Cholestatic Liver Diseases

Kolestatske bolesti jetre predstavljaju rijetke bolesti koje zahvaćaju hepatocite, ekstrahepatalne i/ili intrahepatalne žučne vodove, a dovode do smetnji u stvaranju ili otjecanju žuči. Primarni bilijarni kolangitis (PBC) predstavlja novi naziv za bolest ranije poznatu kao primarna bilijarna ciroza. Imunološki napad dovodi do progresivnog oštećenja malih žučnih vodova unutar jetrenih lobula s razvojem fibroze, a u konačnici može dovesti do ciroze i zatajenja jetrene funkcije. Primarni sklerozirajući kolangitis (PSC) obilježava kronična upala praćena oštećenjem i fibrozom žučnih vodova s posljedičnom segmentalnom obliteracijom lumena, a može zahvatiti intrahepatalne ili ekstrahepatalne žučne vodove, ili oboje. PBC češće zahvaća žene, a PSC mušku populaciju. Umor, svrbež kože i žutica predstavljaju najčešće simptome kolestatskih bolesti jetre. Obje bolesti često se otkrivaju u asimptomatskoj fazi, kolestatskim profilom jetrenih enzima u laboratorijskim nalazima, odnosno dominantno povišenim vrijednostima alkalne fosfataze (ALP) i gama-glutamil transpeptidaze (GGT). Bolesnici često imaju pridružene druge autoimune bolesti. Za PBC karakterističan je nalaz antimitohondrijskih protutijela (AMA), dok se PSC dokazuje kolangiografijom. Komplikacije bolesti mogu biti posljedica kolestaze, upalnog (autoimunog) zbivanja te ciroze jetre ili razvoja tumora. Ursodeoksikolna kiselina predstavlja terapiju izbora u liječenju PBC-a jer usporava tijek bolesti, dok za PSC ne postoji dokazano djelotvorna medikamentozna terapija koja utječe na tijek osnovne bolesti. U obje bolesti primjenjuju se i simptomatske mjere te postupci usmjereni zbrinjavanju komplikacija, kao što su svrbež, malapsorpcija masti i vitamina topivih u mastima, ili striktura žučnih vodova. Povećana učestalost tumora zahtijeva trajni nadzor i pravodobno liječenje koje utječe na preživljenje bolesnika. Transplantacija jetre predstavlja metodu izbora u završnom stadiju obje bolesti.Cholestatic liver diseases are rare diseases that affect hepatocytes and intrahepatic and/or extrahepatic bile ducts, causing interruptions in bile production or flow. Primary biliary cholangitis (PBC) is a new term for primary biliary cirrhosis. Immune-mediated attack leads to progressive destruction of small intralobular bile ducts and may lead to the development of fibrosis, cirrhosis and liver failure. Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation with damage and fibrosis of bile ducts, causing structuring and obliteration of the lumen. It can affect the intrahepatic and/or extrahepatic biliary tree. PBC mostly affects women, while PSC is more common in men. Fatigue, pruritus and jaundice represent the most common complaints of patients with cholestatic liver diseases. Both diseases are often diagnosed in early, asymptomatic phase, as part of the assessment of abnormal liver tests which demonstrate cholestatic pattern, with predominant elevation of the alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT). Patients often have other concurrent autoimmune diseases. PBC is characterized by the presence of anti-mitochondrial antibodies (AMA), while cholangiography is the method of choice for the diagnosis of PSC. Complications can result from cholestasis, inflammatory (autoimmune) process, liver cirrhosis or cancer development. Ursodeoxycholic acid is the therapy of choice for PBC as it slows the disease progression. However, there is no proven treatment that significantly impacts the course of PSC. For both diseases management is aimed at treating symptoms and managing complications such as pruritus, malabsorption of fat and fat-soluble vitamins, or bile duct strictures. Increased incidence of malignant tumours requires ongoing monitoring and timely treatment in order to improve patient survival. Liver transplantation represents the treatment of choice in the advanced stage of both diseases

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base

Drug therapy of primary biliary diseases: classical and modern strategies

Definition: Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are both cholestatic liver diseases. A common feature of these disorders is the accumulation of bile acids in the liver and blood, presumably because of decreased biliary secretion and reduced bile flow. Etiology: Etiology and pathogenesis of PBC and PSC are still unknown. PBC is considered to be an autoimmune disease. Immunological mechanisms may also be involved in PSC since there is an association with ulcerative colitis and autoantibodies can be detected. Furthermore, genetic factors seem to play an important role in both diseases. Therapy: Since the pathogenesis of both diseases is unclear, there is no definite causal treatment. However, ursodeoxycholic acid (UDCA) was shown to be highly effective. Other drugs which can be used alone or in combination with UDCA are promising and might further improve the outcome of the diseases

Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology

Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver-damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC

A genome-wide association study identifies a susceptibility locus for biliary atresia on 2p16.1 within the gene EFEMP1

Biliary atresia (BA) is a rare pediatric cholangiopathy characterized by fibrosclerosing obliteration of the extrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and eventual liver failure. The etiology of BA remains unknown, although environmental, inflammatory, infectious, and genetic risk factors have been proposed. We performed a genome-wide association study (GWAS) in a European-American cohort of 343 isolated BA patients and 1716 controls to identify genetic loci associated with BA. A second GWAS was performed in an independent European-American cohort of 156 patients with BA and other extrahepatic anomalies and 212 controls to confirm the identified candidate BA-associated SNPs. Meta-analysis revealed three genome-wide significant BA-associated SNPs on 2p16.1 (rs10865291, rs6761893, and rs727878; P < 5 ×10-8), located within the fifth intron of the EFEMP1 gene, which encodes a secreted extracellular protein implicated in extracellular matrix remodeling, cell proliferation, and organogenesis. RNA expression analysis showed an increase in EFEMP1 transcripts from human liver specimens isolated from patients with either BA or other cholestatic diseases when compared to normal control liver samples. Immunohistochemistry demonstrated that EFEMP1 is expressed in cholangiocytes and vascular smooth muscle cells in liver specimens from patients with BA and other cholestatic diseases, but it is absent from cholangiocytes in normal control liver samples. Efemp1 transcripts had higher expression in cholangiocytes and portal fibroblasts as compared with other cell types in normal rat liver. The identification of a novel BA-associated locus, and implication of EFEMP1 as a new BA candidate susceptibility gene, could provide new insights to understanding the mechanisms underlying this severe pediatric disorder

A pilot study exploring the role of glucocorticoid receptor variants in primary biliary cirrhosis and primary sclerosing cholangitis

BACKGROUND: In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) significant therapeutic effects of glucocorticoids have not been documented. The most important clinical problem in patients with these diseases is fatigue, which is occasionally invalidating. Abnormalities in the hypothalamo-pituitary-adrenal axis have been suggested as a cause of fatigue. Most effects of glucocorticoids are mediated by the glucocorticoid receptor (hGR alpha). Recently a causative role for a splicing variant of the glucocorticoid receptor (hGR beta) has been proposed in glucocorticoid resistance in asthma and ulcerative colitis, whereas another splicing variant (hGR P) might be associated with glucocorticoid-resistant haematological malignancies. The aims of the present pilot study were to assess abnormalities in glucocorticoid receptor expression and to relate these abnormalities to the development of fatigue and to disease activity and severity in autoimmune cholestatic liver disease. METHODS: Five fatigued and five nonfatigued patients with PBC or PSC were included, and the results were compared with healthy controls. RESULTS: The expression of hGR P was not different from controls, but hGR beta mRNA was significantly increased (p=0.02) and hGR alpha mRNA decreased (p=0.015). There were no significant differences between fatigued and nonfatigued patients. A significant negative correlation between the serum activity of alkaline phosphatase and hGR alpha and hGR P mRNA was found. CONCLUSION: Although there was no relation with fatigue, abnormalities in hGR expression appear to occur in patients with these diseases, and may play a role in its pathophysiology and the poor response to glucocorticoid treatment