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Diagnosis and classification of primary sclerosing cholangitis
Autoimmunity Reviews 13 (2014) 445–450
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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Diagnosis and classification of primary sclerosing cholangitis Kidist K. Yimam a, Christopher L. Bowlus b,⁎ a b
Division of Hepatology and Liver Transplant, California Pacific Medical Center, San Francisco, CA, United States Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, United States
a r t i c l e
i n f o
Article history: Accepted 13 November 2013 Available online 11 January 2014 Keywords: Primary sclerosis cholangitis Clinical manifestation Etiopathogenesis inflammatory bowel disease Liver transplantation
a b s t r a c t Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of the liver and that is characterized by progressive inflammation, fibrosis, and stricturing of the intrahepatic and extrahepatic bile ducts. It is progressive in most patients and leads to cirrhosis. It is a rare disease, mostly affecting people of northern European descent, males greater than females. The diagnosis is best established by contrast cholangiography, which reveals a characteristic picture of diffuse, multifocal strictures and focal dilation of the bile ducts, leading to a beaded appearance. Inflammatory bowel disease (IBD) is present in ~ 75% of the patients with PSC, mostly ulcerative colitis (~85% of the cases). In addition to biliary cirrhosis, complications of PSC include dominant strictures of the bile ducts, cholangitis, cholangiocarcinoma, colon dysplasia and cancer in patients with IBD, gallbladder polyps and cancer, and hepatic osteodystrophy. The etiology of PSC is not clear, but studies are ongoing. The median survival without liver transplantation is 12 to 15 years after diagnosis. Currently there are no effective treatments except liver transplantation. Immunosuppressive medications have not been shown to be effective but antibiotics and anti-fibrotic agents seem promising. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . Clinical manifestations of PSC . . . . . . . . . . . . . . 3.1. Symptoms and signs . . . . . . . . . . . . . . 3.2. Biochemical features . . . . . . . . . . . . . . 3.3. Serological features . . . . . . . . . . . . . . . 3.4. Radiological features . . . . . . . . . . . . . . 3.5. Histological features . . . . . . . . . . . . . . 4. Diagnostic criteria . . . . . . . . . . . . . . . . . . . 5. Variant forms of PSC . . . . . . . . . . . . . . . . . . 5.1. Small duct PSC . . . . . . . . . . . . . . . . . 5.2. PSC-autoimmune hepatitis (AIH) overlap syndrome 5.3. IgG4-related sclerosing cholangitis . . . . . . . . 6. Clinical course and prognosis . . . . . . . . . . . . . . 7. Etiopathogenesis . . . . . . . . . . . . . . . . . . . 8. Medical management . . . . . . . . . . . . . . . . . 8.1. Ursodeoxycholic acid (UDCA) . . . . . . . . . . 8.2. Immunosuppression . . . . . . . . . . . . . . 8.3. Promising novel agents . . . . . . . . . . . . . 9. Liver transplantation . . . . . . . . . . . . . . . . . 10. Conclusion . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author at: 4150 V Street, PSSB 3500, Sacramento, CA 95817, United States. Tel.: +1 530 752 6128; fax: +1 530 752 3604. E-mail address: [email protected] (C.L. Bowlus). 1568-9972/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autrev.2014.01.040
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1. Introduction Primary sclerosing cholangitis (PSC) is a chronic cholestasis disease of the liver and bile ducts of unknown cause characterized by progressive inflammation, fibrosis, and stricturing of the intrahepatic and extrahepatic bile ducts [1]. The disease progresses slowly in most patients over a 10 to 15 year period and usually leads to cirrhosis complicated by portal hypertension and premature death from liver failure [1]. The first description of sclerosing cholangitis is credited to Delbet in 1924 [2]. Although considered for many years to be an extremely rare disorder, the advent of endoscopic retrograde cholangiography (ERC) in the 1970s and magnetic resonance cholangiography (MRC) in the 1990s has allowed an improved understanding of the true prevalence of this disorder and facilitated careful study of its natural history. Nevertheless, many aspects of PSC remain poorly understood; most notably lacking is a detailed knowledge of its etiology and proven effective medical therapy. 2. Epidemiology PSC is more common in men than woman, and the majority of patients are diagnosed in the third to fourth decades [1]. However, cases are seen in all age groups, and studies in Japan have suggested a bimodal age distribution with a second peak in the seventh decade [3]. In addition to liver disease, PSC is closely associated with inflammatory bowel disease (IBD). Approximately 75% of patients with PSC have IBD, and of these, nearly 80–90% are diagnosed with ulcerative colitis (UC) [4–6]. This association with IBD has been noted to be greater in the Northern European and American populations than Southern European (50%) and Asian (35%) populations with IBD [3,7–9]. The true incidence of PSC is unknown, though studies from Oslo, Norway, Sweden, Wales, and Olmstead County, Minnesota estimate it to be between 0.9 and 1.3 cases per 100,000 person-years [4,10–14]. However, a recent study in the UK noted an incidence of 0.41 cases per 100,000 person-years [15]. Our own analysis in a population of over three million members enrolled in a large health care system in Northern California found a similar annual incidence of 0.41 cases per 100,000 person-years [16]. This discrepancy may be explained by the ethnic diversity of the populations in these latter analyses. We also evaluated the population-stratified demographic, clinical, and HLA data from 6767 liver transplant (LT) registrants of the United Network for Organ Sharing who had a diagnosis of PSC (4.7% of the registrants) and found that European Americans and African Americans were more frequently listed with a diagnosis of PSC relative to Hispanics and other ethnic groups. PSC accounted for 5.4% and 6.4% of all LT listings in European Americans and African Americans, respectively, compared to less than 2% in any other group [17]. Overall, there appears to be a higher prevalence of PSC in the Northern Europeans and Caucasians. Regardless, the true incidence of this disease may be underestimated, as it is a relatively rare condition with an insidious course that requires specialized expertise and invasive procedures for diagnosis.
Table 1 Signs and symptoms of PSC at diagnosis. Adopted from references [19,20]. Symptoms
Prevalence
Asymptomatic Fatigue Pruritus Jaundice Hepatomegaly Abdominal pain Splenomegaly Hyperpigmentation Weight loss Variceal bleeding Ascites
15–44% 43–75% 25–59% 30–69% 34–62% 16–37% 14–30% 25% 10–34% 2–14% 2–10%
Physical examination is abnormal in approximately half of symptomatic patients at the time of diagnosis; jaundice, hepatomegaly, and splenomegaly are the most frequent abnormal findings [19–21]. 3.2. Biochemical features Elevations in serum alkaline phosphatase values are the biochemical hallmark of PSC. Increases between 3 and 10 times the upper limit of normal occur in 95% of cases. Serum alanine and aspartate aminotransferase levels are usually 2–3 fold higher than normal levels [20,21]. The serum total bilirubin level is normal in 60% of individuals at diagnosis [22]. IgG serum levels are modestly elevated in approximately 60% of patients (1.5 times the upper limit of normal). The liver tests can be normal and can fluctuate during the course of the disease [23,24]. 3.3. Serological features Several autoantibodies have been detected in the serum of PSC patients, indicating an altered state of immune responsiveness or immune regulation (Table 2) [21]. However, none have been found to have sufficient specificity or sensitivity to be used for screening or diagnosis. The most prevalent autoantibody, perinuclear antineutrophil cytoplasmic autoantibodies, is seen in 65–95% of patients with PSC, 50–80% of those with UC, and 10–20% of patients with CD [20,21,25–27]. IgG4 levels are often elevated in patients with autoimmune pancreatitis, as well as IgG4-related sclerosing cholangitis, which should be distinguished from typical PSC [28,29]. Notably, an elevated level of IgG4 in PSC patients is associated with a worse clinical outcome [29]. 3.4. Radiological features Cholangiography remains the gold standard for the diagnosis of PSC. Findings of segmental strictures with proximal dilation and sacculation of the bile ducts create the “beaded” appearance that is classic for PSC (Fig. 1). Intrahepatic duct involvement is nearly universal with most
3. Clinical manifestations of PSC 3.1. Symptoms and signs The clinical presentation of PSC can vary greatly. Asymptomatic patients represent about 15% to 40% of the patients at time of diagnosis in early studies [18,19]. More recently, more patients are identified at an earlier stage of the disease with fewer symptoms. Due to its close association to IBD, many cases come to medical attention when patients with IBD are screened for liver disease. The most common symptoms in patients with PSC are fatigue, jaundice, pruritus and abdominal pain, whereas ascites, bleeding from esophageal varices and acute cholangitis are much less frequent (Table 1) [19,20].
Table 2 Prevalence of autoantibodies in patients with PSC. Adopted from reference [19]. Autoantibody
Prevalence
Anti-neutrophil cytoplasmic antibody Anti-nuclear antibody Anti-smooth muscle antibody Anti-endothelial cell antibody Anti-cardiolipin antibody Thyroperoxidase Thyroglobulin Rheumatoid factor
50–80% 7–77% 13–20% 35% 4–66% 7–16% 4% 15%
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Table 3 Secondary causes of sclerosing cholangitis. Adopted from reference [19]. Cryptosporidium/AIDS cholangiopathy Cholangiocarcinoma Choledocholithiasis Metastatic carcinoma Eosinophilic cholangitis IgG4-associated cholangitis Intra-arterial chemotherapy Ischemic cholangitis Mast cell cholangiopathy Portal hypertensive biliopathy Recurrent cholangitis Iatrogenic biliary trauma Histiocytosis X Hepatic inflammatory pseudotumor
5. Variant forms of PSC 5.1. Small duct PSC Fig. 1. Cholangiographic finding in PSC. Magnetic resonance cholangiogram demonstrating multifocal strictures with intervening dilatation (small arrows) as well as large sacculations (large arrow) characteristic of PSC.
patients affected by intrahepatic and extrahepatic disease [29,30]. Traditionally, cholangiography has been performed by ERC. However, a recent meta-analysis found that MRC is sufficiently sensitive and specific to make the diagnosis in many cases of PSC and thus is a more appropriate first-line diagnostic tool [31,32]. However, if there is a high index of suspicion and MRC is negative or equivocal, ERC should be performed, as MRC has been found to be less sensitive in cases of early disease and cirrhosis [32]. Additionally, ERC has the advantage of also being therapeutic, allowing ductal dilation and stenting, and providing further diagnostic information with brush cytology and biopsies. However, procedure related complication from ERC can occur in 3% to 8% of patients [33,34].
3.5. Histological features Liver biopsy in patients with radiographic evidence of PSC is not needed for diagnosis, although it may help in excluding other diseases. It is not reliable alone for the diagnosis of PSC, as it is non-specific and may be normal when only large ducts are involved [35] However, when performed, characteristic findings include bile duct proliferation, periductal fibrosis with typical “onion-skinning” lesions (present in less than 15% of the patients with PSC), periductal inflammation, and bile duct obliteration [35]. These histologic features may be classified into four stages using Ludwig criteria: cholangitis or portal hepatitis (stage I); periportal fibrosis or hepatitis (stage II); septal fibrosis and/ or bridging necrosis (stage III); biliary cirrhosis (stage IV) [36,37].
4. Diagnostic criteria Given the heterogeneous nature of PSC and the lack of a quantifiable diagnostic test, strict criteria for establishing the diagnosis of PSC have not been established. Typically, the diagnosis is based upon the presence of a cholestatic pattern of liver biochemistries, typical cholangiographic findings, and the absence of secondary causes of sclerosing cholangitis (Table 3) [21]. Patients who present with clinical, biochemical and histological features compatible with PSC, but have a normal cholangiogram, are classified as small duct PSC (38).
Small duct PSC refers to disease that affects bile ducts that are too small to be identified by ERC but have classic findings on liver biopsy. This variant accounts for approximately 6–16% of the PSC population [12,39]. Most patients with small duct PSC have been noted to have slower clinical progression, with higher rates of survival and fewer cases of cholangiocarcinoma or transplantation [38,39]. However, approximately 12% of patients with small duct PSC will progress to large duct disease [38,39]. 5.2. PSC-autoimmune hepatitis (AIH) overlap syndrome PSC-AIH overlap syndrome is the classification given to patients with both the cholangiographic features of PSC and the biochemical and histologic features AIH. More common in children and young adults, the prevalence of PSC-AIH overlap has been reported to be as low as 8% and as high as 49% [40,41]. Such high degree of variability is likely due to the lack of defined diagnostic criteria for this condition. These patients should be categorized by their predominant disease, namely PSC or AIH, rather than labeled as an overlap syndrome. Furthermore, there has been some evidence to suggest that PSC patients with AIH features may benefit from immunosuppressive therapy, particularly corticosteroids [42]. 5.3. IgG4-related sclerosing cholangitis Recently, patients with steroid responsive sclerosing cholangitis but not always associated with autoimmune pancreatitis have been described [43]. The hepatobiliary changes described include stenosis of the bile ducts, biliary duct wall thickening, stenosis of the portal vein, portal fibrosis, and hepatic inflammatory pseudotumor [44,45]. IgG4related sclerosing cholangitis could be a distinct entity from autoimmune pancreatitis [45], similar to PSC with regard to cholangiographic features, but in contrast to PSC, is susceptible to steroid therapy and is reversible [45]. Therefore, identifying patients with IgG4-related sclerosing cholangitis and distinguishing them from patients with PSC could have major therapeutic implications [46]. 6. Clinical course and prognosis PSC has a variable clinical course, though the disease most often progresses to end-stage liver disease. The median time from diagnosis to death or liver transplantation ranges from 12 to 18 years [18,47,48]. Many models have been developed to provide prognostic prediction for life expectancy in PSC patients. The Mayo Clinic Revised Natural History Model for PSC is the most widely accepted model for predicting
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survival probability [49]. This score is based on objective findings of age, bilirubin, albumin, aspartate transaminase, and history of variceal bleeding. However, it should be noted that prognostic models are useful in predicting outcomes in patient cohorts, but their ability to precisely predict outcomes in an individual patient is limited [21]. 7. Etiopathogenesis Despite a number of proposed models to explain the mechanisms involved in PSC, none of them fully explain all the features of PSC, and most lack sufficient supporting evidence. The current understanding of the mechanistic hypotheses that have been proposed to explain the pathogenesis of PSC includes those involving genetic susceptibility, lymphocyte homing, innate immunity, biliary duct fibrosis and toxic bile. Barriers to the further elucidation of these hypotheses of PSC pathogenesis include: 1) the difficulty in obtaining target tissue, especially in early stages of disease, 2) phenotypic variability and the lack of consensus on classification, 3) the relative rarity of the condition requiring collaboration between multiple institutions, and 4) the absence of an animal model that adequately recapitulates the human condition. Table 4 summarizes the proposed models of PSC pathogenesis. 8. Medical management As the pathogenesis for PSC remains elusive, targeted medical therapy for this disease has not yet been established. At this time, there are no proven medical therapies for PSC, and the goals of treatment are primarily symptom and complication management. Liver transplantation is the only effective treatment currently available for end-stage PSC at this time. 8.1. Ursodeoxycholic acid (UDCA) UDCA is a hydrophilic bile acid that is the most studied drug in randomized control trials (RCTs) for PSC. It is a well-established treatment for primary biliary cirrhosis, though its efficacy in PSC appears to be much less certain. Early randomized control trials examined UDCA therapy at low doses (13–15 mg/kg/day) and found that there were improvements in liver biochemistries. However, UDCA did not affect disease progression [63]. More recent studies using higher doses of UDCA have been less than promising. Olsson, et al. performed a randomized study comparing UDCA (17–23 mg/kg/day) with placebo in 219 patients with a 5-year follow-up, and they did not note any significant benefit in survival [64]. A more recent study by Lindor, et al. randomized 150 patients to even higher doses of UDCA (28–30 mg/kg/day) or placebo, noted an improvement in liver tests but worse outcomes in patients taking UDCA [65]. Currently, the American Association for the Study of Liver Diseases (AASLD) recommends against the use of UDCA therapy in PSC patients while the European Association for the Study of the
Liver (EASL) believes that there is insufficient evidence to make a clear recommendation at this time [21,66]. 8.2. Immunosuppression Immunosuppressants including budesonide, cyclosporine, tacrolimus, methotrexate, and mycophenolate mofetil have been studied in randomized trials, though none were found to prolong survival or time to transplantation, and all have serious side effects [21,67–72]. TNF-α inhibitors including pentoxifylline and etanercept, have also been studied, but have not been found to be beneficial [73,74]. There is no role for immunosuppressant agents to treat classic PSC at this time. 8.3. Promising novel agents Simtuzumab (formerly GS-6624), a humanized monoclonal antibody with an immunoglobulin IgG4 isotype directed against human lysyl oxidase like 2 (LOXL2), an enzyme that promotes the crosslinking of type I collagen and a key component in the core regulatory pathway of fibrogenesis, has been studied in pulmonary fibrosis and other fibrosing diseases. Its first use in patients with liver fibrosis has been recently reported. It was safe and shown to have possible antiinflammatory and anti-fibrotic effects [75]. A phase 2b, dose-ranging, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of simtuzumab in subjects with PSC is currently open for enrolment (clinicaltrial.gov NCT01672853). Antibiotics have also been suggested with some promising results. A recent pilot study with 16 patients found that minocycline decreased alkaline phosphatase levels and Mayo risk scores though long-term effects were not established [76]. In a randomized control trial of 80 patients, those receiving metronidazole combined with UDCA in comparison to UDCA and placebo were found to have lower levels of alkaline phosphatase and Mayo risk score in the study arm, though no significant difference in disease progression [77]. Furthermore, a study evaluated the role of long-term treatment of PSC in children with oral vancomycin, and the results showed improvement in their alanine aminotransferase, gamma-glutamyl transpeptidase, erythrocyte sedimentation rate, and clinical symptoms [78]. There was less improvement noted in the patients with cirrhosis when compared with the patients without cirrhosis [78]. A recent pilot RCT in adult patients with PSC also showed while both metronidazole and oral vancomycin were efficacious, vancomycin was better tolerated than metronidazole [79]. Vancomycin seems a very promising agent to treat PSC in both children and adults and warrants larger studies. 9. Liver transplantation LT is currently the treatment of choice for patients with end-stage PSC. LT in patients with PSC is associated with patient survival rates of
Table 4 Etiopathogenesis of PSC. Hypothesis
Evidence
Genetic susceptibility o o o o Innate immunity o
Adaptive immunity Biliary fibrosis Toxic bile
o o o o o o o
Increased prevalence in 1st degree relatives [50,51] Strong association with HLA Susceptible haplotypes: HLA-DRB1*1501-DQB1*0602, HLA-DRB1*1301-DQB1* 0603, and HLA-A1-B8-DRB1*0301-DQB1*0201 [52–55]. Genome-wide association studies reported that the strongest genetic risk to PSC lies within the major histocompatibility complex Pathogen-associated molecular patterns (PAMPs) enter portal circulation, activate macrophages, dendritic cells, and natural killer (NK) cells through pattern recognition receptors, including Toll-like receptors (TLRs) and CD14; then signal cholangiocytes through TLR; leading to secretion of cytokines and recruitment of inflammatory cells [56] Intestinal PAMPs can induce biliary inflammation in rodent models [57] Macrophages accumulate in PSC livers sinusoidal and peri-sinusoidal more than PBC [58] Aberrant trafficking of intestinal memory T-lymphocytes to the PSC liver [59,60] Portal fibroblast and hepatitis stellate cell activation Multidrug resistance gene 2 (Mdr2) knockout mouse Biliary phospholipids are absent in Mdr2−/−, which may lead to toxic bile acid-induced damage, resulting in sclerosing cholangitis [61] Variants and functional mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described in patients with PSC [62]
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up to 90% at 1 year, and 85% at 5 years [21]. Indications for LT are similar to those for other chronic liver diseases. Additional indications include intractable pruritus, recurrent cholangitis, and early cholangiocarcinoma. Recurrence of PSC occurs in up to 20–25% of patients after 5–10 years of LT [80–86]. 10. Conclusion Primary sclerosing cholangitis is a chronic cholestatic liver disease associated with significant morbidity and mortality. There is no proven medical treatment available except liver transplantation for end stage PSC. Further studies are needed for better understanding of the etiopathogenesis of the disease and for development of an optimal therapeutic strategy. The goal is to improve health related quality of life and halt progression of disease, thereby decreasing incidence of complications of advanced liver disease and the need for transplantation. The development of better and non-invasive prognostic tools is critical to the pursuit of effective treatments for PSC. Currently, drug development is hampered due to the slow progression of the disease, infrequent meaningful clinical outcomes, and rarity of the disease. Finally we note two recent reviews on genomewide association studies in PSC and on a comprehensive evaluation of mucosal immunity in liver autoimmunity [87,88]. References [1] Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995;332:924. [2] Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th Ed. [3] Takikawa H. Characteristics of primary sclerosing cholangitis in Japan. Hepatol Res Oct. 2007;37(Suppl. 3):S470–3. [4] Bambha K, Kim WR, Talwalkar J, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology 2003;125:1364. [5] Broomé U, Bergquist A. 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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Diagnosis and classification of primary sclerosing cholangitis Kidist K. Yimam a, Christopher L. Bowlus b,⁎ a b
Division of Hepatology and Liver Transplant, California Pacific Medical Center, San Francisco, CA, United States Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, United States
a r t i c l e
i n f o
Article history: Accepted 13 November 2013 Available online 11 January 2014 Keywords: Primary sclerosis cholangitis Clinical manifestation Etiopathogenesis inflammatory bowel disease Liver transplantation
a b s t r a c t Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of the liver and that is characterized by progressive inflammation, fibrosis, and stricturing of the intrahepatic and extrahepatic bile ducts. It is progressive in most patients and leads to cirrhosis. It is a rare disease, mostly affecting people of northern European descent, males greater than females. The diagnosis is best established by contrast cholangiography, which reveals a characteristic picture of diffuse, multifocal strictures and focal dilation of the bile ducts, leading to a beaded appearance. Inflammatory bowel disease (IBD) is present in ~ 75% of the patients with PSC, mostly ulcerative colitis (~85% of the cases). In addition to biliary cirrhosis, complications of PSC include dominant strictures of the bile ducts, cholangitis, cholangiocarcinoma, colon dysplasia and cancer in patients with IBD, gallbladder polyps and cancer, and hepatic osteodystrophy. The etiology of PSC is not clear, but studies are ongoing. The median survival without liver transplantation is 12 to 15 years after diagnosis. Currently there are no effective treatments except liver transplantation. Immunosuppressive medications have not been shown to be effective but antibiotics and anti-fibrotic agents seem promising. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . Clinical manifestations of PSC . . . . . . . . . . . . . . 3.1. Symptoms and signs . . . . . . . . . . . . . . 3.2. Biochemical features . . . . . . . . . . . . . . 3.3. Serological features . . . . . . . . . . . . . . . 3.4. Radiological features . . . . . . . . . . . . . . 3.5. Histological features . . . . . . . . . . . . . . 4. Diagnostic criteria . . . . . . . . . . . . . . . . . . . 5. Variant forms of PSC . . . . . . . . . . . . . . . . . . 5.1. Small duct PSC . . . . . . . . . . . . . . . . . 5.2. PSC-autoimmune hepatitis (AIH) overlap syndrome 5.3. IgG4-related sclerosing cholangitis . . . . . . . . 6. Clinical course and prognosis . . . . . . . . . . . . . . 7. Etiopathogenesis . . . . . . . . . . . . . . . . . . . 8. Medical management . . . . . . . . . . . . . . . . . 8.1. Ursodeoxycholic acid (UDCA) . . . . . . . . . . 8.2. Immunosuppression . . . . . . . . . . . . . . 8.3. Promising novel agents . . . . . . . . . . . . . 9. Liver transplantation . . . . . . . . . . . . . . . . . 10. Conclusion . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author at: 4150 V Street, PSSB 3500, Sacramento, CA 95817, United States. Tel.: +1 530 752 6128; fax: +1 530 752 3604. E-mail address: [email protected] (C.L. Bowlus). 1568-9972/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autrev.2014.01.040
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1. Introduction Primary sclerosing cholangitis (PSC) is a chronic cholestasis disease of the liver and bile ducts of unknown cause characterized by progressive inflammation, fibrosis, and stricturing of the intrahepatic and extrahepatic bile ducts [1]. The disease progresses slowly in most patients over a 10 to 15 year period and usually leads to cirrhosis complicated by portal hypertension and premature death from liver failure [1]. The first description of sclerosing cholangitis is credited to Delbet in 1924 [2]. Although considered for many years to be an extremely rare disorder, the advent of endoscopic retrograde cholangiography (ERC) in the 1970s and magnetic resonance cholangiography (MRC) in the 1990s has allowed an improved understanding of the true prevalence of this disorder and facilitated careful study of its natural history. Nevertheless, many aspects of PSC remain poorly understood; most notably lacking is a detailed knowledge of its etiology and proven effective medical therapy. 2. Epidemiology PSC is more common in men than woman, and the majority of patients are diagnosed in the third to fourth decades [1]. However, cases are seen in all age groups, and studies in Japan have suggested a bimodal age distribution with a second peak in the seventh decade [3]. In addition to liver disease, PSC is closely associated with inflammatory bowel disease (IBD). Approximately 75% of patients with PSC have IBD, and of these, nearly 80–90% are diagnosed with ulcerative colitis (UC) [4–6]. This association with IBD has been noted to be greater in the Northern European and American populations than Southern European (50%) and Asian (35%) populations with IBD [3,7–9]. The true incidence of PSC is unknown, though studies from Oslo, Norway, Sweden, Wales, and Olmstead County, Minnesota estimate it to be between 0.9 and 1.3 cases per 100,000 person-years [4,10–14]. However, a recent study in the UK noted an incidence of 0.41 cases per 100,000 person-years [15]. Our own analysis in a population of over three million members enrolled in a large health care system in Northern California found a similar annual incidence of 0.41 cases per 100,000 person-years [16]. This discrepancy may be explained by the ethnic diversity of the populations in these latter analyses. We also evaluated the population-stratified demographic, clinical, and HLA data from 6767 liver transplant (LT) registrants of the United Network for Organ Sharing who had a diagnosis of PSC (4.7% of the registrants) and found that European Americans and African Americans were more frequently listed with a diagnosis of PSC relative to Hispanics and other ethnic groups. PSC accounted for 5.4% and 6.4% of all LT listings in European Americans and African Americans, respectively, compared to less than 2% in any other group [17]. Overall, there appears to be a higher prevalence of PSC in the Northern Europeans and Caucasians. Regardless, the true incidence of this disease may be underestimated, as it is a relatively rare condition with an insidious course that requires specialized expertise and invasive procedures for diagnosis.
Table 1 Signs and symptoms of PSC at diagnosis. Adopted from references [19,20]. Symptoms
Prevalence
Asymptomatic Fatigue Pruritus Jaundice Hepatomegaly Abdominal pain Splenomegaly Hyperpigmentation Weight loss Variceal bleeding Ascites
15–44% 43–75% 25–59% 30–69% 34–62% 16–37% 14–30% 25% 10–34% 2–14% 2–10%
Physical examination is abnormal in approximately half of symptomatic patients at the time of diagnosis; jaundice, hepatomegaly, and splenomegaly are the most frequent abnormal findings [19–21]. 3.2. Biochemical features Elevations in serum alkaline phosphatase values are the biochemical hallmark of PSC. Increases between 3 and 10 times the upper limit of normal occur in 95% of cases. Serum alanine and aspartate aminotransferase levels are usually 2–3 fold higher than normal levels [20,21]. The serum total bilirubin level is normal in 60% of individuals at diagnosis [22]. IgG serum levels are modestly elevated in approximately 60% of patients (1.5 times the upper limit of normal). The liver tests can be normal and can fluctuate during the course of the disease [23,24]. 3.3. Serological features Several autoantibodies have been detected in the serum of PSC patients, indicating an altered state of immune responsiveness or immune regulation (Table 2) [21]. However, none have been found to have sufficient specificity or sensitivity to be used for screening or diagnosis. The most prevalent autoantibody, perinuclear antineutrophil cytoplasmic autoantibodies, is seen in 65–95% of patients with PSC, 50–80% of those with UC, and 10–20% of patients with CD [20,21,25–27]. IgG4 levels are often elevated in patients with autoimmune pancreatitis, as well as IgG4-related sclerosing cholangitis, which should be distinguished from typical PSC [28,29]. Notably, an elevated level of IgG4 in PSC patients is associated with a worse clinical outcome [29]. 3.4. Radiological features Cholangiography remains the gold standard for the diagnosis of PSC. Findings of segmental strictures with proximal dilation and sacculation of the bile ducts create the “beaded” appearance that is classic for PSC (Fig. 1). Intrahepatic duct involvement is nearly universal with most
3. Clinical manifestations of PSC 3.1. Symptoms and signs The clinical presentation of PSC can vary greatly. Asymptomatic patients represent about 15% to 40% of the patients at time of diagnosis in early studies [18,19]. More recently, more patients are identified at an earlier stage of the disease with fewer symptoms. Due to its close association to IBD, many cases come to medical attention when patients with IBD are screened for liver disease. The most common symptoms in patients with PSC are fatigue, jaundice, pruritus and abdominal pain, whereas ascites, bleeding from esophageal varices and acute cholangitis are much less frequent (Table 1) [19,20].
Table 2 Prevalence of autoantibodies in patients with PSC. Adopted from reference [19]. Autoantibody
Prevalence
Anti-neutrophil cytoplasmic antibody Anti-nuclear antibody Anti-smooth muscle antibody Anti-endothelial cell antibody Anti-cardiolipin antibody Thyroperoxidase Thyroglobulin Rheumatoid factor
50–80% 7–77% 13–20% 35% 4–66% 7–16% 4% 15%
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Table 3 Secondary causes of sclerosing cholangitis. Adopted from reference [19]. Cryptosporidium/AIDS cholangiopathy Cholangiocarcinoma Choledocholithiasis Metastatic carcinoma Eosinophilic cholangitis IgG4-associated cholangitis Intra-arterial chemotherapy Ischemic cholangitis Mast cell cholangiopathy Portal hypertensive biliopathy Recurrent cholangitis Iatrogenic biliary trauma Histiocytosis X Hepatic inflammatory pseudotumor
5. Variant forms of PSC 5.1. Small duct PSC Fig. 1. Cholangiographic finding in PSC. Magnetic resonance cholangiogram demonstrating multifocal strictures with intervening dilatation (small arrows) as well as large sacculations (large arrow) characteristic of PSC.
patients affected by intrahepatic and extrahepatic disease [29,30]. Traditionally, cholangiography has been performed by ERC. However, a recent meta-analysis found that MRC is sufficiently sensitive and specific to make the diagnosis in many cases of PSC and thus is a more appropriate first-line diagnostic tool [31,32]. However, if there is a high index of suspicion and MRC is negative or equivocal, ERC should be performed, as MRC has been found to be less sensitive in cases of early disease and cirrhosis [32]. Additionally, ERC has the advantage of also being therapeutic, allowing ductal dilation and stenting, and providing further diagnostic information with brush cytology and biopsies. However, procedure related complication from ERC can occur in 3% to 8% of patients [33,34].
3.5. Histological features Liver biopsy in patients with radiographic evidence of PSC is not needed for diagnosis, although it may help in excluding other diseases. It is not reliable alone for the diagnosis of PSC, as it is non-specific and may be normal when only large ducts are involved [35] However, when performed, characteristic findings include bile duct proliferation, periductal fibrosis with typical “onion-skinning” lesions (present in less than 15% of the patients with PSC), periductal inflammation, and bile duct obliteration [35]. These histologic features may be classified into four stages using Ludwig criteria: cholangitis or portal hepatitis (stage I); periportal fibrosis or hepatitis (stage II); septal fibrosis and/ or bridging necrosis (stage III); biliary cirrhosis (stage IV) [36,37].
4. Diagnostic criteria Given the heterogeneous nature of PSC and the lack of a quantifiable diagnostic test, strict criteria for establishing the diagnosis of PSC have not been established. Typically, the diagnosis is based upon the presence of a cholestatic pattern of liver biochemistries, typical cholangiographic findings, and the absence of secondary causes of sclerosing cholangitis (Table 3) [21]. Patients who present with clinical, biochemical and histological features compatible with PSC, but have a normal cholangiogram, are classified as small duct PSC (38).
Small duct PSC refers to disease that affects bile ducts that are too small to be identified by ERC but have classic findings on liver biopsy. This variant accounts for approximately 6–16% of the PSC population [12,39]. Most patients with small duct PSC have been noted to have slower clinical progression, with higher rates of survival and fewer cases of cholangiocarcinoma or transplantation [38,39]. However, approximately 12% of patients with small duct PSC will progress to large duct disease [38,39]. 5.2. PSC-autoimmune hepatitis (AIH) overlap syndrome PSC-AIH overlap syndrome is the classification given to patients with both the cholangiographic features of PSC and the biochemical and histologic features AIH. More common in children and young adults, the prevalence of PSC-AIH overlap has been reported to be as low as 8% and as high as 49% [40,41]. Such high degree of variability is likely due to the lack of defined diagnostic criteria for this condition. These patients should be categorized by their predominant disease, namely PSC or AIH, rather than labeled as an overlap syndrome. Furthermore, there has been some evidence to suggest that PSC patients with AIH features may benefit from immunosuppressive therapy, particularly corticosteroids [42]. 5.3. IgG4-related sclerosing cholangitis Recently, patients with steroid responsive sclerosing cholangitis but not always associated with autoimmune pancreatitis have been described [43]. The hepatobiliary changes described include stenosis of the bile ducts, biliary duct wall thickening, stenosis of the portal vein, portal fibrosis, and hepatic inflammatory pseudotumor [44,45]. IgG4related sclerosing cholangitis could be a distinct entity from autoimmune pancreatitis [45], similar to PSC with regard to cholangiographic features, but in contrast to PSC, is susceptible to steroid therapy and is reversible [45]. Therefore, identifying patients with IgG4-related sclerosing cholangitis and distinguishing them from patients with PSC could have major therapeutic implications [46]. 6. Clinical course and prognosis PSC has a variable clinical course, though the disease most often progresses to end-stage liver disease. The median time from diagnosis to death or liver transplantation ranges from 12 to 18 years [18,47,48]. Many models have been developed to provide prognostic prediction for life expectancy in PSC patients. The Mayo Clinic Revised Natural History Model for PSC is the most widely accepted model for predicting
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survival probability [49]. This score is based on objective findings of age, bilirubin, albumin, aspartate transaminase, and history of variceal bleeding. However, it should be noted that prognostic models are useful in predicting outcomes in patient cohorts, but their ability to precisely predict outcomes in an individual patient is limited [21]. 7. Etiopathogenesis Despite a number of proposed models to explain the mechanisms involved in PSC, none of them fully explain all the features of PSC, and most lack sufficient supporting evidence. The current understanding of the mechanistic hypotheses that have been proposed to explain the pathogenesis of PSC includes those involving genetic susceptibility, lymphocyte homing, innate immunity, biliary duct fibrosis and toxic bile. Barriers to the further elucidation of these hypotheses of PSC pathogenesis include: 1) the difficulty in obtaining target tissue, especially in early stages of disease, 2) phenotypic variability and the lack of consensus on classification, 3) the relative rarity of the condition requiring collaboration between multiple institutions, and 4) the absence of an animal model that adequately recapitulates the human condition. Table 4 summarizes the proposed models of PSC pathogenesis. 8. Medical management As the pathogenesis for PSC remains elusive, targeted medical therapy for this disease has not yet been established. At this time, there are no proven medical therapies for PSC, and the goals of treatment are primarily symptom and complication management. Liver transplantation is the only effective treatment currently available for end-stage PSC at this time. 8.1. Ursodeoxycholic acid (UDCA) UDCA is a hydrophilic bile acid that is the most studied drug in randomized control trials (RCTs) for PSC. It is a well-established treatment for primary biliary cirrhosis, though its efficacy in PSC appears to be much less certain. Early randomized control trials examined UDCA therapy at low doses (13–15 mg/kg/day) and found that there were improvements in liver biochemistries. However, UDCA did not affect disease progression [63]. More recent studies using higher doses of UDCA have been less than promising. Olsson, et al. performed a randomized study comparing UDCA (17–23 mg/kg/day) with placebo in 219 patients with a 5-year follow-up, and they did not note any significant benefit in survival [64]. A more recent study by Lindor, et al. randomized 150 patients to even higher doses of UDCA (28–30 mg/kg/day) or placebo, noted an improvement in liver tests but worse outcomes in patients taking UDCA [65]. Currently, the American Association for the Study of Liver Diseases (AASLD) recommends against the use of UDCA therapy in PSC patients while the European Association for the Study of the
Liver (EASL) believes that there is insufficient evidence to make a clear recommendation at this time [21,66]. 8.2. Immunosuppression Immunosuppressants including budesonide, cyclosporine, tacrolimus, methotrexate, and mycophenolate mofetil have been studied in randomized trials, though none were found to prolong survival or time to transplantation, and all have serious side effects [21,67–72]. TNF-α inhibitors including pentoxifylline and etanercept, have also been studied, but have not been found to be beneficial [73,74]. There is no role for immunosuppressant agents to treat classic PSC at this time. 8.3. Promising novel agents Simtuzumab (formerly GS-6624), a humanized monoclonal antibody with an immunoglobulin IgG4 isotype directed against human lysyl oxidase like 2 (LOXL2), an enzyme that promotes the crosslinking of type I collagen and a key component in the core regulatory pathway of fibrogenesis, has been studied in pulmonary fibrosis and other fibrosing diseases. Its first use in patients with liver fibrosis has been recently reported. It was safe and shown to have possible antiinflammatory and anti-fibrotic effects [75]. A phase 2b, dose-ranging, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of simtuzumab in subjects with PSC is currently open for enrolment (clinicaltrial.gov NCT01672853). Antibiotics have also been suggested with some promising results. A recent pilot study with 16 patients found that minocycline decreased alkaline phosphatase levels and Mayo risk scores though long-term effects were not established [76]. In a randomized control trial of 80 patients, those receiving metronidazole combined with UDCA in comparison to UDCA and placebo were found to have lower levels of alkaline phosphatase and Mayo risk score in the study arm, though no significant difference in disease progression [77]. Furthermore, a study evaluated the role of long-term treatment of PSC in children with oral vancomycin, and the results showed improvement in their alanine aminotransferase, gamma-glutamyl transpeptidase, erythrocyte sedimentation rate, and clinical symptoms [78]. There was less improvement noted in the patients with cirrhosis when compared with the patients without cirrhosis [78]. A recent pilot RCT in adult patients with PSC also showed while both metronidazole and oral vancomycin were efficacious, vancomycin was better tolerated than metronidazole [79]. Vancomycin seems a very promising agent to treat PSC in both children and adults and warrants larger studies. 9. Liver transplantation LT is currently the treatment of choice for patients with end-stage PSC. LT in patients with PSC is associated with patient survival rates of
Table 4 Etiopathogenesis of PSC. Hypothesis
Evidence
Genetic susceptibility o o o o Innate immunity o
Adaptive immunity Biliary fibrosis Toxic bile
o o o o o o o
Increased prevalence in 1st degree relatives [50,51] Strong association with HLA Susceptible haplotypes: HLA-DRB1*1501-DQB1*0602, HLA-DRB1*1301-DQB1* 0603, and HLA-A1-B8-DRB1*0301-DQB1*0201 [52–55]. Genome-wide association studies reported that the strongest genetic risk to PSC lies within the major histocompatibility complex Pathogen-associated molecular patterns (PAMPs) enter portal circulation, activate macrophages, dendritic cells, and natural killer (NK) cells through pattern recognition receptors, including Toll-like receptors (TLRs) and CD14; then signal cholangiocytes through TLR; leading to secretion of cytokines and recruitment of inflammatory cells [56] Intestinal PAMPs can induce biliary inflammation in rodent models [57] Macrophages accumulate in PSC livers sinusoidal and peri-sinusoidal more than PBC [58] Aberrant trafficking of intestinal memory T-lymphocytes to the PSC liver [59,60] Portal fibroblast and hepatitis stellate cell activation Multidrug resistance gene 2 (Mdr2) knockout mouse Biliary phospholipids are absent in Mdr2−/−, which may lead to toxic bile acid-induced damage, resulting in sclerosing cholangitis [61] Variants and functional mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described in patients with PSC [62]
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up to 90% at 1 year, and 85% at 5 years [21]. Indications for LT are similar to those for other chronic liver diseases. Additional indications include intractable pruritus, recurrent cholangitis, and early cholangiocarcinoma. Recurrence of PSC occurs in up to 20–25% of patients after 5–10 years of LT [80–86]. 10. Conclusion Primary sclerosing cholangitis is a chronic cholestatic liver disease associated with significant morbidity and mortality. There is no proven medical treatment available except liver transplantation for end stage PSC. Further studies are needed for better understanding of the etiopathogenesis of the disease and for development of an optimal therapeutic strategy. The goal is to improve health related quality of life and halt progression of disease, thereby decreasing incidence of complications of advanced liver disease and the need for transplantation. 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