Impact of inflammatory bowel disease and ursodeoxycholic acid therapy on small-duct primary sclerosing cholangitis

Authors


  • Potential conflict of interest: Dr. Lindor received grants from Axcan.

Abstract

A longitudinal, cohort study was performed to characterize the clinical features of patients with small-duct primary sclerosing cholangitis (PSC) occurring with and without inflammatory bowel disease (IBD) and to determine the influence of IBD and the effect of ursodeoxycholic acid (UDCA) therapy on the course of the liver disease. Forty-two patients with small-duct PSC (14 women and 28 men; mean age, 36.7 ± 13.3 years) were followed for up to 24.9 years. At presentation, prevalence of signs of liver disease (none versus 35%, P = 0.002), gastroesophageal varices (5% versus 30%, P = 0.03), and stage III/IV disease (9% versus 45%, P = 0.008) were lower in those with IBD versus those without IBD. During follow-up, 6 patients underwent liver transplantation, and another died of cirrhosis. Using the Cox proportional hazard analysis, concomitant IBD was not associated with liver death or transplant, whereas the revised Mayo risk score for PSC was the only prognostic factor associated with liver-related outcomes (relative risk, 6.47; 95% confidence interval, 1.75-137.5). UDCA (13-15 mg/kg/day) therapy for an average of 40 months showed biochemical improvement (P < 0.001) in UDCA-treated patients, while no significant change occurred in untreated patients. UDCA therapy had no effect on delaying progression of disease (relative risk, 0.95; 95% confidence interval, 0.38-2.36). Conclusion: Small-duct PSC often is recognized at an early stage in patients with IBD; however, IBD has no impact on long-term prognosis. Although UDCA therapy improves liver biochemistries, it may not delay disease progression during the short period of treatment. (HEPATOLOGY 2008.)

Small-duct primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology characterized by fibrosing inflammation and destruction of interlobular and septal bile ducts in the absence of cholangiographic evidence of sclerosing cholangitis.1, 2 Small-duct PSC represents approximately 6% to 11% of patients with sclerosing cholangitis and commonly coexists with inflammatory bowel disease (IBD).3, 4 Three groups have reported follow-up information from patients with small-duct PSC, which showed that the clinical course of small-duct PSC was more benign than large-duct PSC.3–5 Unfortunately, some patients with small-duct PSC follow a progressive course over time, develop the typical cholangiographic features of large-duct PSC, and advance to biliary cirrhosis and its complications with the consequent necessity of liver transplantation.3–5 However, given that the definition of small-duct PSC varied from study to study in terms of evidence of IBD, the influence of concomitant IBD on the long-term prognosis of patients with small-duct PSC remains largely unstudied.

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid that is widely used in the treatment of cholestatic liver disease of all causes. UDCA appears to exert a number of effects, all of which may be beneficial in chronic cholestasis: a choleretic effect by an increase in bile flow, a direct cytoprotective effect, an indirect cytoprotective effect by displacement of the more hepatotoxic endogenous hydrophobic bile acids from the bile acid pool, an immunomodulatory effect, and finally an inhibitory effect on apoptosis.6 UDCA is beneficial for patients with primary biliary cirrhosis,7–11 another cholestatic liver disease involving small bile ducts that has some features in common with small-duct PSC. With the small number of patients with small-duct PSC that have been reported, there is no information specifically pertaining to the treatment of small-duct PSC. Thus, we conducted this study to determine the clinical presentation of patients with small-duct PSC occurring in association with and without IBD and to determine the influence of IBD and the effect of UDCA therapy on the natural history of small-duct PSC.

Abbreviations

AST, aspartate aminotransferase; CI, confidence interval; ERC, endoscopic retrograde cholangiography; IBD, inflammatory bowel disease; MRC, magnetic resonance cholangiography; PSC, primary sclerosing cholangitis; RR, relative risk; UDCA, ursodeoxycholic acid.

Patients and Methods

Patient Population.

Our patient population was composed of 42 patients with small-duct PSC who were identified using a computerized master diagnosis index. These patients had their first medical evaluation for their liver disease at our institution during the period from January 1993 to December 2004. The diagnosis of small-duct PSC was established on the basis of the following criteria: (1) chronic cholestasis of at least 6 months duration and serum alkaline phosphatase activity at least 1.5 times the upper limit of normal, (2) diagnostic-quality cholangiogram showing a normal biliary tree, and (3) liver histology consistent with PSC. Other causes of liver diseases such as drug-induced cholestasis, primary biliary cirrhosis, autoimmune hepatitis, viral hepatitis, alcoholic and nonalcoholic fatty liver disease, and metabolic/hereditary liver disease were excluded in all patients. Patient follow-up was extended up to December 2005.

All medical records were reviewed to obtain information regarding demographics, symptoms and physical findings, complications of liver disease, laboratory values, liver histology, type and findings of cholangiogram, treatment for small-duct PSC, IBD (type, duration, severity, details of medical therapy, requirement for surgery, colon dysplasia, and colon cancer), and cause of death. Laboratory evaluation included liver biochemistries, autoantibodies (nuclear, mitochondrial, and smooth muscle), and serum carbohydrate antigen 19-9 levels. Abdominal ultrasonography was performed annually and repeated when clinically indicated. Esophagogastroduodenoscopy to investigate for gastroesophageal varices and colonoscopy for IBD surveillance were also performed. The revised Mayo risk score12 was calculated at the time of diagnosis of liver disease, the first Mayo Clinic visit, and the start of UDCA therapy.

Liver biopsies were performed at the time of first visit to our institution in 19 patients, while 23 patients in whom liver biopsies were performed at other institutions had their specimens reviewed at our institution. In each case, histopathologic changes consistent with PSC were found, and stage of disease was determined using Ludwig's classification, in which stage 1 represents cholangitis or portal hepatitis, stage 2 represents periportal fibrosis or periportal hepatitis, stage 3 represents septal fibrosis or bridging necrosis or both, and stage 4 represents cirrhosis.13 Patients with liver biopsy features of histological stage 1 or 2 were considered to have early-stage disease; those with features of stage 3 or 4 were considered to have advanced-stage disease.

Endoscopic retrograde cholangiography (ERC) was performed in 39 patients and magnetic resonance cholangiography (MRC) was performed in 3 patients at the time of diagnosis of small-duct PSC. All cholangiogram images were reviewed by independent radiologists with experience in biliary tree imaging. Evaluation for the development of large-duct PSC on a subsequent cholangiogram was performed with ERC or MRC in 10 patients using standard criteria as previously described.14

Statistical Analysis.

Continuous variables were summarized as means + standard deviation or medians (range), where appropriate, and the comparisons between and within groups were performed using the nonparametric test. Categorical variables were summarized as percentages of the group, and comparison between groups was performed using the χ2 test or Fisher's exact test, where appropriate. Event-free survival was estimated by the Kaplan-Meier method and compared between groups using the log-rank test. Survival in small-duct PSC patients was calculated from the date of diagnosis of liver disease to the date of death or liver transplantation. Patients were censored at the last contact. A Cox regression analysis was performed to identify factors associated with liver-related outcomes. Variables with a skewed distribution, such as alkaline phosphatase, total bilirubin, and aspartate aminotransferase (AST), were brought toward a more symmetric distribution by logarithmic transformation.

We sought to evaluate the influence of small-duct PSC on the natural history of IBD. Six patients with small-duct PSC were excluded because they had undergone colectomy prior to a diagnosis of liver disease. Thus, our cohort included 16 IBD patients with small-duct PSC, and these were blindly matched with 32 IBD patients with large-duct PSC by age at liver disease diagnosis (±1 year), sex, and type of IBD. Colectomy-free probability in patients with IBD and PSC was calculated from the date of liver disease diagnosis to the date of colectomy. The relative risk (RR) of colonic neoplasia and colectomy for IBD was estimated by a Cox regression analysis.

Disease progression–free survival among the subgroup of small-duct PSC patients was calculated from the date of start UDCA therapy or the first date of follow-up in our institution to death, liver transplantation, disease advancing to large-duct PSC, or histologic progression by two stages. The RR of the treatment effect of UDCA was estimated by a Cox regression analysis. A 2-sided P value less than 0.05 was considered statistically significant. The study was approved by the Mayo Institutional Review Board, and written informed consent was obtained from all patients for participation in medical research.

Results

Demographic and Characteristic of the Patients.

The main demographic and clinical data are summarized in Table 1. The 42 patients with small-duct PSC included 14 female and 28 male patients with a mean age of 36.7 ± 13.3 years (range, 15-61 years). Twenty-two (52%) patients had symptomatic IBD, of whom 73% had chronic ulcerative colitis and 27% had Crohn's disease with colonic involvement. Of these patients, 12 patients had a history of ulcerative colitis with a mean duration of 4.6 ± 9.1 years (range, 0-25.1 years) before diagnosis of liver disease, while 3 patients did not have IBD at the time of diagnosis but developed ulcerative colitis at 1, 1, and 3 years of follow-up. Seven patients with Crohn's disease were followed with a mean duration of 9.3 ± 3.8 years (range, 0-25.2 years) before diagnosis of liver disease. All patients with coexisting IBD initially had clinical symptoms of IBD, and almost all required medical and/or surgical therapy for inducing and maintaining remission of disease. At the time of diagnosis of small-duct PSC, 10 patients with concomitant IBD had quiescent disease, and the remaining 12 patients had mild to moderate severity as evaluated by the Clinical Practice Guideline of the American College of Gastroenterology.15, 16

Table 1. Demographic and Clinical Features of Patients with Small-Duct PSC and Comparison Between the Patients with and Without IBD
 Patients without IBD (n = 20)Patients with IBD (n = 22)Patients with
Ulcerative colitis (n = 15)Crohn's disease (n = 7)
  • Data are expressed as mean ± standard deviation. The normal ranges are follows: alkaline phosphatase, 90-234 IU/L; AST, 12-31 IU/L; total bilirubin, 0.1-1.1 mg/dL; albumin, 3.5-5 g/dL; prothrombin time, 8.4-12 seconds; and globulin, 2.9-3.1 g/dL.

  • *

    Age at liver disease diagnosis was the age at which the first liver biopsy was performed with histology consistent with PSC.

  • **

    Some patients presented with more than 1 symptom/sign at the time of diagnosis of small-duct PSC. An asymptomatic patient was defined as one with the absence of specific symptoms of liver disease, including pruritus, otherwise unexplained fatigue, jaundice, right upper quadrant pain, cholangitis, ascites, leg edema, encephalopathy, and variceal bleeding.

  • P = 0.01 for the comparison between the group with IBD and without IBD.

  • P = 0.002 for the comparison between the group with IBD and without IBD.

  • P = 0.03 for the comparison between the group with IBD and without IBD.

  • P = 0.008 for the comparison between the group with IBD and without IBD.

Age at diagnosis (years)*37.3 ± 14.736.1 ± 12.135.8 ± 12.936.7 ± 11.2
Sex (female/male)8/126/163/123/4
White race (%)13 (65)21 (95)15 (100)6 (86)
Symptom/sign (%)**    
 Asymptomatic8 (40)13 (59)9 (60)4 (57)
 Pruritus5 (25)6 (27)5 (33)1 (14)
 Fatigue6 (30)5 (23)2 (13)3 (43)
 Abdominal pain2 (10)3 (14)1 (7)2 (29)
 Weight loss1 (5)000
 Cholangitis1 (5)000
 Jaundice3 (15)000
 Hepatomegaly3 (15)000
 Splenomegaly5 (25)000
 Ascites1 (5)000
Gastroesophageal varices6 (30)1(5)1(5)0
Laboratory test    
 Alkaline phosphatase (IU/L)646 ± 426802 ± 647761 ± 615866 ± 741
 AST (IU/L)96 ± 7674 ± 5086 ± 5255 ± 45
 Total bilirubin (mg/dL)1.7 ± 1.80.9 ± 0.40.9 ± 0.30.9 ± 0.5
 Albumin (g/dL)3.9 ± 0.74.0 ± 0.44.0 ± 0.44.1 ± 0.4
 Globulin (g/dL)3.3 ± 0.43.3 ± 1.03.7 ± 1.02.7 ± 0.6
 Prothrombin time (s)10.3 ± 1.69.8 ± 1.09.9 ± 1.19.7 ± 0.7
Mayo risk score for PSC0.23 ± 1.26−0.34 ± 0.77−0.35 ± 0.83−0.31 ± 0.63
Histologic stage (%)    
 Stage I8 (40)14 (64)9 (60)5 (71)
 Stage II3 (15)6 (27)4 (27)2 (29)
 Stage III3 (15)2 (9)2 (13)0
 Stage IV6 (30)¶000

Twenty patients with small-duct PSC were categorized into the non-IBD group, and none of them had any clinical symptoms or signs of IBD. Twelve (60%) patients without IBD underwent colonoscopy with biopsy-confirmed normal mucosa, while the remaining 8 patients were categorized into the non-IBD group on the basis of clinical data during a mean follow-up of 4.2 years (range, 1.1-10 years). The demographic, clinical, biochemical, and histological features and duration of follow-up of these patients were similar to those of patients without IBD who had colonoscopy performed (data not shown).

Clinical Features.

The median time that elapsed since the first clinical manifestation, biochemical, or histological abnormalities leading to the diagnosis of small-duct PSC was 9.0 months (range, 0-228 months) for patients with coexisting IBD and 11.5 months (range, 0-117 months) for patients without IBD (P = 0.8). At the time of diagnosis of small-duct PSC, there was no significant difference in age, sex, frequency of symptoms of liver disease, liver biochemistries, or Mayo risk score between the 2 groups, as shown in Table 1. The prevalence of white race in patients with coexisting IBD was higher than the prevalence in patients without IBD (P = 0.01). The signs of liver disease and portal hypertension, including jaundice, hepatosplenomegaly, ascites, and gastroesophageal varices, were more common in the patients without IBD than in the patients with coexisting IBD. None of these patients had documented variceal bleeding. The proportion of advanced-stage disease on diagnostic liver biopsy was significantly greater among patients without IBD than patients with coexisting IBD (45% versus 9%, P < 0.05). Demographic, clinical, biochemical, and histological features were similar between subgroups with ulcerative colitis and Crohn's disease, as shown in Table 1.

Cholangiographic and Histological Follow-Up.

Subsequent cholangiography was performed in 6 patients with coexisting IBD and in 4 patients without IBD. Of the patients with coexisting IBD, a serial cholangiogram was performed with ERC in 4 patients and with MRC in 2 patients with a median follow-up of 34 months (range, 15-250 months) because of persistent right upper quadrant abdominal pain, worsening of liver biochemistries, and ultrasonographic evidence for a thickened common bile duct wall. In 2 asymptomatic patients with a rising alkaline phosphatase activity and common bile duct wall thickening, cholangiograms of intrahepatic and extrahepatic bile ducts showed the typical changes of sclerosing cholangitis at 27 and 41 months of follow-up. Another asymptomatic patient with a rising alkaline phosphatase activity showed the typical changes of only extrahepatic sclerosing cholangitis after 15 months of follow-up. In another 2 patients with abdominal pain and 1 patient with worsening liver test results, the bile ducts remained normal on examination by cholangiography. Of the patients without IBD, a follow-up cholangiogram was performed with ERC in 2 patients and with MRC in 2 patients with a median follow-up of 48 months (range, 15-72 months) because of persistent elevation of serum alkaline phosphatase activity in 3 patients and the presence of ultrasonographic evidence of common bile duct wall thickening in another patient. All of these patients had normal cholangiography.

A follow-up liver biopsy was performed in 4 patients with coexisting IBD during an average time period of 127 months (range, 15-247 months) and in 4 patients without IBD during an average time period of 64 months (range, 33-119 months) because of worsening of liver biochemistries, evaluation of possible coexisting liver disease, and monitoring of the progression of the disease during treatment with UDCA. No change in histological stage was noted in 5 patients, whereas histologic progression occurred in 2 patients with rising alkaline phosphatase activity. The first patient without IBD had histologic progression by two stages 11 years after a diagnosis of small-duct PSC. In the second patient with IBD, subsequent liver biopsy showed histologic progression by one stage 7 years after liver disease diagnosis. Histologic regression by one stage occurred in one patient on a subsequent intraoperative liver biopsy at the time of colectomy for IBD. No follow-up liver biopsy was performed in patients whose disease progressed to large-duct PSC.

Long-Term Survival and Assessment of Prognostic Variables.

Median time of follow-up, from the time of diagnosis of small-duct PSC to the last follow-up (death or up to December 2005), was 4.8 years (range, 1.0-24.9 years). During this time, 1 patient died of cirrhosis, and another 6 patients presenting with advanced-stage liver disease underwent liver transplantation after 0.1, 0.4, 1, 2, 7, and 7.3 years of diagnosis. All of the transplanted patients were alive during follow-up. Transplant-free survival or death of all the small-duct PSC patients at 1, 5, and 10 years was 95%, 90%, and 67%, respectively (Fig. 1). Survival free of liver-related outcomes (liver death or transplant) was significantly longer among patients with coexisting IBD than patients without IBD (P = 0.004). None of the patients in both groups developed hepatobiliary malignancy during follow-up evaluation.

Figure 1.

Kaplan-Meier curves of survival free of liver-related outcomes (liver death or transplant).

In the univariate analysis, the following variables had a significant influence on patient survival (Table 2): IBD; signs of liver disease; gastroesophageal varices; cirrhosis on the diagnostic liver biopsy; serum levels of total bilirubin, AST, and albumin and prothrombin time; and the Mayo risk score. Risk of death or liver transplantation was not significantly associated with age, sex, white race, symptoms of liver disease, or the serum levels of alkaline phosphatase and globulin. The serum levels of AST, total bilirubin, and albumin and prothrombin time were excluded from the final multivariate model, although the effects of these variables on survival were statistically significant in the univariate analysis, because most of these variables are already incorporated into the model for the Mayo risk score. In the multivariate analysis, only the Mayo risk score remained significantly associated with risk of death or liver transplantation [RR, 6.47; 95% confidence interval (CI), 1.75-137.5; P = 0.0015].

Table 2. Univariate Cox Regression Survival Analysis—Death or Liver Transplantation
VariableParameter EstimateStandard ErrorHazard Ratio (95% CI)P Value
  1. “Symptoms of liver disease” is defined as presenting with fatigue, pruritus, or right upper quadrant abdominal pain; “signs of liver disease” is defined as presence of jaundice, hepatomegaly, splenomegaly, or ascites; and “cirrhosis at diagnosis” is defined as stage IV disease on diagnostic liver biopsy.

Age at diagnosis0.030.031.03 (0.98–1.10)0.2
Male sex0.160.421.17 (0.54–3.10)0.7
White race−0.040.540.96 (0.39–4.21)0.9
IBD−1.260.550.28 (0.07–0.70)0.005
Symptoms of liver disease0.840.542.31 (0.95–10.1)0.07
Signs of liver disease1.480.424.38 (2.02–11.6)0.0002
Varices at diagnosis1.800.546.05 (2.49–26.3)<0.0001
Cirrhosis at diagnosis1.540.424.68 (2.16–12.4)0.0001
Alkaline phosphatase (log)0.680.591.98 (0.65–6.85)0.2
AST (log)1.160.523.20 (1.19–9.62)0.02
Total bilirubin (log)1.310.433.71 (1.61–9.37)0.003
Albumin−2.460.770.09 (0.01–0.35)0.0006
Globulin0.100.701.11 (0.22–4.20)0.9
Prothrombin time0.840.322.31 (1.29–4.84)0.004
Mayo risk score for PSC1.940.576.99 (2.78–29.6)<0.0001

Clinical Course of IBD in Small-Duct PSC.

IBD associated with small-duct PSC was characterized by a lower prevalence of pancolitis with or without ileal involvement compared to IBD associated with large-duct PSC. The groups did not differ significantly with respect to duration of IBD, temporal relationship of IBD and liver disease, severity of liver disease, history of UDCA therapy, and number of colonoscopy procedures during follow-up at our institution (Table 3). None of the patients in either group developed colorectal cancer during follow-up evaluation. Reasons for colectomy for IBD among the small-duct PSC group included multifocal low-grade dysplasia in one and intractability to medical therapy in two. The observed number of colectomies for all reasons in patients with small-duct PSC was similar to that in patients with large-duct PSC (RR, 1.08; 95% CI, 0.49-2.19; P = 0.8), as shown in Fig. 2. The risk of developing colonic dysplasia in IBD among small-duct PSC patients was not significantly different from that among large-duct PSC patients (RR, 0.58; 95% CI, 0.13-1.45; P = 0.3).

Table 3. Clinical Features and Outcome of IBD in Small-Duct PSC Patients and Large-Duct PSC Patients
 Small-Duct PSC (n = 16)Large-Duct PSC (n = 32)P Value
  1. The extent of disease was categorized on the basis of histological changes at any time during the study period: pancolitis with or without ileal involvement, left-sided colitis (disease extending to but not beyond the splenic flexure), and right-sided colitis (disease involving colon proximal to the splenic flexure).

Sex (female/male)3/136/261.0
Age at PSC diagnosis (years)35.4 ± 13.135.9 ± 12.80.8
Age at IBD diagnosis (years)33.8 ± 14.229.0 ± 12.80.3
IBD (%)  1.0
 Ulcerative colitis13 (81%)26 (81%) 
 Crohn's disease3 (19%)6 (19%) 
Temporal relationship of IBD and PSC  0.1
 IBD >30 days before PSC (%)8 (50%)24 (75%) 
 Simultaneous (±30 days; %)4 (25%)6 (19%)
 IBD >30 days after PSC (%)4 (25%)2 (6%) 
Duration of IBD at first Mayo visit (years); median (range)1.2 (0.4–3.5)4.6 (1.2–13.6)0.09
Extent of IBD (%)   
 Pancolitis11 (69%)30 (94%)0.03
 Left-sided colitis3 (19%)1 (3%)0.1
 Right-sided colitis2 (12%)1 (3%)0.3
Mayo risk score for PSC−0.33 ± 0.830.21 ± 1.000.1
UDCA therapy (%)13 (81%)19 (59%)0.2
Number of colonoscopy; median (range)2.5 (1–4)2.0 (1–3)0.5
Reasons for colectomy for IBD; n   
 Low-grade dysplasia12 
 Dysplasia-associated lesion or mass02
 Intractability to medical therapy21
Figure 2.

Kaplan-Meier estimated colectomy-free survival for IBD patients with small-duct PSC and patients with IBD and large-duct PSC. Time to colectomy for all reasons among the small-duct PSC group was similar to those among the large-duct PSC group (P = 0.8, log-rank test).

UDCA Therapy and Outcomes.

To determine the efficacy of UDCA therapy for small-duct PSC, 5 patients were excluded because they underwent liver transplantation within 1 year after treatment with UDCA or diagnosis of small-duct PSC. Thus, the remaining 37 patients with small-duct PSC comprised our population for this purpose. Thirty patients (81%) have been treated with UDCA at a dose of 13-15 mg/kg/day because of a persistent elevation of serum alkaline phosphatase activity. The average time period for UDCA therapy was 40 months (range, 13-151 months). Twenty-three (72%) patients have been treated with UDCA for at least 2 years, and nine of these patients have been on UDCA therapy more than 4 years. UDCA was well tolerated, but one patient stopped medication after 4 years of therapy because of a flare of ulcerative colitis. Seven (19%) patients were not treated with UDCA because of mild and transient elevation of serum alkaline phosphatase activity.

The main clinical and laboratory data are summarized in Tables 4 and 5. The two groups did not differ significantly with respect to age, sex, race, type of IBD and medical treatment, clinical presentation, liver biochemistry values, histological stage of liver disease, and presence of autoantibodies. However, there was a trend toward higher baseline levels of serum alkaline phosphatase in treated patients when compared with untreated patients. Antinuclear antibodies were found in 6 patients. Smooth muscle and antimitochondrial antibodies were negative in all patients. No patient met the criteria for diagnosis of autoimmune hepatitis according to the revised international scoring system.17

Table 4. Baseline Demographic and Clinical Features of Patients with Small-Duct PSC and Comparison between UDCA-Treated and Untreated Groups
 UDCA Treatment (n = 30)No UDCA Treatment (n = 7)P Value
  • *

    Some patients were treated with more than 1 medication.

  • **

    Some patients presented with more than 1 symptom/sign at the time of starting UDCA therapy (UDCA-treated group) or the first evaluation of liver disease in our institution (untreated group).

  • Comparison between group treated with or without 5-aminosalicylic acid compounds, including sulfasalazine, mesalamine, and olsalazine.

  • Comparison proportion of asymptomatic and symptomatic between groups.

  • Comparison between early-stage disease (stage I/II) and advanced-stage disease (stage III/V).

Age (years)36.2 ± 12.138.6 ± 15.20.7
Sex (female/male)11/192/50.7
White race (%)24 (80)6 (86)0.8
IBD (%)16 (50)6 (86)0.1
 Ulcerative colitis11 (69)5 (83)0.3
 Crohn's disease5 (31)1 (17) 
IBD treatment (n)*  0.4
 Mesalamine102 
 Sulfasalazine12 
 Olsalazine01 
 Azathioprine32 
 Corticosteriods32 
 Budesonide10 
 Methotrexate12 
 Infliximab21 
Symptom/sign (%)**  0.3
 Asymptomatic15 (50)5 (71) 
 Pruritus9 (30)0 
 Fatigue7 (23)2 (29) 
 Abdominal pain6 (20)0 
 Weight loss1 (3)0 
 Cholangitis1 (3)0 
 Jaundice1 (3)0 
 Hepatomegaly1 (3)0 
 Splenomegaly2 (7)0 
 Ascites00 
Mayo risk score for PSC−0.47 ± 0.66−0.04 ± 0.800.3
Autoantibodies (%)5 (17)1 (14)0.9
Histologic stage (%)  0.9
 Stage I17 (57)4 (57) 
 Stage II8 (27)1 (14) 
 Stage III4 (13)2 (29) 
 Stage IV1 (3)0 

An overall significant improvement in serum levels of alkaline phosphatase (P < 0.001) and AST (P < 0.001) occurred during 2 years of treatment with UDCA, but they did not change significantly in the untreated group, as shown in Table 5. Furthermore, improvements to more than 50% of the baseline value of serum alkaline phosphatase occurred in 50% of patients and improvements to more than 50% of the baseline value of AST occurred in 29% of patients at 2 years of UDCA therapy. Although no significant changes in serum levels of bilirubin and albumin occurred with UDCA therapy, 2 of 5 UDCA-treated patients, who had elevation of serum bilirubin levels at baseline, became normal after 6 and 24 months of treatment with UDCA. Only 1 patient had complete biochemical normalization during treatment with UDCA.

Table 5. Biochemical Changes in UDCA-Treated and Untreated Patients
Biochemical ValuesUDCA-Treated Patients (n = 30)Untreated Patients (n = 7)
Baseline12 Months24 MonthsBaseline12 Months24 Months
  • Data are expressed as mean ± standard deviation. For alkaline phosphatase, the normal range is 90 to 234 IU/L; for AST, 12 to 31 IU/L; for total bilirubin, 0.1 to 1.1 mg/dL; and for albumin, 3.5 to 5.0 g/dL.

  • *

    Baseline biochemical values did not significantly differ between UDCA-treated patients and untreated patients.

  • There was a statistically significant improvement in serum alkaline phosphatase activity (P < 0.001) and AST level (P < 0.001) from baseline to 1 year and 2 years, but no significant changes in serum total bilirubin or albumin were noted during 2 years of treatment with UDCA (P > 0.05).

  • There were no significant changes in serum alkaline phosphatase activity, AST level, total bilirubin, or albumin among untreated patients during 2 years of follow-up (P > 0.05).

Alkaline phosphatase (IU/L)*740 ± 610331 ± 306249 ± 127537 ± 335400 ± 450217 ± 53
AST (IU/L)*78 ± 4642 ± 3337 ± 1452 ± 3952 ± 1439 ± 12
Total bilirubin (mg/dL)*0.9 ± 0.40.7 ± 0.40.7 ± 0.30.8 ± 0.50.6 ± 0.30.7 ± 0.6
Albumin (g/dL)*4.2 ± 0.34.2 ± 0.34.2 ± 0.33.8 ± 0.53.7 ± 0.53.9 ± 0.4

Three (10%) of the UDCA-treated patients and 3 (43%) of the untreated patients had evidence of disease progression during a mean follow-up of 62 months. One of the UDCA-treated patients developed liver failure with the consequent necessity of liver transplantation, and another of the untreated patients died of cirrhosis. On subsequent cholangiography, development of sclerosing cholangitis was observed in 2 of the 7 UDCA-treated patients and 1 untreated patient. Histological progression was observed on follow-up liver biopsy in 1 of the 7 UDCA-treated patients who had repeat biopsy by one stage and in 1 untreated patient by two stages. When death, liver transplantation, development of large-duct PSC, and histologic progression by two stages, whichever occurred first, were counted as outcomes, UDCA therapy had no significant effect on time to disease progression (RR of disease progression in the UDCA-treated group, 0.95; 95% CI, 0.38-2.36; P = 0.9) in this small sample, as shown in Fig. 3.

Figure 3.

Kaplan-Meier estimated disease progression–free survival for patients with small-duct PSC who were treated with or without UCDA. Time to disease progression of the UDCA-treated group was not significantly different compared to those of the nontreated group (P = 0.9, log-rank test).

Discussion

Small-duct PSC is generally considered a rare disease, but a growing body of knowledge about its natural history has developed, especially in the early 2000s through American, British, and Scandinavian studies.3–5 However, little is known about the influence of IBD and the effect of UDCA therapy on the natural course of patients with small-duct PSC. Our study showed that small-duct PSC often is recognized at an early stage in patients with IBD. However, IBD is not likely to affect liver-related outcomes in small-duct PSC patients. The risk of colonic dysplasia and colectomy for IBD after diagnosis of liver disease among small-duct PSC patients does not differ from that for large-duct PSC patients. UDCA therapy for small-duct PSC was associated with biochemical improvement as in the large-duct PSC studies.18–20 However, UDCA therapy could not show the obvious benefit of delaying disease progression in this small sample with the short period of treatment.

The close association between small-duct PSC and IBD has been recognized for several years, and previous studies have reported a 50%-88% prevalence of IBD in small-duct PSC.3–5 We report a low rate of IBD (52%); in particular, chronic ulcerative colitis was seen in only 36% of total patients. However, we cannot exclude the possibility that the prevalence of IBD was underestimated in this retrospective cohort study since colonoscopy to look for IBD was performed only in 12 of 20 patients without symptoms related to bowel disease. This situation may be similar to patients with large-duct PSC in that IBD is often quiescent and discovered only if endoscopy with random biopsy is performed.21, 22

The general characteristics of the patients in our series resemble those found in previous studies with a male predominance,3–5 the average age of onset being 40 years with a large span (15-61 years). With regard to the gender distribution, small-duct PSC occurring in association with or without IBD was more common in men than women, in contrast with a Swedish study that showed a female predominance among patients without IBD.5 A high proportion of white race in patients with small-duct PSC and IBD may be related to concomitant IBD. The most common symptoms in small-duct PSC patients were fatigue and pruritus in our series, whereas fatigue and abdominal pain were the most common symptoms in previous studies.3–5 In this study, the important differences between patients with or without IBD were the severity of liver disease at the time of diagnosis. Nearly one-third of patients without IBD presented with signs of liver disease, while none of the patients with coexisting IBD presented with these features on examination. We also found that a substantial proportion (30%) of patients without IBD presented with signs of portal hypertension. This prevalence is higher than that detected in patients with coexisting IBD and when compared to overall patients (6%-18%) regardless of IBD in previous studies.3–5 In addition, nearly half of our patients without IBD present with advanced-stage disease on the diagnostic liver biopsy. In contrast, only 9% of patients with coexisting IBD had advanced-stage liver disease. One possible explanation is the fact that patients with coexisting IBD usually are under medical care, and liver enzyme monitoring is performed frequently in such cases. Therefore, it is not unexpected that abnormal liver test results would lead to recognition of early-stage disease before the disease manifested with signs of liver disease. However, this difference may be related to individual genetic susceptibility to disease progression and the variability of disease progression between patients as in large-duct PSC or anti-inflammatory and immunomodulatory effects of medical treatment for concomitant IBD.

No data exist as to the natural course of patients with small-duct PSC depending on the presence or absence of IBD in terms of development of large-duct PSC. Our results show that patients with coexisting IBD seem to be at increased risk of developing cholangiographic changes of large-duct PSC. However, we should cautiously interpret this finding because few patients in our series had cholangiograms performed during follow-up. Further prospective studies with regular noninvasive evaluation such as MRC are necessary to better define the progressive nature of the disease. Interestingly, we also found that a common bile duct wall thickening was detected by ultrasonography in 3 of 42 (7%) patients, and cholangiography confirmed development of large-duct PSC in 2 and excluded it in 1. From this observation, ultrasonography may be useful as a tool for monitoring disease progression, particularly in patients with a rising alkaline phosphatase.

The natural history of small-duct PSC in our series confirmed a benign course as in other previous reports;3–5 at 10 years, the estimated survival rate was 67%. However, distinct clinical subsets of patients may have different courses of disease. In our series, patients with coexisting IBD were associated with a longer apparent survival. However, IBD had no impact on liver-related morbidity and mortality in Cox regression analysis. These discordant results may be due to “lead time bias,” patients with coexisting IBD being more frequently screened and more likely to be diagnosed at the early course of disease. When we calculated survival using the date of diagnosis of liver disease, it seemed to indicate that patients with IBD have a better prognosis than those without IBD. Furthermore, this study showed that only the Mayo risk score was associated with death or liver transplantation in the multivariate model. Although the Mayo risk score for PSC has not been validated in patients with small-duct PSC, we believe that this model may be used as a clinical tool in assessing the risk of small-duct PSC patients and making treatment decisions. This belief is based on the fact that biliary cirrhosis in large-duct PSC seems to be caused by disease processes involving small bile ducts in almost all instances.13

All case series of small-duct PSC patients have focused on the hepatobiliary manifestations of the condition, and there are few details about the clinical course of IBD associated with small-duct PSC.3–5 Our study showed that there was no difference in the rates of colectomy for IBD due to any indications between small-duct PSC and large-duct PSC. Importantly, the risk of colonic dysplasia in IBD associated with small-duct PSC is comparable to the risk of colonic dysplasia in IBD in large-duct PSC. However, we should cautiously interpret this finding when considering that the small-duct PSC group has a lower prevalence of pancolitis and a trend toward shorter duration of IBD compared to the large-duct PSC group. Moreover, our prevalence of colonic neoplasia is a minimal estimate. To better define the role of small-duct PSC as a risk factor for colorectal neoplasia in IBD, a prospective colonoscopic surveillance program is warranted. Nevertheless, it seems that IBD associated with small-duct PSC may have a risk of colorectal neoplasia, and patients should be enrolled in a colonoscopic surveillance program after diagnosis of liver disease as in large-duct PSC.

In the current study, UDCA therapy showed biochemical improvement, but it did not seem to prevent progression of disease as in large-duct PSC.20 We hypothesized that any medical treatment for concomitant IBD might have confounding effects on the progression of disease. However, we did not differentiate treatment effects of specific medications because the study would not have enough power to detect a difference in disease progression between treatment regimens. On the basis of the current data, we cannot strongly recommend empirical therapy with UDCA for patients with small-duct PSC. Despite the lack of benefit of treatment with UDCA at a dose of 13-15 mg/kg/day on clinical relevant outcomes in this series, recent pilot studies of UDCA therapy at a dose of 25-30 mg/kg/day showed a significant improvement in liver biochemistries, histology, and cholangiographic appearance in patients with large-duct PSC.23, 24 Thus, high-dose UDCA may be beneficial for patients with small-duct PSC. Larger prospective studies are warranted to evaluate the long-term effects of UDCA in these patients.

In summary, this series of patients with small-duct PSC who were followed up long-term suggests that the presence or absence of IBD has no impact on long-term prognosis. Treatment with UDCA at a dose of 13-15 mg/kg/day improves liver tests, but it may not impact on progression of disease. However, because our study has only a relatively small number of patients, along with a short period of treatment, it could not definitively evaluate the long-term effects of UDCA therapy with respect to clinically relevant endpoints.

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