INTRODUCTION Primary sclerosing cholangitis (PSC) results in chronic fibroinflammatory disease of the intrahepatic and/or extrahepatic biliary tree and is of unknown etiology. Damage and fibrosis can progress to biliary cirrhosis and end-stage liver disease. Treatment modalities that can alter the natural history of PSC have not been identified. Research in the field of PSC has been a major focus within the pediatric community in recent years. Herein we explore the current approaches to prognostication and management of these patients. Epidemiology and PSC phenotypes PSC affects ~1.5 per 100,000 children in the United States.1,2 Males are more often affected, representing approximately two-thirds of cases.3 Large duct PSC, includes bile duct irregularities with discontinuous ductal narrowing interspersed with dilatation, detected on cholangiography (Figure 1). As magnetic resonance cholangiopancreatography can identify large duct PSC with high sensitivity, endoscopic retrograde cholangiopancreatography is no longer recommended for the diagnosis of PSC due to the increased risks, unless a dominant stricture requires intervention.4,5 Intrahepatic biliary abnormalities are common, affecting 66% to 87% of children with PSC,3,6 whereas a dominant stricture isolated to the extrahepatic biliary tree is uncommon in pediatrics (4%).6FIGURE 1: Coronal magnetic resonance cholangiopancreatography static image demonstrating multifocal regions of intrahepatic biliary ductal dilatation and narrowing. No dominant strictures are identified.Within the pediatric population, 13% to 24% of patients present with histologic features of PSC, but without typical findings on cholangiography, and are classified as small duct PSC.3,6 Specific histological findings consistent with PSC include: fibrosing cholangiopathy, including periductal fibrosis and fibro-obliterative duct lesions (Figure 2).7 Approximately a quarter of children with small duct PSC will develop large duct disease over a period of 7 years.8 Transplant-free survival is longer in patients with small duct compared to large duct PSC, suggesting that this might be the natural history of a progressive disease.9FIGURE 2: Liver biopsy demonstrating concentric “onion skin” periductal fibrosis. Other histologic features include bile duct proliferation, chronic periportal inflammatory change, cholangiectasis, ductopenia, and varying degrees of fibrosis and cirrhosis.Patients with PSC can develop other autoimmune conditions. Specifically, 70% of patients with PSC develop inflammatory bowel disease (IBD), and 5% of patients with IBD develop PSC. PSC-IBD is the terminology used to describe this overlap disease as well as the specific IBD phenotype that is associated with PSC: mild pancolitis, with increased right-sided disease severity, rectal sparing, and backwash ileitis.10 In children with IBD and persistent elevations of gamma glutamyl transferase (GGT) >250 IU/L, PSC should be suspected and additional investigations obtained, especially if these are detected within the first 3 months of an IBD diagnosis.11,12 The etiology of PSC has not been elucidated. However, the strong association between PSC and IBD is compelling, and thus a common or causal pathophysiology seems likely. Recent literature has explored the role of the microbiome in the pathogenesis of PSC.13 Certain fecal, luminal, and mucosal bacteria are increased in patients with PSC and PSC-IBD compared to healthy controls such as Veillonella, Enterococcus, and Streptococcus, while others are depleted such as faecalibacterium and coprococcus. Bacterial translocation, with hepatic exposure through the portal vein, may be the link between the gut and liver. Overlap with autoimmune hepatitis (AIH) is also well described, and an international multicenter pediatric PSC consortium of 781 children with PSC identified overlap with AIH in 33% of patients.3 The term autoimmune sclerosing cholangitis is increasingly used in the setting of a simultaneous diagnosis of both AIH and PSC, based on their respective diagnostic criteria.14 Prognostic evaluation Staging PSC is challenging because of the variability of disease severity at presentation. Patients may remain asymptomatic, and PSC undiagnosed, for prolonged periods until pruritus or elevated transaminases are detected. In the pediatric PSC consortium, the overall median 5-year transplant-free survival was 88%.3 However, portal hypertensive complications, including ascites, esophageal varices, or encephalopathy, occurred in 38%, and biliary obstructive complications in 25%, within 10 years of PSC diagnosis.3 Portal hypertensive and biliary complications were associated with a median transplant-free survival of 2.8 and 3.5 years, respectively. Evaluation for disease progression is performed with every clinical encounter. Normalization of GGT at 1-year postdiagnosis has been associated with better 5-year event-free survival, regardless of medications.15 In this setting, reassurance can be provided. In addition to liver biochemistry, elastography may be a valuable noninvasive alternative to biopsies to evaluate progression of hepatic fibrosis.16,17 The pediatric PSC consortium developed The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) index as a means of risk stratification (Table 1).8 The SCOPE index is a validated tool utilizing total bilirubin, albumin, platelet count, GGT, and presence of large duct disease on cholangiography to estimate the risk of liver transplant or death at 1 and 5 years postdiagnosis.8 In Table 2 we present 2 cases and calculate their SCOPE indices over time. The first patient (Table 2A) had advanced disease at presentation with compensated cirrhosis, who ultimately decompensated and underwent liver transplantation (LT). She had a “medium risk” SCOPE index at PSC diagnosis and then a “high risk” SCOPE index 2 years later, at the time of transplant. Meanwhile, Table 2B presents the SCOPE index for a patient who presented with pruritus and scored as “low risk.” She clinically became quiescent on ursodeoxycholic acid (UDCA) without any disease progression. Five years later, her SCOPE index remained in the “low risk” category. These cases illustrate a clear distinction in disease severity that is discernable using the SCOPE index, which can complement the clinical evaluation. TABLE 1 - Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) index8 Variable Traditional units SI units Points Total bilirubin mg/dL μmol/L ≤0.6 ≤11 0 0.7–2.7 11.1–46.7 1 2.8–4.8 46.8–82.4 2 ≥4.9 ≥82.5 3 Albumin g/dL g/L ≥4 ≥40 0 3.2–3.9 32–39 1 ≤3.1 ≤31 2 Platelet count ×103/μL ×109/L ≥225 ≥225 0 136–224 136–224 1 ≤135 ≤135 2 GGT U/L U/L ≤100 ≤100 0 101–249 101–249 2 ≥250 ≥250 3 Cholangiography on MRCP/ERCP Normal 0 Large duct involvement 1 Sum total To predict risk of liver-related outcomes Low risk 0–3 Medium risk 4–5 High risk 6–11 Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; GGT, gamma glutamyl transferase; MRCP, magnetic resonance cholangiopancreatography. TABLE 2 - Use of Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) index to predict risk of death or need for liver transplantation in children with PSC At PSC diagnosis At time of liver transplant 2 y postdiagnosis Predictors Result SCOPE points Result SCOPE points Table 2A: patient #1 Total bilirubin (mg/dL) 1.9 +1 4.4 +2 Albumin (g/dL) 3.5 +1 2.5 +2 Platelets (×1000/μL) 28 +2 23 +2 Gamma glutamyl transferase (U/L) 48 0 20 0 Cholangiography Normal versus large duct involvement Normal 0 Not done 0 Total SCOPE Index 4=Medium risk 6=High risk At PSC diagnosis 5 y postdiagnosis Predictors Result SCOPE points Result SCOPE points Table 2B: patient #2 Total bilirubin (mg/dL) 0.5 0 0.8 +1 Albumin (g/dL) 4.7 0 4.4 0 Platelets (×1000/μL) 184 +1 290 0 Gamma glutamyl transferase (U/L) 168 2 75 0 Cholangiography Normal versus large duct involvement Normal 0 Not done 0 Total SCOPE index 3=Low risk 1=Low risk Patient #1 is a female who was 17 years of age at the time of diagnosis with autoimmune sclerosing cholangitis (ASC). She already had cirrhosis at the time of ASC diagnosis and the SCOPE index of 4 indicated a “medium risk” of death or need for liver transplantation. At time of liver transplantation her SCOPE index had increased to 6 consistent with “high risk” of death or need for liver transplantation.Patient #2 is a female who was 12 years of age at the time of diagnosis with primary sclerosing cholangitis (PSC). She presented with pruritus and had a SCOPE index of 3 indicating a “low risk” of death or need for liver transplantation. Ursodeoxycholic acid was initiated and pruritus resolved. After 5 years of surveillance, her SCOPE index decreased to 1, low risk, and she has not developed biliary complications or end-stage liver disease. Medical management Medications that may alter the natural history of PSC continue to be under investigation. Frequently UCDA is initiated in pediatrics, and while it may improve liver biochemistry, it has not been shown to have an impact on the progression of disease.18 Nonetheless, its use may have a limited benefit in a subset of patients. A prospective study of UDCA withdrawal in children found that PSC “flares,” increases in alanine aminotransferase, responded favorably to its reinstitution.19 Notably, one-third of the patients studied maintained normal liver biochemistries despite UDCA withdrawal. The long-term impact of UDCA use and the significance of a biochemical flare are unclear. Antibiotic therapies have been reported in the treatment of PSC. A disordered gut microbiome has been suspected in the pathogenesis of PSC and is a potential therapeutic target.20 Oral vancomycin therapy (OVT) was reported as beneficial in 3 children with PSC-IBD and Clostridium difficile-associated diarrhea.21 Liver transaminases normalized while receiving OVT, increased following discontinuation, and then normalized again when OVT was resumed. A recent analysis of retrospective data from the Pediatric PSC Consortium however, found that neither OVT nor UDCA resulted in improved outcomes when compared to the untreated group.18 Moreover, vancomycin is expensive and little guidance exists regarding duration of therapy. Randomized controlled trials with meaningful clinical endpoints are needed to determine the role of this treatment in the management of PSC. Therapeutic considerations have also included immunosuppressive and anti-inflammatory agents such as prednisone, colchicine, penicillamine, infliximab, methotrexate, and mycophenolate mofetil, etc. A meta-analysis of 266 patients in 5 randomized control trials and 2 retrospective comparative studies concluded that these agents did not affect the rate of liver-related deaths or LT.22 Oral budesonide also appeared to be of minimal, if any, benefit and was associated with a significant worsening of osteoporosis in patients with PSC.23 Azathioprine, a first line therapy for patients with AIH, and often utilized in children with autoimmune sclerosing cholangitis, does not appear to affect disease progression related to biliary injury and fibrosis.14 It is recommended that all patients with PSC undergo screening for IBD. There is a high prevalence of IBD in patients with PSC, and the symptoms are often mild.10 Thus, it is imperative to proactively investigate for IBD in order to institute appropriate management.13 In fact, updated PSC guidelines are recommending repeated endoscopy every 5 years in patients with normal histology at PSC diagnosis. However, the rate of malignancy is extremely rare in children with PSC. Accordingly, routine surveillance for cholangiocarcinoma is not recommended for patients with PSC who are <18 years of age.13 However, in patients with PSC-IBD, annual surveillance with high-definition colonoscopy should be provided to patients ≥15 years of age.13 LT LT is the only effective treatment modality once a patient has decompensated from end-stage liver disease.24 Unfortunately, this life-saving procedure is not curative for all patients with PSC. A study of 140 children who underwent LT for PSC demonstrated a probability of PSC recurrence (rPSC) on biopsy or cholangiography at least 90 days post-LT of 27% at 5 years.25 A diagnosis of rPSC was not made in the setting of LT vascular complications or biliary anastomotic strictures. Children with rPSC tended to be younger at LT, with shorter durations from PSC diagnosis to LT, and had relatively higher alanine aminotransferase, aspartate aminotransferase and bilirubin values prior to LT. Additionally, an examination of United Network for Organ Sharing data did not identify statistically significant differences in patient or graft survival in children who underwent liver transplant for PSC versus AIH.26 CONCLUSION Well‐designed prospective clinical studies are needed to better understand a progressive biliary disease with no established effective therapy beyond LT. Advances in medical therapy will likely parallel a better understanding of the pathogenesis of PSC. The recent advent of the SCOPE index, a validated risk stratification tool, should serve as a guide for clinicians tasked with caring for children with PSC.
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May 1, 2024
Christoph Schramm + 4
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