primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with...

Primary Sclerosing Cholangitis in 32 Children: Clinical, Laboratory, and Radiographic Features,

With Survival Analysis

MICHAEL WILSCHANSKI, 1'5 PETER CHAIT, 2 JUDY A. WADE, 3'5 LORI DAVIS, ~'5 MARY COREY, ~'5 PATRICK ST. LOUIS, 4'5 ANNE M. GRIFFITHS, 1'5 LAURENCE M. BLENDIS, 3'5 STANLEY P. MOROZ, 6

LINDA SCULLY, 7 AND EVE A. ROBERTS L3'5

The cl inical presen ta t ion and o u t c o m e o f 32 ch i ldren w i t h pr imary sc leros ing cho langi t i s (PSC) are rev iewed , the largest Nor th A m e r i c a n series. The major i ty o f pa- t ients w e r e d iagnosed in the ir s e c o n d decade (median age: 13 years) . F o u r ch i ldren presented before the age of 2 years , but n o n e in the n e o n a t a l period. S e v e n t e e n pat ients had inf lRmmatory b o w e l d i sease (IBD), all w i t h colitis, 14 u lcerat ive colitis, and 3 Crohn's disease . Eight pat ients presented w i t h chron ic l iver d isease before c l inical onse t o f IBD. Only 8 o f 32 pat ients w e r e jaun- d iced at presentat ion . Fi f teen o f 32 bad a n o r m a l s e r u m AlkAline p h o s p h a t a s e (ALP) level at presentat ion . Nine ch i ldren p r e s e n t e d w i t h features s imilar to those of au- t o l m m u n e hepati t is . Cho lang iography w a s per formed in all cases and c lass i f ied by a scor ing sy s t em specif ical ly deve loped for pediatr ic pat ients . Intrahepat ic d i sease predominated; in on ly three cases a c o m m o n bile duct str icture w a s ident i f ied requir ing stent ing. F indings o n the init ial l iver b iopsy w e r e c lass i f ied accord ing to Lud- wig's cri teria for s tag ing PSC: there w e r e 15 b iops ies in s tages 1 to 2 and 17 b iops ies s tages 3 to 4. HLA class I and II ant igens w e r e d e t e r m i n e d in 27 pat ients . An increased inc idence o f HLA B8 and DR2(15) but no t D R w52a (DRB3*0101) w a s found. Ant i -neutrophi l cyto- p lasmic ant ibody (ANCA) w a s pos i t ive in 10 o f 24 pa- t ients tested. Survival analys i s ind icated that a later age at presentat ion , sp lenomegaly , and pro longed prothrom-

Abbreviations: PSC, primary sclerosing cholangitis; ERCP, endoscopic retrograde cholangiopancreatography; ANCA, anti-neutrophil cytoplasmic antibodies; Ig, immunoglobulin; IBD, inflammatory bowel disease; PT, prothrombin time; ALP, alkaline phosphatase.

From the Division of Gastroenterology and Nutrition, 'Department of Pedi- atrics, Departments of 2Diagnostic Imaging and 4Clinical Biochemistry, The Hospital for Sick Children, Toronto, Ontario; the 3Department of Medicine, The Toronto Hospital, Toronto, Ontario, and the 5University of Toronto, Toronto, Ontario; and the 6Department of Pediatrics, The Health Sciences Centres, Winnipeg, Manitoba; and the 7Department of Medicine, The Ottawa Civic Hospital, Ottawa, Ontario, Canada.

Received November 25, 1994; accepted June 22, 1995. Dr Michael Wilschanski is supported by the American Physicians Fellow-

ship and a grant from Janssen Pharmaceutica. This study was supported in part by the Heather Walker Hepatic Research Fund.

Address reprint requests to: Eve A. Roberts, MD, Division of Gastroenterol- ogy & Nutrition, Room 8415, University Wing, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G lX8, Canada.

Copyright © 1995 by the American Association for the Study of Liver Diseases.

0270-9139/95/2205-001253.00/0

bin t ime (PT) at presen ta t ion w e r e s ignif icant contribu- tors to the predic t ion o f poor o u t c o m e (i.e., dea th or listing for transplantat ion) . Liver trmn~plantation w a s success fu l ly per formed in s e v e n chi ldren. P h y s i c i a n s m u s t ma in ta in a h igh index o f susp ic ion o f PSC in any chi ld or y o u n g adult presen t ing w i t h chron ic l iver disease , e spec ia l ly in the presence o f IBD, e v e n wi th a nox~ mal s e r u m AlkAline p h o s p h a t a s e level . (HEPATOLOGY 1995;22:1415-1422.)

P r i m a r y sclerosing cholangit is (PSC) is an u n co mmo n disorder of unknown cause affecting both the in t rahepat ic and ex t rahepa t ic bi l iary system. I t is charac ter ized by a chronic f ibrosing in f l ammat ion of medium-s ized bile ducts followed by obl i terat ion of the bile duct lumen. Cirrhosis usua l ly develops. 13 The disease m a y be associ- a ted wi th i n f l ammato ry bowel disease, especial ly ulcera- t ive colitis. 4-6 I t m a y also occur in associat ion wi th other diseases, e.g., i m m u n e deficiency s tates , 7's h u m a n immunodeficiency v i rus infection, 9 c ryp tospor idum infection, 1° histiocytosis X, 11 sickle cell anemia , 12 Hodgkin ' s disease, ~3 and cystic fibrosis. 14 PSC is r a re ly diagnosed in children, bu t wi th the adven t of the increased rout ine use of mode rn imaging techniques such as pe rcu taneous cholangiography and endoscopic re t rograde cholangio- panc rea tog raphy (ERCP), the diagnosis is now m a d e more f requent ly in the pediatr ic populat ion. 15'~e

The pu rpose of th is r epo r t is to p r e s e n t our exper i - ence wi th 32 chi ldren who were d iagnosed b e t w e e n 1986 and 1994 as h a v i n g PSC. Twen ty - s ix chi ldren were d iagnosed a t The Hosp i t a l for Sick Chi ldren, To- ronto, one a t the H e a l t h Science Cent re , Winnipeg, Mani toba , and one 18-year-old a t the Toronto G en e ra l Hospi ta l . Four chi ldren, one each f rom Winnipeg, Ot- t awa , Hal i fax , and Saska toon , were r e f e r r ed to The Hosp i t a l for Sick Chi ld ren for diagnosis . Clinical findings, l abo ra to ry inves t iga t ions , cho lang iography , and l iver h is to logy were examined . H L A typ ing was per- fo rmed for the f i r s t t ime in a la rge ser ies of chi ldren wi th PSC; r e su l t s were c o m p a r e d wi th f indings in adu l t s wi th PSC.

PATIENTS AND METHODS

Thirty-two patients (23 male) were diagnosed as having PSC. Ch0langiography was taken as the basis for definitive

1415

1416 WILSCHANSKI ET AL HEPATOLOGY November 1995

TABLE 1. Age at Presentat ion and Gender of Patients

Age (yr) Number Male Female

<2 4 1 3 2-10 7 5 2

11-18 21 17 4 Median age = 13 32 23 (72%) 9

diagnosis. All cholangiograms were reviewed and classified by one radiologist (P.C.). Initial liver biopsies were also reviewed. Clinical and laboratory findings from onset of any symptomatic liver disease were recorded from chart review. Most of these patients were diagnosed in the Liver Clinic at The Hospital for Sick Children when hepatic symptoms first developed or shortly thereafter. Several patients who were fully diagnosed as having PSC had been followed previously in the Clinic for several years with "cryptogenic" liver disease.

HLA typing on 27 patients was determined by serology and sequence-specific primers-polymerase chain reaction using standard methodology. 17'1s

The presence of anti-neutrophil cytoplasmic antibodies (ANCA) was determined in 24 patients by indirect immunofluorescence. Patient samples (diluted 1:20, 1:40) were ap- plied to neutrophils previously fixed in ethanol and incubated with F(ab)'2 fragment of rabbit anti-human immunoglobulin (Ig) G gamma chain labeled with fluorescein isothiocyanate (Dako). Immunofluorescent staining in the perinuclear zone (P-ANCA) or cytoplasmic compartment (C-ANCA) in the 1:20 sample was taken as positive.

Survival analysis was performed using SAS 19 for data pro- cessing. The Kaplan-Meier product limit method, as well as Cox regression analysis, was used for survival analysis of predictors of a poor outcome (death or listing for transplantation). Variables measured in all 32 patients were age at presentation of liver disease, gender, history of jaundice, pruritus, fatigue, anorexia, weight loss, acholic stools, right upper quadrant pain, arthralgia, delayed puberty; presence of spi- der nevi, hepatomegaly, splenomegaly, ascites; serum bilirubin, alkaline phosphatase, aspartate transaminase, albumin, hemoglobin, platelet count, total white blood cell count, IgG value (n = 31), and histological features on initial liver biopsy.

This study was approved by the Human Subjects Review Committee of the Hospital for Sick Children, Toronto, Can- ada.

RESULTS

The age distribution at presentation is shown in Ta- ble 1. The median age of presentation was 13 years (range, 0.5 to 18). Mean follow-up was 3.8 years. Al- though the majority of patients were men or boys in the second decade, four children presented at younger than 2 years of age. The youngest patient presented at 6 months of age. None presented in the neonatal period.

Seventeen patients had inflammatory bowel disease (IBD). Of these, 14 had ulcerative colitis. T h e r e w e r e t h r e e patients with documented Crohn's disease, all three having Crohn's colitis. In eight patients, IBD developed after presentation with PSC. T h e r e w e r e 15 patients with no clinical evidence of IBD to date. No patient had histiocytosis X. Two patients in this group

had an associated immune deficiency. One (no. 32) had chronic immune deficiency as a result of severe com- bined immune deficiency; crytosporidium infection may have contributed to the bile duct disease. The other child (no. 13) had a more subtle T cell defect not yet fully characterized. The remaining 13 patients were otherwise entirely normal.

Most children presented with relatively nonspecific complaints. The major presenting symptoms as well as findings on physical examination are described in Ta- ble 2, with clinical biochemical data of each patient in Table 3. Only eight patients were jaundiced at presentation. Remarkably, 15 of 32 had a normal serum alkaline phosphatase at presentation.

Given the variability in clinical presentation, two specific clinical patterns deserve special comment. T h e r e were nine children (nos. 1 to 9) who presented with chronic liver disease originally characterized as "chronic active hepatitis" before diagnostic cholangiography. These patients resembled patients with autoimmune hepatitis. They had increased serum IgG and aminotransferases and variable, often normal, alkaline phosphatase levels. None of these patients had low serum complement C3 or C4.2° Six of these patients w e r e treated with steroids or other immunosuppressive agents and deteriorated clinically on this medication. Liver biopsy was consistent with autoimmune hepatitis in five. It showed increased periportal copper deposition in three and duct changes in four. Cholangiogra- phy was diagnostic in all nine patients. Six of these nine patients have progressive liver decompensation. Two have had severe variceal bleeding. Five of these patients have required liver transplantation.

We also identified a further group of five patients (nos. 10 to 14) who had no specific symptoms of chronic l i ver disease but presented with abdominal organome- galy, usually discovered as an incidental or chance finding. In several of these patients, splenomegaly was prominent.

The remaining patients fit the classic presentation of PSC presenting as chronic liver disease with prominent biochemical features of cholestasis. Patient 32 was the immunocompromised patient discussed earlier. Pa- tient 20 presented with associated pancreatitis. 21 Pa- tient no. 23 presented with acute cholecystitis and a pyogenic liver abscess--a most unusual presentation.

Cholangiography. Bile duct imaging studies were performed in all 32 patients. Fifteen were assessed by endoscopic retrograde cholangiopancreatography (ERCP), six

TABLE 2. Clinical Features at Presentat ion in Children With Primary Sclerosing Cholangit is

Symptoms Fatigue 12 Anorexia 12 Jaundice 8 Pruritus 6

Signs Isolated hepatomegaly 11 Isolated splenomegaly 1 Hepatesplenomegaly 11

HEPATOLOGY Vol . 22 , No . 5, 1 9 9 5 W I L S C H A N S K I E T A L 1 4 1 7

TABLE 3. Laboratory Data in 32 Chi ldren With Primary Sclerosing Cholangit is

Liver Age Serum Total ALP AST IgG Biopsy

Gender (yr)* Bilirubin (U/L) (U/L) (G/L) ASMA ANA ANCA IBD Stage OLTt

1 F 18 2 0 0 7 2 7 ?$ 1 3 8 N / A - + - + 4 +

2 M 10 N 3 3 5 6 3 2 3 . 2 + - - - 3 -

3 F 9 N 5 2 9 ? 1 9 0 2 0 . 3 + + N / A + 2 -

4 M 15 N 6 2 8 ? 1 1 6 2 1 . 9 + - - + 3 -

5 M 16 9 2 1 , 3 3 0 ? 2 6 9 4 4 . 7 + + P - 4 +

6 M 12 6 6 3 3 9 1 , 0 9 1 4 3 . 0 + + N / A + 4 -

7 M 16 N 3 3 3 9 8 2 3 . 0 + - P + 4 +

8 M 1 4 5 5 1 , 0 6 1 ? 8 4 7 .0 - + N / A - 1 +

9 M 14 N 1 9 3 3 2 2 1 . 2 - + N / A + 4 +

10 F 12 N 5 0 0 1 1 4 7 .6 . . . . 4 -

11 M 12 N 2 2 8 4 5 2 1 . 1 + + - + 4 +

12 M 11 N 1 3 1 2 1 10. N / A N / A P - 4 -

13 M 12 3 8 2 5 6 71 7 .9 . . . . 1 +

14 M 8 N 6 4 8 ? 2 3 8 19 .6 + + - - 4 +

15 M 7 N 1 , 0 8 5 ? 9 8 18 .1 + + - + 3 -

16 M 15 N 4 7 2 ~ 8 1 5 8 . 2 - - - + 2 -

17 M 16 1 1 1 6 3 0 ? 1 5 9 2 1 . 1 + - - - 3 +

18 M 8 N 9 7 5 ? 1 3 3 11 .3 - + C - 1 -

19 F 1 .5 N 7 3 5 $ 2 5 7 6 .6 + - - - 1 -

2 0 M 14 2 5 2 , 0 4 3 ~ 1 1 4 3 6 . 1 - - C + 4 +

2 1 F 17 N 5 6 6 ? 1 0 1 19 .1 + - P + 2 -

2 2 M 16 N 3 1 9 7 0 2 4 . 3 + - - + 2 -

2 3 M 6 9 1 0 5 1 5 ? 5 8 10 .2 . . . . 1 -

2 4 F 1.5 5 5 1 , 0 6 1 ? 8 4 7 .0 - - N / A + 2 -

2 5 M 15 N 3 4 7 5 7 4 3 . 7 + + C + 1 -

2 6 M 15 2 5 2 7 3 1 2 7 3 5 . 6 + + P + 3 -

2 7 M 0 .5 N 1 4 9 3 0 12 .6 + - - - 3 -

2 8 M 18 5 8 4 8 0 ? 5 0 7 2 2 . 2 + + P + 2 -

2 9 M 5 N 3 5 7 9 3 13 .8 + - N / A + 2 -

3 0 F 0 .7 N 5 5 2 7 9 8 .1 . . . . 4 -

3 1 F 9 N 3 6 4 2 0 7 10 .1 + ÷ N / A - 1 -

3 2 M 15 1 2 9 7 1 2 ? 1 9 0 5 .5 N / A N / A N / A - 1 - ( D i e d )

A b b r e v i a t i o n s : A L P , a l k a l i n e p h o s p h a t a s e ; A S T , a s p a r t a t e a m i n o t r a n s f e r a s e ; I g G , i m m u n o g l o b u l i n G; A S M A , a n t i - s m o o t h m u s c l e a n t i -

b o d y ; A N A , a n t i n u c l e a r a n t i b o d y ; A N C A , a n t i - n e u t r o p h i l c y t o p l a s m i c a n t i b o d y ; P , p e r i n u c l e a r ; C , c y t o p l a s m i c ; I B D , i n f l a m m a t o r y b o w e l

d i s e a s e ; N / A , n o t a v a i l a b l e ; N , n o r m a l .

* A t p r e s e n t a t i o n .

t L i s t e d f o r l i v e r t r a n s p l a n t a t i o n o r t r a n s p l a n t a t i o n p e r f o r m e d .

$ I n d i c a t e s e l e v a t e d a b o v e n o r m a l r a n g e f o r a g e a n d g e n d e r .

by percutaneous transhepatic cholangiography, and nine patients by percutaneous transcholecystic transhepatic cholangiography. In two patients, cholangiography was performed on the diseased liver posthepatectomy at liver transplantation. These two patients (nos. 7, 11) had been followed for years as having autoimmune hepatitis and chronic liver disease of unknown cause, respectively. In two patients who underwent percutaneous transhepatic cholangiography and 1 who had ERCP visualization of the intrahepatic tree was inadequate.

We devised a scoring system for disease severity in the various parts of the biliary tree, with each number under a particular heading representing the number of children with disease in tha t category (Table 4). "Mild" lesions were classified as mucosal irregularity or dilatation/stricture formation occupying less than one third of the duct diameter. Moderate lesions were described as mucosal irregularity or dilatation or stricture forma-

tion constituting one to two thirds of the duct diameter. Severe lesions were defined as mucosal irregularity, dilatation, or stricture formation equivalent to more than two thirds of the diameter of the normal duct. For

TABLE 4. Cholangiographic Findings in Chi ldren With Primary Sclerosing Cholangit is Within 5

Years of Presentat ion

Mild Moderate Severe

I n t r a h e p a t i c b i l i a r y t r e e

S m a l l i n t r a h e p a t i c d u c t s 7 8 6

R i g h t h e p a t i c d u c t 6 10 0

L e f t h e p a t i c d u c t 4 10 0

E x t r a h e p a t i c b i l i a r y t r e e

C o m m o n h e p a t i c d u c t 6 7 0

C o m m o n b i l e d u c t 5 5 3

1418 WILSCHANSKI ET AL I-IEPATOLOGY November 1995

FIG. 1. Percutaneous transcholecystic t ranshepat ic cholangiography with good visualization of ent ire ductal system demonstra t ing mucosal i rregulari ty of central bile duct and dilatation of left hepatic duct; small ducts appear normal. In this pat ient the common bile duct, common hepatic duct, and r ight and left hepatic ducts were scored as "moderate"; in t rahepat ic ducts were scored as "mild."

the purpose of this study, intrahepatic lesions were defined as ductal lesions proximal to the formation of the right and left hepatic ducts. Figure 1 shows predominantly large duct disease, scoring "moderate" for extrahepatic ducts, "moderate" for hepatic ducts, and "mild" for intrahepatic ducts, and Fig. 2 shows an example of predominantly intrahepatic disease scoring "severe" for intrahepatic ducts, "moderate" for hepatic ducts, and no score for extrahepatic ducts, which were normal. In six patients, intrahepatic disease alone was observed. In three patients (nos. 17, 20, 28), cholangiography demonstrated severe common bile duct stric- tures requiring repeated stenting. In two of these cases (nos. 17, 20), hepatic transplantat ion was eventually performed.

Histopathology. All 32 patients underwent at least one liver biopsy. The initial liver biopsy was classified according to the staging criteria proposed by Ludwig for PSC in adults. 22'23 The biopsy specimens proved to be distributed fairly evenly among the four stages. There were eight patients in stage 1 (portal stage), seven in stage 2 (periportal stage), six in stage 3 (septal stage), and eleven in stage 4 (cirrhotic stage). In patients with the "chronic active hepatitis" presentation of PSC, liver biopsy disclosed evidence of chronic cholangitis with circumferential fibrosis of medium-sized bile ducts in some patients. In some of these patients, portal inflammation or active cirrhosis was found.

The copper stain was positive for periportal copper accumulation in 8 of 29 biopsies. In some patients this

FIG. 2. Percutaneous transcholecystic t ranshepat ic cholangiography shows small and medium duct involvement with str ictures and dilatations: "beaded" appearance. In this pa t ient the intrahepatic bile ducts were scored as "severe"; the right, left, and common hepatic ducts were "mild," and the common bile duct was "normal."

was the only clue to chronic cholestasis. This increased copper deposition in PSC is a well-recognized histological feature, but it is not specific and may be absent in the early stages of the disease. 23

Genetic Studies. HLA determination was carried out in 27 patients by serology and sequence-specific primers-polymerase chain reaction. Results are shown in Table 5. There is a significantly increased incidence of B8 and DR2 (15) but no increase with DR B3*0101 (DRw52a). Of the 11 patients who were DR B1"1501 positive, seven were DR Bl*0301 negative.

Anti-Neutrophil Cytoplasmic Antibody (ANCA). ANCA was positive in only 10 of 24 (40%) patients with PSC. Seven were P-ANCA positive, and three were C- ANCA positive. Of the 10 patients who were positive, 6 had IBD (all UC). Five patients with UC were ANCA negative. In the "chronic active hepatitis" group, two patients were ANCA positive.

TABLE 5. ~ T y p i n g in Chi ldren With P r i m a r y Sclerosing Cholangit is

HLA Frequency

Patients Allele Antigen Control (%) (n = 27)

B8 17 37% (10)* DR B1"1501 DR 2(15) 23 41% (11)* DR B1"0301 DR 3(17) 27 30% (8) DR B3*0101 DR52a 35 41% (11)

* P < .01.

HEPATOLOGY Vol. 22, No. 5, 1995 WILSCHANSKI ET AL 1419

100

A

80

8o

~ 40

20

0 0

I,

I I I 1 2 3

No Splenomegaly I I I I I I

Splenomegaly I I

1 i i I

Time (Years)

100

B

80

60

20

L P T < 14s

I I I I I I I I I

--I PT > 14s I

. . . . ' . . . . . . '0 'I 2 '3 O0 1 2 3 4 5 6 7 8 9 1 1 1 1

Time (Years)

FIG. 3. Survival curves using the Kaplan-Meier method with (A) the presence of splenomegaly at presentation and (B) prolonged prothrombin time at presentation. (Vertical lines indicate censored ob- servations, i.e., those in whom failure has not yet been observed.)

Surv iva l Analysis. Mean follow-up time was 3.8 years (range, 0 to 15 years). Poor outcome was defined as death or being listed for liver transplantation. There has been one death, and 10 patients are listed for transplant or have undergone liver transplant.

Univariate Cox regression analysis showed that poor outcome of PSC in this series of children was associated with jaundice, prolonged prothrombin time (PT), and abnormal serum bilirubin (P < .05). There was also a marginal association (P < .08) of outcome with older age at presentation, history of pruritus, and the presence of splenomegaly. Each variable was considered in a model with age at presentation. The effects of jaundice, pruritus, and abnormal bilirubin were diminished when age at presentation was entered into the model; this indicates some degree of association of these variables with age at presentation. Figure 3 illustrates the effect of time on poor outcome associated with splenomegaly and prolonged PT.

The best variable model for the prediction of poor

outcome included prolonged PT (P = .01) and age at presentation (P = .09). The significance of prolonged PT and the presence of splenomegaly were unchanged in two-variable models with age at presentation, and all three variables likewise in a three-variable model. In summary, older age at presentation (P = .08), prolonged PT (P = .02) and splenomegaly (P = .08) to- gether provided the best predictor equation of poor outcome.

D I S C U S S I O N

Primary sclerosing cholangitis is a cholestatic liver disease with characteristic changes in large or medium-sized bile ducts on cholangiography. Excluded from PSC are cholestatic diseases with duct damage associated with choledocholithiasis, congenital biliary tract anomalies, cholangiocarcinoma, or previous biliary tract surgery. These are often categorized as sec- ondary sclerosing cholangitis. 24 Although PSC was first described in 1867, the disease was rarely diagnosed until the advent of endoscopic cholangiography in the 1970s. Endoscopic or percutaneous cholangiography has recently permitted adequate examination of the biliary system in children. This study, the largest published series of PSC in childhood in North America, suggests that PSC is a more frequent cause of chronic liver disease in children than previously appreciated. Its presentation in children is highly variable. In this age-group, "chronic active hepatitis" presentation, vir- tually indistinguishable from that of autoimmune hepatitis, is relatively common. The serum alkaline phosphatase level is often normal for age. By multivariate analysis, poor prognosis was found to be associated with later diagnosis, jaundice, and prolonged PT at presentation.

Fifty-five percent of our patients had colitis due to IBD and, as in adults, most have ulcerative colitis. This is less than the 70% figure commonly quoted for adults. 23 Non-IBD asymptomatic patients did not routinely undergo colonoscopy, although several patients underwent colonoscopy for a variety of indications, most commonly anemia or abdominal pain. However, most patients had routine rectal suction biopsies, which were normal. Crohn's disease with associated PSC is rare both in adults 25 and in children. 26 However, all previous cases in the l i terature including the three presented here had Crohn's colitisY '26 A noteworthy feature in our series is the high percentage (50%) of patients who were diagnosed with IBD after the diagnosis of PSC has been made. Our data do not support the theory that PSC results from invasion into the portal system by a putative hepatotoxin in the denuded bowel mucosa.

The most common presenting symptoms were fatigue and anorexia, and only 38% were jaundiced at presentation. The most remarkable laboratory feature in this series is that the alkaline phosphatase (ALP) was normal in nearly 50% of the patients. Normal ALP has been reported rarely in adults, occurring in only 3% of patients 27'2s and in at least one other child. 29 In one


patient the ALP fluctuated, remaining normal for at least 1 year; this fluctuation in ALP has also been reported in adul t sY The indication for cholangiography in the 15 patients with normal ALP included evident chronic liver disease of unknown cause, in some cases associated with IBD, and chronic liver disease with autoimmune phenomena. Other causes of low ALP, for example, hypothyroidism, zinc deficiency, pernicious anemia, and anticoagulant drug ingestion, were excluded. Why patients with PSC should have a normal ALP is unclear, but this finding suggests that PSC may be more prevalent than hitherto realized if the index of suspicion is based on elevated ALP levels. Of the 15 patients with normal ALP, seven had serum gamma- glutamyl-transpeptidase measured at the same time, and in six this was raised (gamma-glutamyl-transpeptidase has only been measured routinely since 1986). This suggests that gamma-glutamyl-transpeptidase may be more sensitive than ALP and should be routinely ordered when PSC is suspected.

Cholangiography is mandatory for the diagnosis of PSC 3°'31 and in expert hands is as safe in children as in adults. We encountered no complications from these procedures in this series of patients. Adult studies have subdivided the ductal lesions of PSC in various ways. 2~'32 Most of these classifications require measure- ment of the duct diameter. This is impractical in children, because duct diameter varies with age. Thus, we devised a pediatric classification for the ductal lesion in PSC where severity is scored in relationship to degree of narrowing/dilatation in a given duct. Unlike most adult series, only three patients had significant large duct disease. 31'~3'34 Generally, intrahepatic disease predominated. Two children in whom the intrahepatic biliary tree was poorly visualized by ERCP had percutaneous cholangiography subsequently performed. Nevertheless, we do recommend ERCP as the preferred diagnostic method. This recommendation is echoed in the adult l i te ra tureY '33

The histological findings of bile ductular prolifera- tion, portal inflammation, and fibrosis, resulting in septal damage and biliary cirrhosis, have been well documented. The distribution among the stages of the disease as classified by Ludwig is similar to the adult experience. However, with so many of the changes being nonspecific, a good cholangiographic study is mandatory.

In 1987, E1-Shabrawi et al reported 13 cases of PSC in children, 15 10 of whom had IBD, and, unlike our study, there was a predominance of females. No patients presented under the age of 2 years. All 13 patients were reported as having increased ALP, and all had intrahepatic duct abnormalities on cholangiography. Five patients had been initially diagnosed histo- logically as having autoimmune hepatitis. Debray et al recently reported 56 children with sclerosing cholangitis, presenting over a 20-year period. 16 This large series included 15 infants who had sclerosing cholangitis of neonatal onset, 14 children with histiocytosis X, only 8 children with chronic IBD, and 10 children with no

other disease. Unlike our study, they reported a very high rate of consanguinity (23%).

Neonatal sclerosing cholangitis was first reported in 1987Y Subsequently others have identified additional patients. 36 Because the definition of PSC excludes congenital biliary tract anomalies, it is unclear if neonatal sclerosing cholangitis is part of the spectrum of PSC or indeed a separate entity. We did not identify any children with neonatal sclerosing cholangitis in this series. No patient in this series presented with cholestatic jaundice in the first 3 months of life.

The cause of PSC is as yet unknown. Genetic and immunologic factors are important. There have been various reports of familial occurrence of this disease and of an increased incidence of HLA B8 and DR3 over control subjects. 37 Prochazka et al 3s reported a series of 29 adult patients with PSC, all of whom possessed the DRw52a antigen. In this series, we found that this allele was no more common than the control popula- tion. At least two other groups have refuted the 100% association of DRw52a with PSC in adults, although an increased incidence has been reported in some stud- i e s . 3941 The positive association found with DR2 has been previously reported, as has the high percentage of DR3-negative patients who are DR2 positiveY Thus, possession of DR2 may be a significant association in these patients. It has been suggested that the dual association of PSC with either DR3, DR52, or DR2 may be because of differences in cause with different ex- pected outcomes, t3

The importance of immunologic factors has been em- phasized by several groups that have shown cellular and humoral abnormalities in PSC. 4t49 ANCA was reported in adults to be sensitive and specific for PSC. 5°'51 In the only pediatric study published to date, 8 of 10 PSC patients were correctly identified by ANCA; however, three of eight patients with autoimmune hepatitis tested positive for perinuclear staining, and the re- mainder were positive for cytoplasmic staining. 29 We performed ANCA estimation using a s tandard indirect immunofluorescence assay. Ten of 24 PSC patients were positive at the dilution stated (1:20). A lower dilution ratio (1:10) might have yielded more positive results, as reported by others, 29 but we thought this might increase false-positive results. ANCA appears to be present in chronic liver disease with a variety of causes. One group has even suggested that it is an epiphenomenon in chronic liver disease, 52 but family studies may refute this view. 53 We believe that autoimmune phenomena, including ANCA, may play an important role in this disease.

This series confirms that PSC can mimic autoimmune hepatitis clinically, 15 as shown by the nine patients who were clinically similar and numerous other patients with elevated serum IgG (17 of 31), anti- smooth muscle antibodies (19 of 30), or anti-nuclear antibody (14 of 30). Thus, the "chronic active hepatitis" presentation seems to be common in children. Clinical clues that may help to differentiate PSC from autoimmune hepatitis before cholangiography are normal

HEPATOLOGY Vol. 22, No. 5, 1995 WILSCHANSKI ET AL 1421

complement (C3 and C4) levels and poor response to corticosteroid therapy.

Although PSC is said to progress relentlessly to cirrhosis, patients may remain stable for many years. PSC is a common indication for liver transplantation. Thus it is important to identify at the time of diagnosis of PSC prognostic factors which could predict rapid progression. In a large multicenter study of patients older than 16 years, anemia, serum bilirubin, histological stage of disease, age, and splenomegaly were found to be independent variables predicting high risk. 54 In this series of 32 patients, we found that poor outcome is associated with diagnosis at an older age, possibly because of clinically silent disease of longer duration, and with prolonged PT and splenomegaly at presentation. Histological findings at presentation were not found to predict outcome. Numerous studies in adults with PSC have shown that the presence of cirrhosis indicates a poor prognosis. ~4'ss Among the children with PSC reported here, most undergoing liver transplantation have had cirrhosis or a high-grade extrahepatic biliary stricture. Our multivariate analysis of prognostic features in children indicates that some children with cirrhosis are not showing rapid clinical decompensation. The time spectrum for PSC in children may be longer than in adults. Alternatively, initial histological findings may underestimate disease severity, and in children serial biopsies may be necessary to stage disease progression adequately. We are currently addressing this question by reviewing serial liver biopsies in this group of patients (Wilschanski M, Phillips MJ, Roberts EA, Manuscript in preparation).

In conclusion, PSC occurs commonly in children. The prevalence of PSC in children has been underestimated partly because its clinical presentation frequently varies from the classic pattern in adults. It may present as a "chronic active hepatitis" or be clinically silent from an early age. Jaundice is uncommon, and serum ALP may be normal. A high index of suspicion is required to make the diagnosis in any child presenting with chronic liver disease. There may be an association with specific genetic or immunologic markers, which could serve as noninvasive flags for the diagnosis. Poor outcome is associated with diagnosis later in childhood, splenomegaly, and prolonged PT at presentation. Dif- ferences between PSC in children and adults may pro- vide clues to the pathogenesis of this disease.

Acknowledgment: The authors thank Drs P. Durie, R. Issenman, G. A. Levy, P. Marcon, E. Prokipchuk, P. Sherman, P. Wren, and A. Zaher for permitting us to study their patients. We thank Dr M. James Phillips for reviewing liver biopsy specimens and Dr Ernst Cutz for reviewing colonic biopsy specimens. We would also like to thank our clinical nurse specialists C. Smith and N. Graham in the Inflammatory Bowel Disease and Liver Clinics, respectively.

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