after re-administration of the drug. In adults treated with high-dose UDCA 16 the reduction in ALP and ALT levels did not reach statistical significance and has not been shown to slow the course of illness or prolong survival. 14,16 Our cohort, as well as the Mayo cohort, 10 has proven dramatic improvement in transaminase levels in children treated with UDCA, which may show a potential long-term benefit. With the existing data and lack of other therapeutic alternatives, we suggest that all children with PSC commence UDCA therapy and those with autoimmune overlap be given additional immunosuppression. The Studies of Pediatric Liver Transplantation registry reports that PSC was the indication for pediatric liver transplantation in 3.5% and patients were more likely to be older, male, and Caucasian, in relation to other diagnoses. 27 In our

6 244 MILOH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 2 series, 19% of the patients underwent liver transplantation with a mean time to transplant of 7 years, similar to adults. 4 Because our program is a transplant referral center, this proportion may be biased toward a higher rate owing to referral patterns. The most common indication for transplant was recurrent cholangitis and/or decompensated cirrhosis. In our patients who have undergone liver transplantation, we found an autoimmune overlap predominance, perhaps explaining the female preponderance. Most of our transplanted patients had intrahepatic and extrahepatic involvement, presented with advanced fibrosis, suggesting that low-stage fibrosis may be a positive prognostic factor, explained either by early or no fibrosis progression. Patients with small-duct PSC had a slightly better outcome. Retransplantation rates were higher for patients with PSC than other diagnoses (9.6% vs 4.9% within 2 years). 4 PSC recurrence in grafts is reported to be up to 27% in children, 10 and risk factors are the presence of posttransplant UC, steroid maintenance, 28 history of acute cellular rejection, and presence of HLA-DRB1* We had 1 patient with PSC recurrence 10 years after the transplant who also had associated CD. In summary, in our study most children with PSC were symptomatic at presentation; had either IBD, autoimmune overlap, or both; and had advanced fibrosis on initial biopsy. IBD may be subclinical and rectal sparing was common. Smallduct PSC was diagnosed in one third of patients (in whom CD was more prevalent) and had a more benign course. Asymptomatic patients at presentation may have progressive disease. GGT is a reliable marker and transaminase levels were more increased in children than adults, most prominent in overlap syndrome, and lower in small-duct disease. Serum liver enzyme levels improved with UDCA, but its effect on outcome remains unclear. Patients with autoimmune overlap improved with the addition of immunosuppression. PSC is progressive in children and may require liver transplantation. In our cohort liver transplantation was associated with female sex, autoimmune overlap, intrahepatic and extrahepatic disease, recurrent cholangitis, and advanced fibrosis at. Prospective randomized controlled trials of therapy of PSC in children, although desirable, are nearly impossible to power and alternative ways to address this issue are greatly needed. References 1. Vergani D, Mieli-Vergani G. Autoimmune hepatitis and PSC connection. Clin Liver Dis 2008;12: Kaplan GG, Laupland KB, Butzner D, et al. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol 2007; 102: Mendes FD, Jorgensen R, Keach J, et al. 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7 February 2009 PSC IN CHILDREN Berstad AE, Aabakken L, Smith HJ, et al. Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2006;4: McDiarmid SV, Anand R. Studies of Pediatric Liver Transplantation (SPLIT): a summary of the 2003 Annual Report. Clin Transpl 2003; Cholongitas E, Shusang V, Papatheodoridis GV, et al. Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl 2008;14: Alexander J, Lord JD, Yeh MM, et al. Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl 2008;14: Address requests for reprints to: Nanda Kerkar, MD, Associate Professor of Pediatrics and Surgery, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1104, New York, New York nanda.kerkar@mountsinai.org; fax: (212) The authors disclose no conflicts.