Current Treatments of Primary Sclerosing Cholangitis

Current Medicinal Chemistry, 2007, 14, 2081-2094

2081

Current Treatments of Primary Sclerosing Cholangitis M. Vacca1, M. Krawczyk2, M. Petruzzelli1,3, R.C. Sasso1, K.J. van Erpecum4, G. Palasciano1, G.P. vanBerge-Henegouwen4, A. Moschetta1,3 and P. Portincasa*,1 1

Clinica Medica “A. Murri”, Dept. of Internal Medicine and Public Medicine (DIMIMP), University of Bari, Italy; 2Medical University of Lublin, Poland; 3 Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy; 4Department of Gastroenterology, University Medical Center, Utrecht, The Netherlands Abstract: Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic disease characterized by hepatic inflammation and obliterative fibrosis, resulting in both intra- and extra-hepatic bile duct strictures. End-stage liver disease and bile duct carcinoma represent frequent complications. Incidence and prevalence of PSC in USA have been recently estimated as 0.9 per 100,000 person-years, and 1-6 per 100,000 person-years, respectively. Major diagnostic criteria include the presence of multifocal strictures, beadings of bile ducts, and compatible biochemical profile, once excluded secondary causes of cholangitis. Since the aetiology of PSC remains poorly defined, medical therapy is currently limited to symptom improvement and prolonged survival. Ursodeoxycholic acid (UDCA), corticosteroids and immunosuppressants have been proposed alone or in combination to improve the clinical outcome. In selected cases, surgical or endoscopic procedures need to be considered. Orthotopic liver transplantation (OLT) is at the moment the only definitive approach although disease relapse has been reported. In this article the state of the art in PSC treatment and future promises in this field are reviewed.

Keywords: Liver, cirrhosis, inflammation, UDCA, immunosuppressant, IBD, cholestasis, biliary obstruction. INTRODUCTION Primary sclerosing cholangitis (PSC), firstly described in 1924 by Delbet [1], is a rare chronic cholestatic disease of unknown origin, characterized by liver inflammation and obliterative fibrosis of intra- and extra-hepatic bile ducts, leading to liver fibrosis, cirrhosis and end-stage liver disease with portal hypertension. Cholangiocarcinoma is a potential fearful complication of PSC. Liver transplantation is required in end-stage PSC [2-5]. The exact prevalence of PSC is currently unknown but might be significantly greater than previously estimated: in the 1976-2000 Rochester Epidemiology Project in Olmsted County, Minnesota, the age-adjusted incidence of PSC in men was 1.25 per 100,000 person-years and 0.54 per 100,000 person-years in women. The prevalence of PSC was 20.9 per 100,000 men but only 6.3 per 100,000 women. About 75% of cases are associated with inflammatory bowel disease (IBD) [2], especially ulcerative colitis (UC) [6]. UC, in parallel, is associated with PSC in a percentage varying between 2.5 and 7.5% [7,8]. The mean age at diagnosis of PSC is 39-40 years [4] with men affected about two times more than women [9]. PSC is frequently asymptomatic and may progress slowly although irreversibly towards liver failure due to biliary cirrhosis, portal hypertension, or bile duct carcinoma (8%). As the aetiology of PSC is still unknown, the ultimate medical therapy is elusive. So far, symptom improvement and prolonged survival are the sole goals of the therapy. Ursodeoxycholic acid (UDCA) and its analogues (at high doses or in combination with other drugs) and immunosuppressants have been proposed for improving the clinical outcome. Orthotopic liver transplantation (OLT), however, is currently the only definitive treatment and this approach makes PSC the fifth most common indication for OLT [5,10,11]. PATHOGENIC HYPOTHESES PSC is a multifactorial disease but its origin remains unknown so far. Present and past pathogenic theories are depicted in Table 1. A genetic background is likely, as confirmed by the familial occurrence of PSC: HLA type II haplotypes B8, DR3, DRw52a are associated with PSC in 60%, 56% and 52%-100% of cases, respectively *Address correspondence to this author at the Clinica Medica “A. Murri”, Dipartimento di Medicina Interna e Medicina Pubblica (DIMIMP), University of Bari Medical School - Policlinico - 70124 Bari, Italy; Tel: +39-80-5478.227; Fax: +39-80.5478.232; E-mail: [email protected] 0929-8673/07 $50.00+.00

[12-16]; DR2 is a marker of a younger onset of the disease [13], while DR4 is found in rapidly progressive PSC [17]. Some HLA type I haplotypes, including A1 and Cw7 genes, might play a role in PSC onset. The increased association of PSC with several autoimmune diseases points to the imbalance of the immune system as either primary or secondary involvement, despite the exact mechanism is still unclear. PSC might even represent the "arteriosclerosis of the bile duct" as toxic bile acids determine the increased expression of MCP-1 and TNF-. This, in turn, would lead to enhanced tight junction permeability of cholangiocytes, and overexpression/oversecretion of adhesion molecules (a first hit in determining all the inflammatory response and immune system imbalance), an observation to be confirmed in humans [18]. The involvement of the immune system is confirmed by the presence of several classes of serum autoantibodies in PSC patients. A number of other immunologic abnormalities can also be present in PSC, including circulating immune complexes, hypergammaglobulinemia, high serum IGM, decreased circulating T cells, increased CD4:CD8 ratio, decreased C3, an increase of class II major histocompatibility complex (MHC II) on biliary epithelial cells in hystologic samples. The role of nicotine intake remains controversial; whereas we found that the frequency of PSC and UC was significantly lower in smokers [19], transdermal nicotine either improved symptoms in patients with UC [20] or was uneffective on PSC progression [21]. It is uncertain whether bacterial-toxic damage can play a role, based on PSC-IBD overlap [22]. Toxic luminal bile acids and bacteria might cause increased mucosal permeability [2,22] and expression of tumor necrosis factor (TNF) [23]. Bile duct inflammation and hepatobiliary lesions would follow. Against this theory is the finding that PSC patients show mild or absent portal phlebitis [24] and IBD severity may not follow the severity of PSC (which can develop years before the onset of colitis or even years after total colectomy) [25]. The role of viral infection (i.e. CMV and retrovirus type III) and biliary arteriolar injury (alteration of peribiliary vascular plexus [26,27]) in PSC has been investigated; although suggestive, these theories are not supported by experimental data [26-28]. Because PSC and cystic fibrosis show histological similarities, mutations of the cystic fibrosis transmembrane regulator (CFTR) have been searched in PSC [29]. Results have been discordant with either higher or unchanged prevalence of CFTR mutations in PSC if compared with controls [30,31]. CLINICAL FEATURES Patients with PSC can remain asymptomatic (15% to 44%) or develop symptoms, as reported in Fig. (1). After a variable initial © 2007 Bentham Science Publishers Ltd.

2082 Current Medicinal Chemistry, 2007, Vol. 14, No. 19

Table 1.

Vacca et al.

Different Pathogenic Theories for PSC. Theory

Evidence

Findings

Ref.

GENETIC BACKGROUND

Familial occurrence

HLA type II haplotypes (B8, DR3, DRw52a, DR2, DR4) HLA type I haplotypes (A1 and Cw7) MHC class III (MICA and TNFA)

[5,12-17]

IMBALANCE OF THE IMMUNE SYSTEM

Antibodies found positive in PSC patients

Perinuclear anti-neutrophil cytoplasmatic auto-antibodies (p-ANCA) Anti-colon auto-antibodies Anti-neutrophil nuclear auto-antibodies (ANNA) Anti-mitochondrial auto-antibodies (AMA) Anti-nuclear auto-antibodies (ANA) Anti-smooth muscle auto-antibodies (ASMA) Anti-endothelial cell antibodies (AECA) Rheumatoid factor (RF) Anticardiolipin antibody (ACA) Anti-thyroperoxidase antibody (Anti-TPO) Anti-thyroglobulin antibody (Anti-TG)

[204-209]

Other immunologic abnormalities

Circulating immune complexes (80%) Hypergammaglobulinemia (30%) High serum IgM (50%) Decreased circulating T cells Increased ratio of CD4:CD8 Decreased C3 Increased MHC II on biliary epithelial cells Liver T lymphocytes impaired function and cell proliferation Gut-specific MAdCAM1 and CCL25 expression in the liver, responsible for the liver infiltration with gut-activated mucosal T cells High levels of TNF Toll-like receptor alterations

[19,210-218]

NICOTINE INTAKE

Smoking behavior

Lower incidence of PSC in smokers

[21,22]

BACTERIAL TOXIC DAMAGE

Bile acid and/or bacterial induced damage promoting mucosal permeability, inflammation and hepatobiliary lesions

Abandoned as PSC patients show mild or absent portal phlebitis

[2,23-27]

CMV

Unconsistent data

[24]

VIRAL INFECTION

Retrovirus type III BILIARY ARTERIOLAR INJURY

Alteration of peribiliary vascular plexus

Lack of supporting evidences

[219]

CFTR GENE MUTATIONS

Anatomical and histological similarities between cystic fibrosis (CF) and PSC

Discordant results

[29-31]

asymptomatic period, the insidious cholestasis progressively worsens leading to cirrhosis and end-stage liver disease. Before establishing the diagnosis of PSC, however, all possible secondary causes of cholangitis must be ruled out, including neoplasms [2], chronic and acute bacterial infections, biliary tree abnormalities and ischemic bile duct damage. No biochemical profile is specific for PSC [32]. Chronic elevation of serum alkaline phosphatase (ALP) (3 to 5 times normal lasting for at least 6 months) is highly suggestive of PSC[6] , despite ALP is normal in up to 6% of PSC patients [33,34]. Mild elevation of serum aminotransferase levels (up to 4-5 times normal) is another finding [35]. Serum bilirubin (usually conjugated) and gamma glutamyl transferase (GGT) can follow a fluctuating course [3,35,36]. Prolongation of the prothrombin time (PTT) and decreased serum albumin levels may reflect advanced liver disease, malnutrition with IBD or even vitamin K malabsorption during cholestasis [35]. Chronic cholestasis in PSC is commonly responsible for elevations in serum ceruloplasmin, copper, cholesterol, and hepatic and urinary copper. Although several immunologic markers and autoantibodies can be found in PSC, none is specific making their clinical usefulness currently poor [11]. The diagnosis of PSC requires imaging techniques: ERCP is the mainstay of diagnosis, but an important role has recently emerged

for MR-cholangiopancreaticography (MRCP) (Fig. (2)): magnetic resonance (MR) and MRCP are currently recommended [37-39] for accurate detection of distinctive features of PSC, including diffuse strictures [40] and a multifocal stricturing and beading involving bile ducts [41,42]. On some occasions fine or deep ulcerations of common bile duct may be the only features at the early stages of the disease [2]. Bile ducts may appear focally narrow with intervening areas of normal diameter [40]. Gallbladder and cystic duct are affected in 15% of patients [43]. In the small-duct PSC variant, cholangiographic features may be silent, since affected bile ducts are too small to be seen by radiology [2]. A rapid deterioration of clinical conditions should always raise the possibility of malignancy. Also, the finding of a polypoid mass into dilated ducts requires further investigations, since the cholangiocarcinoma needs to be ruled out. Further investigations include biopsy, brushing, needle aspiration, cholangioscopy, serum and bile tumoral markers evaluation. Two advanced cytologic techniques for detecting aneuploidy, digital image analysis (DIA) and fluorescence in situ hybridization (FISH), have recently been developed to help identify malignant pancreatobiliary strictures. Both showed increased sensitivity over that obtained by conventional cytology, while maintaining an acceptable specificity [44]. FISH successfully assessed chromosomal

Current Treatments of Primary Sclerosing Cholangitis

Current Medicinal Chemistry, 2007 Vol. 14, No. 19

2083

Fig. (1). Common clinical features of PSC patients.

alterations (polysomy and homozygous 9p21 deletion) not only in sporadic and PSC-associated cholangiocarcinomas, but also in PSC-associated biliary dysplasia [45]. Increased tumor marker carcinoembrionary antigen (CEA) points to malignant transformation, while the role of serum CA 19-9 is still controversial [46,47]. Recently, Mesenas et al. have proposed the use of duodenal endoscopic ultrasonography (EUS) for the diagnosis of PSC, with thickening (above 1.5 mm) of the common bile duct (CBD) as a characteristic feature [48]. Cholangioscopy has a potential role in differentiating benign from malignant stenoses, and in the detection and treatment of biliary stones in patients with PSC as well [49]. Liver biopsy is mostly useful at an early stage. Given the initial focal character of PSC, hepatic histology may appear normal with a rate of false negatives as high as 10% [50]. Hallmark features of PSC at histology include thickened extra- and intra-hepatic bile ducts, necrosis of epithelial cells, inflammatory infiltrates clustering around biliary glands [40,51], concentric fibrosis of portal triads [51,52]. Small bile ducts of portal tracts may vanish and be replaced by collagenous scars. Subsequently, bile ducts may become solid fibrous cords, the distinctive feature of PSC. With the progression of the disease, the hepatic parenchyma may display unspecific changes, which are useful for staging and prognosis. Such changes are classified into four stages [2]: stage I, periductal inflammation and fibrosis; stage II, inflammation and expansion of the connective tissue into the periportal parenchyma; stage III, parenchymal fibrosis and bile duct obliterations; stage IV, biliary cirrhosis. Definitive diagnosis of PSC is confirmed by the presence of characteristic imaging findings and histologic features of the disease, once all other possible causes of secondary sclerosing cholangitis have been excluded [6]. NATURAL HISTORY PSC is a lifelong condition and patients have a significantly lower survival rate than matched healthy subjects [6]; the median survival has been estimated between 8 and 17 years [5,53,54] from the time of diagnosis, without liver transplant. Small duct PSC and asymptomatic PSC have a more favourable prognosis [5,55]. It has been recently suggested that the polymorphisms of the steroid and xenobiotic receptor (SXR) gene might play a role in PSC. SXR

activity might influence PSC natural history and therefore clinical course of the disease by controlling the expression of genes involved in bile acid detoxification during cholestasis [56]. Patients with PSC often develop hepatic and extrahepatic complications with an overall impact on survival (Table 2) [5,10,11,57-62]. In 711% of PSC patients, autoimmune hepatitis coexists as an overlap syndrome; in such association, PSC remains responsible for the clinical course of the disease [63,64]. PSC patients are at a high risk for a number of malignancies [65]. PSC is seen as a premalignant condition of the biliary tract and cholangiocarcinoma is still the leading cause of death in these patients; its pathogenesis is not completely understood but includes chronic inflammation, proinflammatory cytokines, epithelial dysplasia, and malignancy [11,58]. Cholangiocarcinoma occurs in 6% to 30% of patients anywhere in the biliary tract [11,55], including the gallbladder [60,66]. Early diagnosis of cholangiocarcinoma is mandatory due to its high mortality rate (median survival of 5 months after diagnosis [67]), and the almost universal recurrence of this neoplasia following liver transplantation. A careful screening for hepatobiliary carcinoma is also advisable in PSC patients with risk factors such as nicotine abuse, long history of IBD and male gender [68]. Colorectal cancer is another neoplasia observed in PSC patients several of which have UC (cumulative risk of 25%, 10%, and 20% after 10, 20, and 30 years, respectively [69-72]). The mechanisms linking PSC to colonic neoplasia are not fully understood but may imply high colonic concentrations of cytotoxic secondary bile acids [11,73-75]. This possibility is supported by the high frequency of colon cancer in the right colon, as compared with patients who have UC alone [76], and the potential chemoprotective effect of ursodeoxycholic acid (UDCA) versus the development of colonic neoplasia [74,77]. Thus, it is highly advisable to start a colonscopy screening program in PSC patients immediately after diagnosis and this policy should continue after liver transplantation [78,79]. PSC also confers an added risk of pancreatic cancer (14 times higher than in general population [65]) and hepatocellular carcinoma [80]. This possibility should always be kept in mind when planning the workup and follow up of PSC patients. Prognostic models for PSC have been developed (i.e. the Child-Pugh-Turcotte score or the


Vacca et al.

Fig. (2). A) ERCP features of PSC; B) MRCP features of PSC. Arrows indicate the multiple strictures leading to multifocal stricturing and beading that involve intrahepatic and extrahepatic bile ducts (courtesy of Prof. GP vanBerge-Henegouwen, Utrecht).

Mathematical Model for End-stage Liver Disease, MELD) but the most useful to characterize PSC before onset of cirrhosis, is the revised Mayo Model in which age, serum bilirubin, albumin, AST and history of variceal bleeding are included in the formula (available at http://www.mayoclinic.org/gi-rst/mayomodel3.html) [5,81,82]. Table 2.

Common Complications in PSC [5,10,58,59]

Affecting the biliary tract and pancreas

Dominant strictures Bacterial cholangitis Cholelithiasis and choledocholithiasis Gallbladder polyps (frequently malignant) Cholangiocarcinoma Gallbladder cancer Pancreatic cancer

Affecting the liver (End-stage liver failure)

Portal hypertension Esophageal variceal bleeding Portal encephalopathy Ascites Spontaneus bacterial peritonitis Hepatobiliary carcinoma

Affecting the intestine

Bleeding from peristomal varices (after proctocolectomy and ileal stoma for coexisting IBD) Rectal sparing and backwash ileitis (PSC-IBD) Colorectal cancer

Due to malabsorbtion

Steatorrhoea Hydrophobic vitamin deficiency (A, D, E, K) Osteoporosis

THERAPY No current treatment is definitive for PSC. In spite of several drugs having been evaluated alone or in combination, either survival or outcome of PSC patients do not respond to therapy, with the exception of liver transplantation. Ideally therapy should target both intrahepatic and extrahepatic debilitating manifestations of the disease (e.g. pruritus and osteoporosis). Current medical management features hydrophilic bile salts, immunosuppressive, antiinflammatory and antifibrotic drugs. Depending on patient’s condition, endoscopic procedures might represent an option as well. As

PSC may follow a progressive course towards end-stage liver failure, OLT remains the only definitive approach with excellent outcomes, although recurrence has been described after OLT [83]. Different therapeutic approaches will be discussed in the following paragraphs and are summarized in Table 3. A). Ursodeoxycholic Acid (UDCA) UDCA (3,7-dihydroxy-5-cholan-24-oic acid) (Table 4) is a dihydroxy bile acid found in small amount in human bile and formed by colonic microflora after dehydroxylation of the primary bile salt chenodeoxycholic acid. When administered orally as “unconjugated” form, 30 to 60% UDCA is mostly absorbed in the small intestine after solubilization into mixed micelles composed of endogenous bile acids plus phospholipids [74,84]. Hepatocytes actively extract UDCA from the portal vein via specific transporters such as the taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide (OATP) [85]: first pass hepatic metabolism of UDCA reaches 70%, thus blood levels in systemic circulation are very low [86]. Once inside the cell, UDCA is conjugated to glycine (aminoethanoic acid, C2H5NO2), a nonpolar amino acid, or taurine (2-aminoethanesulfonic acid, C2H7NO3S), an amino sulfonic acid [87]. UDCA conjugates, which are considered the active form of UDCA in the treatment of cholestasis [88], are secreted in bile via yet another transport protein, namely the bile salt export pump (BSEP, most recently termed ATP-Binding Cassette Transporter-B11) [85]. UDCA levels in bile peak 1-3 hours after administration. The half-life of UDCA is 3.5-5.8 days [89], and it is mainly eliminated by faeces, although during cholestasis renal excretion may prevail. UDCA conjugates are reabsorbed mainly in the distal ileum via an apical sodium-dependent bile salt transporter (ASBT) [90]. UDCA and its conjugates, which are not absorbed in the small intestine, undergo bacterial conversion into lithocholic acid which is then eliminated into faeces or reabsorbed in a small quantity at colonic level (and then re-secreted after hepatic conjugation) [88]. UDCA has been given to patients with liver disease since the 1980s [91,92] based on the rationale that UDCA, being more hydrophilic (i.e. less and less detergent) than other endogenous bile acids, would dilute the bile acid pool thus reducing cytotoxicity. The therapeutic properties ascribed to UDCA are outlined thereafter.


Table 3.


2085

Therapeutic Approaches in PSC OBSOLETE Ursodeoxycholic acid (UDCA)

UDCA alone at low doses UDCA in combination with corticosteroids, antibiotics

Corticosteroids

Prednisone Prednisolone Budesonide Hydrocortisone

Immunosuppressants

Methotrexate (alone and in combination with UDCA) Cyclosporine Cladibrine D-penicillamine Azathioprine Colchicine Pentoxifylline Mycophenolate mofetil

Other drugs

Transdermal nicotine

CURRENT Ursodeoxycholic acid (UDCA)

UDCA at high doses

Antibiotics

Ciprofloxacin Trimethoprim-sulfametoxazole Metronidazole

Other medical approaches

Nutritional supplementations Vit. A,D,E,K supplementation Pruritus Cholestyramine Naloxone Naltrexone Colestipol Rifampicin Metronidazole Ondansetron Plasmapheresis Osteoporosis Calcium, Vit. D, calcitonin, biphosphonates

Endoscopic procedures

Stents

(in case of strictures)

Dilatations

Surgical procedures

Orthotopic liver transplantation Surgical non-transplant procedures (symptomatic) FUTURE

Ursodeoxycholic acid (UDCA)

UDCA in combination NorUDCA

Imunosuppressants

Tacrolimus

Biological agents

Etanercept

Lipid lowering agents

Bezafibrate

Plasma Lipids

Bile Acid Pool

UDCA reduces biliary cholesterol secretion by 40-60%: this is likely the consequence of reduced intestinal cholesterol absorption due to the lower cholesterol solubilization capacity displayed by more hydrophilic micelle composition [93]. In addition, UDCA also increases the conversion of cholesterol into bile acids, plus it reduces both cholesterol and triglycerides serum levels by more than 10% [94]. PBC patients treated with UDCA for 2 years had lower serum levels of total cholesterol, LDL and HDL. Woollett et al. by contrast, found no effect on intestinal cholesterol absorption in humans with UDCA at a dose of 15 mg/kg/day [95]. Differently from chenodeoxycholic acid, UDCA does not influence the activity of the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (EC 1.1.1.88), the rate limiting enzyme for cholesterol synthesis [94].

The increase in total bile acid serum levels during UDCA therapy is due to increased serum UDCA levels alone (from 19 to 64 %, depending on administered dose), since serum levels of other bile acids are even slightly decreased [96-101]. The mechanisms responsible for UDCA therapeutic effects during cholestatic liver disease and PSC known in part [102,103]. UDCA may reduce ileal absorption of endogenous bile acids (by means of competitive inhibition in distal ileum), and modulate directly bile acid synthesis and excretion in the liver; alternatively, UDCA may reduce the uptake of hydrophobic bile acids by cholangiocytes under cholestatic conditions [104].


Vacca et al.

Table 4. The Structure of Most Important Molecules Used as Therapeutical Agents in PSC Patients NH2

7-[2-amino-2-(4-hydroxyphenyl) -acetyl]amino-3,3-dimethyl-6-oxo -2-thia-5azabicyclo[3.2.0]heptane -4-carboxylic acid (C16H19N3O 5S )

H

H N

Amoxycillin

S N

O HO

O

m.w. 365.4

OH O

N

NO2

N

S

Azathioprine 6-(3-methyl-5-nitro-imidazol-4-yl)sulfanyl-7H-purine

H3C

(C9H7N7O 2S)

NH

N

m.w. 277.264

N

N

Cl

HN

Bezafibrate

O

(2-[4-[2-[(4-chlorobenzoyl)amino] ethyl]phenoxy]-2-methyl-propanoic acid) (C19H20ClNO 4) m.w. 361.819

O O OH HO

Budesonide

O

(16,17-(butylidenebis(oxy))-11,21-dihydroxy-(11-,16-)-pregna-1,4-diene-3,20dione)

O

HO O

H

(C25H34O6)

H

m.w. 430.534 H

H

O

NH

Ciprofloxacin 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-quinoline-3-carboxylic acid

N

N

(C17H18FN3O 3) m.w. 331.346

HO F O CH3

O

CH3

O

O

Colchicine (N-((7S)-5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo(a)heptalen-7-yl)acetamide) (C22H25NO6 )

CH3

H

O

N

C

O O

m.w. 399.437 CH3

O HO

O OH

Hydrocortisone

HO

11,17,21-trihydroxy-,(11beta)-pregn-4-ene-3,20-dione (C21H30O5) m.w. 362.465 O

CH3



2087

(Table 4). Contd….. H 2N

Methotrexate (S)-2-(4-(((2,4-diaminopteridin-6-yl)methyl)methylamino)benzamido) pentanedioic acid

N

N N

N N

O H N

NH2

OH

(C20H22N8O 5) O

m.w. 454.44

O N O-

Metronidazole

N+

N

2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol

O

(C6H9N3O 3) m.w. 171.15 OH

Mycophenolic Acid (E)-6-(4-hydroxy-6-methoxy-7-methyl3-oxo-1,3-dihydroisobenzofuran-5-yl)-

O O O

4-methylhex-4-enoic acid (C17H20O6) m.w. 320.34

OH O

OH HO

Naloxone 17-allyl-4,5-epoxy-3,14-dihydroxymorphinan-6-one

O

(C19H21NO4) N

m.w. 327.27

OH O HO

Naltrexone 17-(cyclopropylmethyl)-4,5-epoxy- 3,14-dihydroxymorphinan-6-one

O

(C20H23NO4) N

m.w. 341.401

OH O

Nicotine

H

(S)-3-(1-Methyl-2-pyrroli-dinyl)pyridine

N

(C10H14N2) m.w. 162.23 N

CH3 O

Ondansetron

N

9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl]-1,2,3,9-tetrahydrocarbazol-4-one (C18H19N3O) N

m.w. 325.9

CH3

SH

Penicillamine (2S)-2-amino-3-methyl-3-sulfanyl-butanoic acid

CH3

C

CH

CH3

NH2

(C5H11NO 2S) m.w. 149.212

COOH

N

OH


Vacca et al. (Table 4). Contd….. O

O

Pentoxifylline

N

N

3,7-Dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione (C13H18N4O 3) O

m.w. 278.31 H N

O

N

N

O

Phenobarbital HN

5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione (C12H12N2O 3)

O

m.w. 232.235

O

HO

Prednisolone

OH

HO

11,17-dihydroxy-17- (2-hydroxyacetyl)- 10,13-dimethyl6,7,8,9,10,11,12,13,14,15,16,17- dodecahydrocyclopenta [a]phenanthren-3-one

H

(C21H28O5 ) H

H

m.w. 360.444 O

O HO

Prednisone

OH

O

17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl- 7,8,9,10,12,13,14,15,16,17decahydro-6H- cyclopenta[a]phenanthrene-3,11-dione

H

(C21H26O5 ) H

H

m.w. 358.428 O

CH3

CH3

O HO

Rifampicin (rifampin)

H 3C

5,6,9,17,19,21-Hexahydroxy-23-methoxy-

O

CH3 O CH3 OH OH

2,4,12,16,18,20,22-heptamethyl8-[N-(4-methyl-1-piperazinyl)formimidoyl]-

H 3C

O

2,7-(epoxypentadeca[1,11,13]trienimino)-

CH3

H 3C

NH

CH3

naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate

N N

O

(C43H58N4O 12) m.w. 822.94

N

OH

O

CH3

O

CH3

O

Sulfamethoxazole

N

O

O

S

4-amino-N-(5-methylisoxazol-3-yl)-benzenesulfonamide

N H

(C10H11N3O 3S) m.w. 253.279

H 2N

H HO

Tacrolimus H3CO

3S-[3R*[E(1S*,3S*,4S*)] *

*

*

*

*

*

*

*

*

*

,4S ,5R ,8S ,9E,12R ,14R ,15S ,16R ,18S ,19S ,26aR ]] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a -hexadecahydro-5, 19-dihydroxy -3-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylethenyl]-14,16-dimethoxy -4,10,12,18-tetramethyl-8-(2-propenyl) -15,19-epoxy-3H-pyrido[2,1-c] [1,4] oxaazacyclotricosine-1,7,20,21(4H,23H) -tetrone, monohydrate

H

H

H H 3C

CH3 O

H O

HO

H

N H

H

O O

CH3

O OH

(C44H69NO12)

H3C

m.w. 804.018

H

CH3 H

O

H H3CO

H

H

OCH3

H2O



2089

(Table 4). Contd….. NH2 O

Trimethoprim N

5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine (C14H18N4O 3)

H2N

m.w. 290.32

O

N O

COOH

Ursodeoxycholic acid (ursodiol) 3,7-dihydroxy-5-cholan-24-oic acid

H

(C24H40O4) m.w. 392.56

H HO

H OH

H

H

Choleretic Effect

Other Effects of UDCA

UDCA improves the biliary excretion of bile acids, bilirubin and glutathione conjugates, and other organic anions [88]. In patients with PBC and PSC undergoing long-term UDCA treatment the transit time of bile acids and bilirubin appeared to be shortened [105] due to increased activity of transport proteins [106-108]. In humans and experimental models, UDCA has been shown to exert post-transcriptional modifications, thus affecting the targeting and insertion of several transport proteins into the plasma membrane (i.e. bile salt export pump, BSEP; anion exchanger, AE2; conjugate export pumps, MRP2, MRP3, MRP4) [56,109-114]. The invoked post-transcriptional mechanisms include cytoplasmatic free calcium- or protein kinase C (PKC)-dependent improvement of exocitosis [88], modulation of integrins, Src kinases, Ras/Rafindependent p38, Ras dependent p44 and p42 [88], and modulation of transporter activity due to UDCA-induced transporter phosphorylation [115]. All these complex mechanisms enhance bile acid and phospholipid secretion [88]. In experimental animals UDCA induces hypercholeresis, i.e. a greater than expected bile secretion, via the so-called “cholhepatic shunt” process [116,117]. In fact, protonated UDCA is more lypophilic and can be rapidly reabsorbed from the bile ductules into the peribiliary plexus [116,117]. This mechanism facilitates UDCA liver reuptake and its further biliary secretion.

Since hydrophobic bile salts seem to play a role in cell proliferation in colorectal cancer, UDCA treatment has been suggested to result in chemoprotection (in IBD alone or associated to PSC): decreased levels of fecal hydrophobic deoxycholate and lithocholate, in fact, could prevent the imbalance of intracellular pathways involved in tumor proliferation including colonic neoplasia [11,7375].

Cholangiocytes HCO3- Secretion UDCA is known to stimulate HCO3- secretion probably via a Ca -dependent mechanism (directly or involving ATP synthesis). This effect might partly take part in the anti-cholestatic effect of UDCA [88,117]. 2+

Immunomodulation UDCA decreases hepatocellular and biliary levels of the major histocompatibility complex (MHC) class I and class II molecules, and subsequently induces the reduction of the T-cell mediated hepatocellular damage [118,119]. Cytoprotection Hydrophobic bile salts might induce cell damage by binding to plasma and mitochondrial membranes thus inducing apoptosis or necrosis [88]. The damage is counteracted or reduced by UDCA as shown by the decrease of LDH (lactate dehydrogenase, EC 1.1.1.27) release in culture medium [120,121]. In PSC and PBC the toxicity of hydrophobic bile acids could further increase the immunologically-mediated cholangiocyte injury [122,123] and effects are prevented by UDCA presumably by modulating micelle formation towards enhanced buffering of toxic bile acids [124].

Therapeutic Use of UDCA in PSC UDCA has been employed alone or in combination with immunosuppressants, as well as UDCA analogues. However, no definitive data exist on the impact of UDCA on survival or time before OLT. UDCA Monotherapy Low doses UDCA (8-15 mg/kg b.w. daily) showed a relevant improvement in liver biochemistry but had no beneficial effects on liver histology, symptoms and survival [125-128]. In a randomized study involving 48 PSC patients [129], no differences were found comparing single dose vs multiple doses (t.i.d. at mealtimes) of UDCA, with a total administered dose of 10-12 mg/kg b.w. daily in both groups. At a 24 months follow up, symptoms, and serum markers of liver injury/cholestasis like alkaline phosphatase (ALP, EC 3.1.3.1), gamma glutamyl transferase (GGT, EC 2.3.2.2), aspartate aminotransferase (AST, EC 2.6.1.2), bilirubin, and histology did not deteriorate in both groups. Due to the lower enrichment of UDCA in bile during cholestasis, it was suggested that higher doses of UDCA were more appropriate. In a placebo-controlled trial, Mitchel et al. used 20 mg/kg/day UDCA [92] and found that UDCA in the total bile acid pool had increased up to 70% in the UDCA group. Nevertheless, no difference in symptoms (i.e. malaise and fatigue), bilirubin and albumin serum levels were found between the two groups. In the UDCA group there was a lower recurrence of pruritus and jaundice, plus an improvement of serum ALP and GGT levels, while there was a minor decrease of the score of portal inflammation. In addition ERCP showed no progression of the disease. Thus, although UDCA at high doses might be effective in PSC, final conclusions cannot be obtained by this study, due to the heterogeneous composition of the population. In another study [91] UDCA was used at the regimen of 25-30 mg/kg/day in 23 PSC patients (77% with UC). Improvement of serum ALP (of more than 50%) was obtained in 38% of patients, while 59% showed improvement of AST and albumin. Of note, in the eleven patients with prior hyperbilirubinemia, bilirubin improved by 44%. In the whole study population the Mayo risk score and the 4-years survival also improved. Olsson [130] recently provided some different results; in a placebo-controlled trial, UDCA given at 17-23 mg/kg/day to 219


PSC patients with PSC during a 5 yrs follow-up, had no effect on survival, quality of life, incidence of adverse events or reduction of either bilirubin, or ALP and ALT. Such negative results might be partly due to pitfalls of the study recently outlined in the Nature Clinical Practice commentary [131]. One additional aspect to consider is that PSC patients with ongoing inflammatory bowel disease might have decreased UDCA enrichment. This was the case in a recent trial including patients with ileo-anal pouch [132]. UDCA Combination Therapy UDCA 650 mg daily has been employed in combination with the active metabolite of prednisone, prednisolone (C21H28O5) (Table 4) (1 to 5-10 mg/kg b.w.), and combined with azathioprine (1-1.5 mg/kg b.w) (Table 4) [133] in 15 PSC patients during 41 months. There was a rapid and consistent decrease of serum ALP, AST (56%), ALT (65%), and bilirubin (27%). ERCP features and liver histology also improved and only one patient developed dominant strictures. A recent study by Floreani et al. confirmed the beneficial effect of combined therapy (UDCA plus immunosupression) in patients with autoimmune hepatitis/PSC and showed better survival rates if compared with individuals with PSC alone [134]. UDCA Analogues NorUDCA is a less hydrophobic C23 homologue of UDCA; this property explains why norUDCA undergoes a lower hepatic conjugation than UDCA and is better reabsorbed by cholangiocytes. This property of norUDCA is also active in damaged cholangiocytes, especially during cholestasis [5]. Fickert et al. studied the Mdr2 ko mice (Mdr2-/-) which resembles the human PSC. The results show an overall improvement of all features of sclerosing cholangitis in mice undergoing UDCA and its analogue after 4 weeks. When compared to UDCA-fed animals, norUDCA was found to reduce ALT and ALP activity; ameliorating effects on liver injury, ductular proliferation and periductal fibrosis – all eventually leading to potential healing from PSC - were also reported [135]. Beneficial effects of norUDCA would include increased bile acid pool hydrophilicity, stimulation of bile flow, improvement of bile acid detoxification and anti-inflammatory properties. In contrast, UDCA resulted in increase of ALP and ALT levels, and it had minor effects on bile acid detoxification enzymes and biliary transporters when compared to norUDCA. B). Corticosteroids Corticosteroid therapy does not appear to be beneficial in PSC; by contrast, systemic side effects [136], including osteoporosis [137] represent major limitations. Prednisone (17-hydroxy-17-(2hydroxyacetyl)-10,13-dimethyl-7,8,9,10,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,11-dione) and budesonide (16,17-(butylidenebis(oxy))-11,21-dihydroxy-,(11-,16-)-pregna1,4-diene-3,20-dione) (Table 4) (a safer nonhalogenated corticosteroid with much higher affinity for the corticosteroid receptor, characterized by high first-pass effect reaching 90%) have been tested without consistent results [138,139]. By contrast, corticosteroids might provide some benefits in patients with another condition, namely “sclerosing pancreato-cholangitis” (i.e. an autoimmune syndrome affecting both pancreatic and bile ducts but different from PSC) [140,141]. Hamano et al. has recently suggested that increased IgG4 immunostaining in bile duct biopsies could be a better marker to identify those patients with sclerosing cholangitis who could respond to corticorticosteroid and immunosuppressant therapy [142,143]. In a recent trials three groups of patients received UDCA (12 mg/kg/day) with prednisone (10 mg/day) or with two doses of budesonide (3 and 9 mg/day). Pruritus, serum ALP and IgG decreased only in the UDCA/prednisone group but neither liver histology nor other liver serum analyses improved with any treatment [144]. Hydrocortisone (cortisol) (11,17,21-trihydroxy,(11beta)-pregn-4-ene-3,20-dione) (Table 4) has been used with biliary lavage and compared with saline lavage in a group of PSC

Vacca et al.

patients, but it was ineffective. Moreover, the onset of adverse effects (e.g. pancreatitis; cholangitis with septicaemia) led to termination of the study [145]. The combination of prednisone and colchicine (N-((7S)-5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo (a)heptalen-7-yl)-acetamide) (Table 4) (an antimitotubular alkaloid interacting with cellular microtubules [146] used in acute gouty arthritis [147] with proven antifibrotic and anti-inflammatory effects [148]) was uneffective on liver histology and standard liver tests [149]. C). Immunosuppressants and Biological Agents Methotrexate ((S)-2-(4-(((2,4-diaminopteridin-6-yl)methyl)methylamino)benzamido) pentanedioic acid) (a 4-amino-10-methyl analog of aminopterin inhibitor of dihydrofolate reductase [150]), is used in the treatment of the immunologic diseases (e.g. psoriasis and rheumatoid arthritis), as well as acute lymphocytic leukaemia [151]. In PSC patients methotrexate was evaluated alone [152] or in combination with UDCA [153] but no evidence supporting its use was reported. The efficacy of tacrolimus (also known as FK506) (Table 4), a macrolide lacton immunosuppressant extensively metabolised in the liver by cytochrome P450 (CYP)3A [154,155] has still to be confirmed in larger trials [156]. A pilot study with etanercept (25 mg subcutaneously twice a week for 6 months), a recombinant human soluble tumor necrosis factor-alpha (TNF) receptor fusion protein (C2224H3475N621O698S36, m.w. 51234.9), proved uneffective on both liver biochemistry and anatomical bile ducts changes. Of note, resolution of pruritus was observed although mean serum bilirubine levels increased. Further studies are therefore required for this or other similar molecules [157]. Other drug used in PSC patients include cladibrine (2-chlorodeoxyadenosine), which was able to interfere with the hepatic lymphocyte infiltration, yet it was only observed at the early stages of PSC and had no relation to any expected radiological or biochemical improvement [158]. Unsatisfactory results were provided by a number of other drugs (Table 4) including D-penicillamine ((2S)-2-amino-3-methyl3-sulfanyl-butanoic acid) [159], azathioprine (6-(3-methyl-5-nitroimidazol-4-yl)sulfanyl-7H-purine) [160], cyclosporine [R-[[R*,R*(E)]]-cyclic(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L--amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valylN-methyl-L-leucyl) [161], colchicine (N-((7S)-5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo(a)heptalen-7-yl)-acetamide) [162], pentoxifylline (3,7-Dihydro-3,7-dimethyl-1-(5-oxohexyl)1H-purine-2,6-dione) [163], mycophenolate mofetil (E)-6-(4hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5yl)-4-methylhex-4-enoic acid (Table 4) [164], transdermal nicotine (S)-3-(1-Methyl-2-pyrroli-dinyl)pyridine (Table 4) [21]. D). Lipid-Lowering Agents Following the observation of reduced serum markers of liver injury in patients treated with bezafibrate (2-[4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy]-2-methyl-propanoic acid) (Table 4), a derivate of fibric acid, the effect of such lipid lowering drug was tested in patients affected by various hepatobiliary diseases [165]. In small, non-randomised, pilot studies, bezafibrate treatment was found to improve serum profile, reducing significantly the levels of biliary and hepatic enzymes in conditions such as PBC, PSC, chronic and autoimmune hepatitis [166,167]. Decreased nitrite production by antigen-presenting dendritic cells has been suggested as the mechanism responsible for the apparent beneficial effect of bezafibrate upon liver damage [168]. While growing evidence suggests combination therapy of bezafibrate plus UDCA as potentially more effective in PBC, the usefulness of such approach on PSC requires additional investigation. E). Antibiotics Ciprofloxacin (1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid) and other antibiotics with high pene-



2091

tration in biliary tract like amoxycillin (7-[2-amino-2-(4hydroxyphenyl)-acetyl]amino-3,3-dimethyl-6-oxo-2-thia-5-azabicyclo[3.2.0]heptane-4-carboxylic acid) and the association trimethoprim (5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine)-sulfametoxazole (4-amino-N-(5-methylisoxazol-3-yl)-benzenesul-fonamide) are reserved for overlapping bacterial cholangitis [169] and as prophylaxis in case of invasive intervention on the bile ducts. A combination of UDCA and metronidazole improved serum ALP in PSC patients, as compared with UDCA alone, although no major differences were evident at histology or ERCP [170].

dominant strictures [186]. In patients with symptomatic dominant strictures, gallstones and debris, it is necessary to consider endoscopic options, such as therapeutic ERCP with stent placement, balloon or catheter dilatation, and nasobiliary drainage [3,187-192]. Surgical non-transplant procedures aimed at palliation (e.g. bilioenteric bypass [193]) should be offered only to patients at uncomplicated early-stages of disease. Invasive procedures in PSC are often associated with high postoperative risk for cholangitis and may hamper future liver transplantation. Both surgical and endoscopic interventions can considerably relieve symptoms; however, none is able to halt disease progression.

F). DIET

OLT remains the only option which can revers or correct the end-stage liver disease in PSC [194]. Indications for liver transplant are similar to those accepted for other forms of end-stage liver disease [2]. The above-mentioned MELD score is currently used to select suitable patients for OLT. Although excellent survival rates following OLT have been reported (90% at 1 year, around 85% at 3 years [195-197]), yet PSC patients are deemed to have higher retransplantation rates (9.6% vs. 4.9% within 2 years) [5,198] and lower survival when compared to PBC [199] or other diseases. Moreover, PSC and its complications appear to recur in 9-30% of patients [83,200-202], irrespective of immunosuppressant therapy with orthoclone or corticosteroids [200]. Lastly, higher incidence of colorectal neoplasia after transplantation has been reported in PSC patients [83,203].

Patients with PSC require adequate supplementation of fatsoluble vitamins (A, D, E, K) and other elements (i.e. calcium) to compensate nutritional deficiencies. In this subgroup of patients those are consequence of chronic steatorrhea which is a common complication in the course of chronic cholestatic liver disease [171]. G). Treatment of Extra-Hepatic Manifestations of PSC Pruritus, as in other chronic cholestatic liver diseases, is a frequent and bothersome complication of PSC [172]. Cholestyramine, a nonadsorbable bile acid sequestrant resin active in the upper intestine, remains the first line drug in PSC patients developing pruritus [173]. When cholestyramine fails, opiate antagonists such as naloxone (17-allyl-4,5-epoxy-3,14-dihydroxymorphinan-6-one) (Table 4) [174] and naltrexone 17-(cyclopropylmethyl)-4,5-epoxy3,14-dihydroxymorphinan-6-one) [175]) must be considered as an alternative. Other drugs like colestipol hydrochloride, rifampicin (rifampin) (5,6,9,17,19,21-Hexahydroxy-23-methoxy-2,4,12,16, 18,20,22-heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]2,7-(epoxypentadeca [1, 11, 13] trienimino)-naphtho[2,1-b]furan-1, 11(2H)-dione21-acetate [176] (Table 4) or metronidazole (2-(2methyl-5-nitro-1H-imidazol-1-yl)ethanol) (Table 4), phenobarbital (5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione) (Table b) [177], serotonin 5-HT3 receptor antagonist like ondansetron (9-methyl-3-[(2methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydrocarbazol-4-one) (Table 4) [178] can have a role, according to the clinical evolution of each patient. As mentioned above, etanercept may gain future recommendations in managing pruritus [157]. Plasmapheresis and liver transplantation should be proposed to patients with otherwise untractable pruritus. Osteoporosis is another common PSC complication though the results concerning the relation between the severity of the liver disease and osteoporosis remain controversial. For patients with high risk of osteoporosis, dual energy X-ray absorptiometry (DXA) scan is recommended for assessing bone mineral density. To date there is no proven therapy for osteoporosis in PSC [179,180]. Firstly, nonpharmacological measures like smoking cessation, regular exercise and balanced diet must be implemented. Supplementation of adequate amounts of calcium and vitamin D (25hidroxyvitamin D plus calcium [173]) must be considered. Other drugs like calcitonin [181], and biphosphonates (etidronate have been evaluated in PBC [182,183]) can be added. Estrogen replacement therapy (administrated transdermaly to diminish hepatotoxicity [184]) has been proposed to protect bone disorders in postmenopausal women [185], but potential hepatotoxicity could be a contraindication in PSC. H). Endoscopic and Surgical Approaches As far, no conservative medical therapy is able to prevent the progression of hepatic and biliary damage in PSC. Dominant strictures are frequent in advanced stages of the disease, and are responsible for major blockage of bile flow. This is a condition that always requires endoscopic therapy. Difficulties to eradicate bacterial infections of the bile are a common finding among patients with

SUMMARY AND FUTURE PERSPECTIVE PSC is a serious chronic progressive cholestatic liver disease of unknown origin: irreversible fibrosis and disappearance of intraand/or extrahepatic ducts are main features and are associated with both hepatic and extrahepatic clinical pictures. Both diagnosis and management of PSC constitute difficult tasks to achieve because symptoms, blood tests and liver histology can be often misleading, especially at the early stage of the disease. Additional diagnostic workup should include MR and MRCP which are also useful as screening tools for potential malignancies. An underlying inflammatory bowel disease should always be investigated in PSC patients; in parallel, PSC should always be suspected in a patient with inflammatory bowel disease. Although many therapeutic trials have been performed, no definitive medical therapy is currently approved for PSC, since currently available drugs display only minor effects on disease progression. Such drugs include hydrophilic bile salts, steroids, immunosuppressants, lipid-lowering agents, antibiotics, and bile saltsequestrant agents. Despite this abundance of different treatments, OLT is currently the only curative therapy for PSC. Undoubtley, future perspectives on PSC must include a better classification and nomenclature with a wider agreement upon staging of the disease, more epidemiological studies to better assess prevalence and incidence of PSC in different groups of patients together with genetic aspects and search for early markers of cholangio-carcinoma. Central for future development of more effective therapies for PSC patients is a better understanding of the molecular mechanisms involved in PSC pathogenesis. In this respect, basic research has provided in recent years powerful tools to investigate disease occurrence and progression: the mdr2 knockout mouse model already offered insights into potentially more effective UDCA analogues. The ball is now handed to physician scientists, who have the responsibility of confirming these preliminary data in the clinical setting. Whether or not norUDCA will constitute the future remedy for PSC management, we believe that only a strong and mutual engagement of both basic and clinical scientists will provide the code to solve the challenging puzzle of PSC pathogenesis. ACKNOWLEDGEMENTS This work was supported in part by research grants from the University of Bari “Ricerca scientifica 2005-2006” and Ministero


dell’Università e della Ricerca “COFIN 2005-6 and 2006-8. PP was also a recipient of the CNR (Consiglio Nazionale delle Ricerche) Short Term Mobility Grant 2005 between The University of Bari Medical School and The Harvard Medical School, USA. M.V. is a recipient of the 2007 European Society of Clinical Investigation travel grant for young investigators. MK was a recipient of the 2003-4 Socrates Erasmus student grant at the University of Bari Medical School. ABBREVIATIONS ALT

=

alanine aminotransferase

ALP

=

alkaline phosphatase

ASBT =

apical sodium-dependent bile salt transporter

AST

aspartate aminotransferase

=

BSEP =

bile salt export pump

CTC

computerised tomographic cholangiography

=

ERCP =

endoscopic retrograde cholangiopancreatography

EUS

endoscopic ultrasonography

=

FISH =

fluorescence in situ ibridization

GGT

=

gamma glutamyl transferase

IBD

=

inflammatory bowel disease

MELD =

model for end-stage liver disease

MR

magnetic resonance

=

Vacca et al. [17] [18] [19]

[20]

[21] [22] [23] [24] [25] [26] [27] [28] [29] [30]

[31] [32]

[33] [34] [35] [36] [37] [38]

MRCP =

MR-cholangiopancreatography

NK

=

natural killer

OLT

=

orthotopic liver transplantation

PBC

=

primary biliary cirrhosis

PSC

=

primary sclerosing cholangitis

[40]

SXR

=

steroid and xenobiotic receptor

[41]

UC

=

ulcerative colitis

[42] [43] [44]

UDCA =

ursodeoxycholic acid

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Received: March 06, 2007

Revised: May 15, 2007

Accepted: May 31, 2007

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