Progressive familial intrahepatic cholestasis (PFIC) comprises a heterogenous group of autosomal recessive disorders that are characterized by intrahepatic cholestasis. The conditions display characteristic clinical, biochemical, and histologic features. Genetic studies have revealed mutations in genes encoding hepatocanalicular transport proteins that are required for normal canalicular bile flow [3]. Mutations in the genes ATP8B1, ABCB11, and ABCB4 are associated with the clinical entities PFIC syndromes type 1, 2, and 3, respectively [4]. Patients often present with cholestasis in the neonatal period or the first year of life, but PFIC3 may become apparent later in childhood or even during young adulthood [5]. Most PFIC patients will become liver transplant candidates.

Mutations in the ATP8B1 gene can also cause benign recurrent intrahepatic cholestasis (BRIC1), characterized by episodic cholestasis at any age. A proportion of patients suffering from intrahepatic cholestasis of pregnancy have mutations in the ABCB4 gene [3].

PFIC is a rare disorder, with an estimated incidence between 1 per 50,000 and 1 per 100,000 births, although exact numbers are not known [5]. PFIC appears to affect girls and boys equally frequent. All PFIC types have a worldwide distribution.

Drugs and other substances, including herbs and dietary supplements, may cause a wide range of liver damage. It is therefore important to consider drug-induced liver injury (DILI) as a differential diagnosis in all cases of hepatobiliary disease with uncertain etiology. DILI is usually classified as being of a hepatocellular, cholestatic, or mixed type, and the various drugs are usually associated with a predominating type of reaction. Genetic variants of biliary transporters (e.g., MDR3 and BSEP) have been associated with a predisposition to drug-induced cholestasis [3]. In most cases, the cholestatic drug-induced liver injury is mild and reversible, but persistent injury with biliary fibrosis and cirrhosis develops in some cases [6, 7].

There is only limited information on the incidence of DILI. In general, the frequency of drug-induced adverse events appears to be underestimated due to incomplete ascertainment of cases. In large DILI series, a cholestatic type of drug injury has been noted in 20–40% of patients [6]. In a population-based study from France from 1997 to 2000, the global crude annual incidence rate for hepatic adverse drug reactions was 13.9 ± 2.4 per 100,000 inhabitants, with a corresponding standardized annual global rate of 8.1 ± 1.5 [8]. For comparison, the annual detection rate of hepatitis C in the same region was approximately 30 per 100,000. Among the 34 cases of DILI recorded, cholestatic and mixed injury patterns accounted for 16 (47%). In a prospective study in Southern Spain during 1994–2004, 461 cases of toxic liver injury were collected. The estimated annual incidence rate in the period 1998–2003 (only reported from the coordinating center) was 3.4 ± 1.1 cases per 100,000 inhabitants, about half of these being classified as serious adverse hepatic reactions [9]. Among the 461 cases, a hepatocellular damage pattern was most common (58%), whereas the mixed and cholestatic types were equally frequent (22% and 20%, respectively). Patients with a cholestatic pattern were significantly older than patients with other patterns of liver injury, as has also been observed by others [7]. A prospective, population-based survey from Iceland during 2010–2011 reported a crude annual incidence rate of DILI as high as 19.1 (95% CI 15.4–23.3) cases per 100,000 inhabitants (excluding cases with acetaminophen toxicity) [10]. Hepatocellular injury was most frequent (42%), followed by the cholestatic (32%) and mixed types (26%). In a recent study from the DILIN Prospective Study in the USA, including 899 cases considered as DILI enrolled between 2004 and 2013, the pattern of damage was hepatocellular in 54% and cholestatic or mixed in 23% each [7]. Among the 899 patients, 10% died or underwent liver transplantation, underscoring the potential serious outcome of DILI. As many as 31% of patients with cholestatic injury had signs of chronic or unresolved injury 6 months after onset, compared with an overall frequency of 18%.

The above studies were carried out in Western countries; even less information on the occurrence of DILI is available from other parts of the world. The real impact of cholestatic DILI on the clinical burden of cholestatic liver disease is thus difficult to assess.

Chapter 7 focuses on the mechanisms and importance of drug-induced cholestasis.

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic, non-suppurative, destructive cholangitis involving the small- to medium-sized intralobular bile ducts [11]. The disease leads to fibrosis and may progress to liver cirrhosis and end-stage liver disease. The diagnosis is conventionally based on a history of elevated cholestatic liver tests for at least 6 months, the presence of antimitochondrial antibodies, and a compatible liver biopsy [12]. According to current guidelines, a liver biopsy is not necessary to diagnose PBC [12]. This disorder predominantly affects females, with a female to male ratio of approximately 10:1. The median age of diagnosis is around 50 years; PBC does not affect children.

The pathogenesis of PBC appears to comprise a complex interaction between genetic and environmental factors, also involving autoimmunity. Ursodeoxycholic acid (UDCA) improves liver tests and delays the disease progression with extended liver transplant-free survival [13]. Around 40% of patients do not, however, display a biochemical response to UDCA. Hepatocellular carcinoma is a rare complication of PBC but occurred more frequently among nonresponders than responders to UDCA in a recent survey that included a large international cohort of 4565 PBC patients [14]. The overall incidence rate of hepatocellular carcinoma was 3.4 cases per 1000 patient-years. PBC patients who develop end-stage liver disease are good candidates for liver transplantation.

There is a large variation in the incidence and prevalence rates of PBC worldwide, ranging from 0.33–5.8 per 100,000 inhabitants/year and 1.91–40.2 per 100,000 inhabitants, respectively [15]. The highest incidence and prevalence rates have been reported from Northern Europe and North America, in particular including the findings in Newcastle upon Tyne, UK (incidence 5.8 per 100,000; prevalence 39.2 per 100,000) [16], and Olmsted County, USA (incidence 2.7 per 100,000; prevalence 40.2 per 100,000) [17]. Incidence rates per 100,000 for PBC from other northern European countries include 1.7 in Finland, 1.6 in Norway, 1.3–2.4 in Sweden, and 3.4 in Iceland [15, 18]. Corresponding prevalence figures per 100,000 inhabitants are 18.0 in Finland, 14.6 in Norway, 9.6–15.1 in Sweden, and 38.3 in Iceland. The largest population-based study on the epidemiology of PBC published until now was performed in the Netherlands during 2000–2008, comprising a population of around 5.8 million [18]. The mean annual incidence was 1.1 per 100,000, and the point prevalence at study end was 13.2 per 100,000. Incidence and prevalence rates increased significantly over time. Apparent increases in incidence and prevalence rates for PBC have also been noted by others, although several contributing factors may be implicated [19].

Good epidemiological studies on PBC from other parts of the world are scarce, but reports indicate generally lower incidence and prevalence numbers. Examples of published prevalence rates per 100,000 include studies from Japan (2.7–5.4), Israel (5.5), Australia (1.91), and Brunei Darussalam (Southeast Asia) (2.6) [15, 19].

Chapter 8 elaborates on the science and practice of PBC.

Primary sclerosing cholangitis (PSC) is characterized by inflammatory and fibrotic processes that primarily affect the medium-sized and large bile ducts, resulting in bile duct irregularities with strictures and dilatations [20]. PSC is more common in males than in females (2:1). The disease affects a rather young population, with median age at diagnosis around 40 years. PSC may also present in childhood and then often with associated features of autoimmune hepatitis [21]. PSC is in most cases a progressive disorder that leads to liver cirrhosis, with estimated survival from diagnosis until PSC-related death or liver transplantation in the range 13–21 years [22]. There is no medical therapy that effectively halts the disease progression, but PSC patients are considered good candidates for liver transplantation. In the Nordic countries, PSC has until recently been the most important indication for liver transplantation [20]. PSC is strongly associated with inflammatory bowel disease (IBD). The highest frequencies of concomitant IBD (70–80%) have been reported from Northern Europe and the lowest (20–50%) from Asia [23].

PSC patients carry an increased risk of cancer. The high risk of cholangiocarcinoma (CCA) development (6–13% in population-based series) in particular adds to the disease burden in PSC patients. In a Swedish cohort of PSC patients, the risk of hepatobiliary malignancy was 161 times higher compared to the general Swedish population and that of cancer of the colon-rectum was ten times increased [24]. The risk of any gastrointestinal cancer was 29 times higher than in the general population. It is recognized that the risk of colorectal malignancies is higher in PSC-IBD than in IBD without hepatobiliary disease.

Epidemiological studies of PSC are hampered by several factors. First, PSC has an insidious onset and can have a prolonged preclinical course before being diagnosed. Approximately 50% of patients are asymptomatic at the time of diagnosis. Second, the diagnosis relies on typical findings by cholangiography and requires that such investigations have been carried out. Incidence and prevalence estimates therefore must be considered minimum numbers. Based on six population-based studies from North America and Europe, the combined incidence rate of PSC was 1.0 (0.82–1.17) per 100,000 [25]. The prevalence of PSC in these regions is around 10 per 100,000 [20]. More specifically, studies have shown an incidence rate per 100,000 of 1.31 in Norway, 1.22 in Sweden, 0.92 in Canada, from 0.41 to 0.91 in the UK, and 0.90 in Minnesota, USA [26]. A lower incidence rate of 0.5 per 100,000 was however noted in a recent study from the Netherlands, based on the identification of 590 PSC patients in an area of almost eight million inhabitants [22]. Markedly lower incidence rates have been observed in Southern Europe (0.07 per 100,000 in Spain) and Asia [20]. An increasing trend in the incidence of PSC has been noted [15]. The prevalence ranges from 8 to 16 per 100,000 inhabitants in Northern Europe and the USA (6.0 in the above study from the Netherlands), while reported numbers are lower in Southern Europe (0.22 per 100,000 in Spain) and Asia.

Small-duct PSC is characterized by the same presenting features as the classical (large-duct) PSC, but displays a normal cholangiogram. The proportion of small-duct PSC relative to classical PSC has been reported to be in the range 5.8–16.3% [26]. Small-duct PSC appears to have a more benign course than classical PSC.

Increasing efforts are directed toward the understanding of disease pathogenesis in PSC, with the ultimate aim to define targets for therapy. Chapter 9 describes current concepts in PSC biology and strategies for new therapy.

Autoimmune sclerosing cholangitis/IgG4 cholangiopathy, also designated IgG4-associated cholangitis (IAC), is the biliary manifestation of immunoglobulin G4-related disease which is characterized by inflammatory lesions and can involve a number of organs [27]. IAC is frequently associated with IgG4 disease of the pancreas (autoimmune pancreatitis). The diagnosis of IAC and autoimmune pancreatitis is based on the HISORt criteria (a combination of histology, imaging, serology, other organ involvement, and response to therapy) [28]. The histological findings in IAC are characterized by dense lymphoplasmacytic infiltrates (>10 IgG4-positive cells per high-power field), storiform fibrosis, and obliterative phlebitis. IAC is also associated with elevated serum IgG4 levels, but levels may be normal in up to 20% of patients [28]. IAC presents with features similar to those of PSC, and the two conditions may be difficult to differentiate [29]. IAC may also be difficult to differentiate from malignant conditions of the pancreas and biliary tract. Elevated serum IgG4 levels were present in 9% among 127 PSC patients [30], and 15.6% of 122 PSC liver explants showed marked hilar IgG4 lymphoplasmacytic infiltration [31].

Age at presentation of IAC varies, but these patients are generally older at diagnosis than patients with classic PSC. In similarity with PSC, there is a male predominance in IAC, whereas concomitant IBD is more uncommon. IAC typically responds to corticosteroid therapy [29] and is therefore important to recognize.

Data on incidence and prevalence of IgG4-related disease are limited. Most reports on IAC and autoimmune pancreatitis have been published from Japan and the Far East. In a nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2007, the estimated annual incidence rate was 0.9 per 100,000 inhabitants, with an overall prevalence rate of 2.2 per 100,000 [32]. With more clinical focus on these conditions, they are increasingly being recognized also in the Western world. Among 3482 cases of IgG4-related disease reported up to March 2014, 2621 originated from Asia, 470 from Europe, and 452 from North America [33]. No separate epidemiological data on IAC are available as of yet.