Pediatric Primary Sclerosing Cholangitis


First author

Wilschanski [7]

Gregorio [5]

Feldstein [4]

Miloh [6]

Deneau [3]

All studies

Year published

1995

2001

2003

2009

2013

1995–2013

# Patients (n)

32

9

27

52

47

29

12

208

PSC

PSC

ASC

PSC/ASC

PSC/ASC

PSC

ASC
 
Median age at diagnosis (year) (range)

13

(0.5–18)

6.6

(2–14.5)

11.8

(2.3–16)

14.7

(1.5–19.6)

12

(2–20)

13.0

(5.3–18)

11.3

(3.1–17.6)

11.7 ± 2.5

Mean follow-up (year) (range)

3.8

(0–15)

6

(5–15)

6

(2–16)

6.6

(0.2–16.0037)

6.5

(0.5–19)

5.6

(0.4–14)

6.4

(0.6–13.3)

5.8 ± 1.0

Gender (% male)

72 %

66 %

45 %

65 %

62 %

76 %

50 %

62 ± 11%

IBD overall

UC

Crohn’s disease

53 %

33 %

30 %

73 %

59 %

96.6 %

75 %

60 ± 24 %

44 %

33 %

18.5 %

58 %

42 %


39 ± 14 %

9 %

0 %

11 %

15 %

17 %


10.4 ± 6.6 %

Overlap syndrome/ASC

28 %

75 %

35 %

25 %

29 %

38.4 ± 20.8 %

PSC/ASC preceded IBD

25 %


15 %

15 %

12 %

16.8 ± 5.7 %

Mean ± SD labs at diagnosis:

AST (U/L)

156.7 ± 195

a90

102

271 ± 310

236 ± 245

a76

167

155 ± 82.6

ALT (U/L)



331 ± 336

233 ± 327

72

160

199 ± 110

GGTP (U/L)


141

129

536 ± 376

553 ± 676

221

275

267.5 ± 223.5

Alk. Phos. (U/L)

589.8 ± 399

474

303

913 ± 652

610 ± 340

316

292

569.8 ± 257.2

Liver transplantation

31 %

0 %

14.8 %

21 %

19 %

17 %

17.1 ± 10 %


aMean only (no standard deviations reported)





Diagnosis of PSC


The majority of cases of pediatric PSC are symptomatic at presentation. Asymptomatic patients are often diagnosed after routine screening of liver biochemistries in the setting of preexisting IBD [4, 6, 7]. The most common symptoms of pediatric PSC are fatigue, abdominal pain, anorexia, and pruritus. Other signs include fever, jaundice, weight loss, delayed growth, and fat-soluble vitamin deficiencies. Approximately 20 % of pediatric PSC patients have pruritus at presentation, of whom ~4 % have extremely debilitating pruritus [4, 6]. Intractable pruritus and fatigue can lead to sleep disturbance, depression, and impairment of quality of life in adults [810]. There is only one published health-related quality of life assessment on children with autoimmune liver diseases which revealed that symptoms of abdominal pain, fatigue, and psychological distress were associated with impaired physical activity and school functioning [11]. Physical exam at presentation may reveal hepatomegaly and splenomegaly.

The diagnosis of PSC relies on the combined clinical findings of a cholestatic liver biochemistry profile, imaging (MRCP or endoscopic retrograde cholangiopancreatography [ERCP]), and/or liver histological findings consistent with PSC [12]. In the past decade, great advances in MRCP imaging for infants and children have occurred, and MRCP has an 84 % accuracy rate in the diagnosis of pediatric PSC [13]. Children with PSC have significantly higher levels of serum gamma-glutamyl transpeptidase (GGTP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) compared to their adult counterparts [12] (see Table 6.1). Reports from large cohorts of adults with PSC have shown that serum alkaline phosphatase (ALP) is of prognostic importance in PSC [1416]. The incidence of cirrhosis and cholangiocarcinoma has been found to be higher in adult PSC patients with persistently elevated serum ALP levels compared to those who achieve normalization of serum ALP [1416]. In pediatric PSC, serum GGTP should be considered as a more accurate measure of bile duct injury compared to ALP for the following reasons: First, in four large retrospective reviews of pediatric PSC, only 53–81 % of patients had an elevated ALP at diagnosis compared to 94–100 % of patients with elevated GGTP [3, 4, 6, 17] Second, the range of normal ALP levels substantially increases during times of rapid bone growth in children, making any single elevated ALP level difficult to interpret in children [18]. For example, the upper limit of normal for ALP in a 13-year-old male is 587 U/L, a value that is fivefold higher than the upper limit of normal in adults (mayomedicallaboratories.com). Lastly, serum GGTP levels have been found to be of prognostic importance in pediatric patients with other cholestatic diseases including total parenteral nutrition-related liver disease [19], idiopathic neonatal hepatitis [20, 21], and pediatric sepsis-related cholestasis [22]. A small study on the use of ursodeoxycholic acid for pediatric PSC revealed that GGTP significantly decreased in response to therapy; however changes in ALP were less impressive [23]. Further research into the use of GGTP as a biomarker of disease severity or treatment response in pediatric PSC is warranted.


Natural History and Outcomes in Pediatric PSC


PSC carries significant morbidity in children. Approximately 30–40 % of pediatric PSC patients will suffer from consequences of chronic biliary disease, including significant pruritus, recurrent bacterial cholangitis, and complications of portal hypertension. The largest pediatric PSC study encompassed 52 children who were seen over a 20-year period and followed for up to 16.7 years [4]. Pediatric PSC often progressed to end-stage liver disease, with approximately one-fifth requiring liver transplantation in childhood. The median transplant-free survival in the population studied was 12.7 years, and the mean time from diagnosis of PSC to liver transplantation was 6.6 years [4]. Miloh et al. analyzed the outcome in 47 children with PSC and found that 65 % had significant fibrosis (>grade II) on liver histology at diagnosis. Patients were followed on average for 6.5 years (range 0.5–19), and 19 % required liver transplant [6]. In children, PSC-autoimmune hepatitis (AIH) overlap syndrome (or autoimmune sclerosing cholangitis) seems to have a more favorable outcome than PSC alone, with an estimated 5-year transplant-free survival of 90 % in children with overlap syndrome compared to 78 % in children with PSC alone [3]. Lastly, cholangiocarcinoma (CCA) is a well-known complication of PSC in adults with incidences ranging from 5 to 36 % [24]. Only three cases of CCA have been reported in the setting of pediatric PSC. The range of ages at presentation of the CCA was 14–18 years old, and the CCA was diagnosed 1.2–6 years after the onset of PSC [25]. Clues to the diagnosis of CCA in pediatric PSC include rapid onset of jaundice and abdominal pain, newly diagnosed dominant stricture, and CA19-9 levels consistently >100 U/mL [26].


Subtypes of Pediatric PSC



Autoimmune Sclerosing Cholangitis (PSC-AIH Overlap Syndrome)


Autoimmune sclerosing cholangitis (ASC) was first described by Gregorio et al. in reference to pediatric patients with AIH and cholangiographic or histological features consistent with sclerosing cholangitis [5]. The combination of concurrent PSC with AIH is also known as “overlap syndrome” in children and adults [27]. ASC is much more common in children, with prevalence rates of ~38 % (range 25–75 %) in pediatric PSC patients compared to only 1–4 % of adult patients [3, 4, 6, 7, 28]. The fact that the incidence of ASC is substantially lower in adults may be due to the possibility that the autoimmune-mediated inflammation of ASC subsides or “burns out” by adulthood. A summary of the incidence of ASC in children is provided in Table 6.1. The study by Gregorio et al. was a prospective analysis of biliary disease in all patients with AIH, which may explain why the majority of patients (75 %) had ASC (data on newly diagnosed PSC cases was also collected during the study time frame). Due to the high prevalence of ASC in children, it is recommended that all children with PSC be screened for concurrent AIH with serum autoantibodies (antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), liver-kidney microsomal antibody (LKM), total IgG), followed by a liver biopsy for histology if any of the autoantibodies are positive. Similarly, for all children with AIH, screening MRCP or ERCP should be performed to determine if ASC is the accurate diagnosis. In addition, because the diagnosis of PSC and ASC can precede the diagnosis of IBD, it is recommended that all children diagnosed with PSC or ASC undergo surveillance upper endoscopy and colonoscopy.

Pediatric ASC patients tend to have higher levels of AST, ALT, and GGTP at presentation compared to PSC only patients [3, 6], and total IgG levels are often >2,000 mg/dL [4, 6]. The vast majority of pediatric ASC cases have positivity for ANA and/or ASMA; to date only two cases of LKM positivity in ASC have been reported [3, 5]. Interestingly, treatment of the AIH component of ASC with immunosuppressive therapy is associated with normalization of AST, ALT, GGTP, and ALP in >70 % of cases. However, this most likely reflects remission of the AIH component, as repeat cholangiographic studies or liver biopsies performed at a median of 5 years after diagnosis revealed that the majority of cases had static disease or progression of biliary disease and fibrosis [5].

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Oct 9, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Pediatric Primary Sclerosing Cholangitis
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