Epidemiology and Natural History of Primary Sclerosing Cholangitis

Region

Study period

Number of cases

Incidence^a

Prevalence^b

Reference

Northern Europe

Norway

1986–1995

1.3

8.5

[9]

Sweden

1992–2005

199

1.22

16.2

[8]

Netherlands

2000–2007

519

0.5

6.0

[12]

1984–2003

0.91

12.7

[10]

1987–2002

149

0.41

3.85

[13]

North America

Rochester, MN

1976–2000

0.9

13.6

[6]

California

2000–2006

169

0.41

4.15

[14]

Calgary, Canada

2000–2005

0.92

[11]

Spain

1984–1988

0.07

0.22

[15]

Japan

2007

415

0.95

[16]

NA not available

^aPer 100,000 person-years

^bPer 100,000 inhabitants

Data on the prevalence of PSC in other parts of the world are limited. From questionnaire data from Spain and Japan, the estimated prevalence rates were 0.22 and 0.95 cases per 1000,000 inhabitants, respectively [15, 16]. PSC appears to be rare in native Alaskans [17], but PSC disproportionately accounts for African-Americans listed for liver transplantation suggesting that they have a prevalence similar to whites [18].

Demographics

The demographic characteristics of patients with PSC have been similar regardless of the cohort being described. PSC disproportionately affects men with approximately two-thirds of patients with PSC being male. The age of diagnosis of PSC ranges from children to the elderly, but the median age of diagnosis is typically in the fourth decade [6–8, 12]. Notably, the peak incidence in men is younger than women. Approximately 10 % of cases are in children. The association between PSC and IBD has been consistently reported; however, earlier data suggested that approximately 80 % of patients with PSC had concomitant IBD. In contrast, more recent data estimate this value to be in the range of 65–70 %, with women having a lower prevalence of IBD compared to men with PSC [6–8, 12]. Across all series, nearly 80 % of PSC patients with IBD have ulcerative colitis, while fewer than 20 % have Crohn’s disease [6–8, 12].

Natural History

Understanding the natural history of PSC is complicated by a multitude of challenges, most notably an unknowable onset of disease (Fig. 1.1). There is likely to be a preclinical period between the onset of disease and the abnormal cholangiographic findings, which represent established fibrosis. In addition, delay in diagnosis is common resulting in an artificially shortened time from diagnosis to clinical outcome. Further, there are several clinically important outcomes, such as cholangiocarcinoma and colorectal cancer, which are unrelated to liver disease severity. Finally, as with the epidemiology of PSC, changes in technology and increased awareness of the disease have likely lead to the diagnosis of less severe cases. Overall, this might lead to the erroneous conclusion that PSC is becoming more common but less severe.

Fig. 1.1

The natural history of primary sclerosing cholangitis (PSC). Prior to the diagnosis of PSC, there is a preclinical stage, which likely involves colitis leading to biliary inflammation. Not until biliary fibrosis is present can the diagnosis of PSC be made by an abnormal cholangiogram. Subsequently, there is a progression of biliary fibrosis leading to portal hypertension, cirrhosis, and its complications. In addition, there are competing risk unrelated to the progression of the liver fibrosis

Most commonly, PSC progresses similar to other chronic liver diseases with liver fibrosis leading to portal hypertension and its associated complications. In early studies, liver-related deaths accounted for approximately 70–80 % of mortality (Fig. 1.2). More recent studies suggest little change with clinical end points of liver transplantation and liver-related deaths still accounting for similar proportion of outcomes. Cancers related to PSC, including cholangiocarcinoma, gallbladder cancer, and colorectal cancer, make up 10–20 % of death in PSC. Like other biliary forms of liver disease, portal hypertension tends to be presinusoidal with esophageal varices developing early in the course of disease. In addition to cirrhosis, biliary strictures can lead to bacterial cholangitis and jaundice. Risks of malignancy are also increased. This includes not only a risk of cholangiocarcinoma and gallbladder cancer but also an increased risk of colorectal cancer in those patients with concomitant IBD.

Fig. 1.2

Distribution of outcomes of death and liver transplantation among patients with PSC. In early studies, the majority of deaths were related to liver failure. Increasingly, the primary outcome has become liver transplantation with a smaller percentage dying from liver failure. A variable, but minor, percentage developed PSC-related cancers or die from unrelated causes [12, 19, 48–55]

The estimated median time from diagnosis of PSC to either death or liver transplantation based upon early studies ranged from 9 to 18 years (Fig. 1.3) [19–21]. However, these studies were from tertiary care and liver transplant centers with the potential for significant referral bias. This was illustrated by a study of all PSC patients treated at 44 hospitals in a large geographically defined area in the Netherlands comprising over 8 million people. In this population-based study, the estimated median survival from diagnosis of PSC until liver transplantation or PSC-related death was 21.3 years in the entire cohort compared to only 13.2 years for patients receiving care at a transplant center [12].

Fig. 1.3

The median transplant-free survival across multiple studies [12, 19, 48–55]

Risk Prediction in PSC

Predicting outcomes from PSC is important not only for individual patients but also for clinical trial design and decisions on liver transplantation. Although the model of end-stage liver disease (MELD) score is used universally for predicting outcomes in patients with cirrhosis regardless of etiology, it is worth noting that the MELD score has not been studied in PSC patients with cirrhosis. Because cholestasis occurs relatively early in PSC compared to hepatocellular-based causes of cirrhosis, commonly used models for cirrhosis such as the Child-Turcotte-Pugh (CTP) classification and the MELD score may not adequately predict outcomes in PSC. In contrast, several risk models have been developed over time to prognosticate and predict outcomes in patients with PSC regardless of cirrhosis status. These models have incorporated different combinations of clinical, histological, and/or laboratory parameters (Table 1.2). As expected, bilirubin and markers of portal hypertension are common to all of the PSC models described. However, it is quite informative that only one model carried alkaline phosphatase into the final predictive model given recent findings that suggest normalization of alkaline phosphatase portends good long-term transplant-free survival.

Table 1.2

Prognostic models of survival in primary sclerosing cholangitis [19, 23, 52, 53, 56]

	King’s (n = 126)	Hannover (n = 273)	Sweden^a (n = 305)	Europe^b (n = 330)	Revised Mayo (n = 405;124)
Demographics
Age	⊗	⊗	⊗	⊗	⊗
Laboratory/pathology
Alkaline phosphatase	⊗
Aspartate aminotransferase (AST)					⊗
Total bilirubin		⊗^c	⊗	⊗	⊗
Albumin		⊗		⊗	⊗
Biopsy stage	⊗		⊗
Clinical findings
Hepatomegaly	⊗	⊗
Splenomegaly	⊗	⊗
Clinical events
Variceal bleeding					⊗

^aCases with variceal bleeding (4 % of total) excluded

^bTime-dependent model

^cPersistently elevated bilirubin

The Mayo risk score, which unlike some other models, does not include histological criteria requiring a liver biopsy, is the only validated model, and remains the most commonly used [22]. It was developed and validated to prognosticate outcomes in patients with all stages of disease and is based purely on objective clinical and laboratory criteria. The revised Mayo risk score includes serum bilirubin, albumin, aspartate aminotransferase, age, and history of variceal bleeding. In derivation and validation cohorts, this score estimated survival up to 4 years after calculation [23].

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