Idiopathic adulthood ductopenia. A cause of chronic cholestatic liver disease and biliary cirrhosis

We describe three adult patients who had chronic cholestatic liver disease associated with unexplained loss of interlobular bile ducts; two of these patients eventually required orthotopic liver transplantation. We have named this condition 'idiopathic adulthood ductopenia' because (1) the etiology is unknown, (2) the age of the patients may be the only distinguishing feature between this newly described condition and neonatal or infantile nonsyndromatic paucity of intrahepatic bile ducts, and (3) morphologic demonstration of ductopenia is an indispensable finding. Our three patients, all males, had a negative drug history, absence of antimitochondrial antibodies, normal cholangiographic findings, and no evidence of inflammatory bowel disease. Idiopathic adulthood ductopenia may be a representation of (1) late onset of infantile paucity of intrahepatic bile ducts, (2) destructive viral cholangitis, and (3) isolated small-duct primary sclerosing cholangitis - that is, 'pericholangitis' unassociated with inflammatory bowel disease.     

原发性硬化性胆管炎的诊断和治疗

原发性硬化性胆管炎（PSC）是一种以胆管的进行性炎症、纤维化和多发性狭窄为主要病理特征的慢性胆汁淤积性肝病,其发病可能与遗传及免疫机制有关,其病变范围可累及肝内和肝外胆管。部分患者具备典型的胆汁淤积表现和PSC的组织学特征,但胆管造影正常,称为小胆管PSC。PSC的病程多呈慢性进行性,最终演变为终末期肝病。60%～80%的PSC患者可并发炎症性肠病,约20%的患者还可并发胆管癌。目前针对PSC的治疗,除肝移植外尚无确切有效的治疗方法     

Ursodeoxycholic acid treatment of vanishing bile duct syndromes

Vanishing bile duct syndromes (VBDS) are characterized by progressive loss of small intrahepatic ducts caused by a variety of different diseases leading to chronic cholestasis, cirrhosis, and premature death from liver failure. The majority of adult patients with VBDS suffer from primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA), a hydrophilic dihydroxy bile acid, is the only drug currently approved for the treatment of patients with PBC, and anticholestatic effects have been reported for several other cholestatic syndromes. Several potential mechanisms of action of UDCA have been proposed including stimulation of hepatobiliary secretion, inhibition of apoptosis and protection of cholangiocytes against toxic effects of hydrophobic bile acids.     

Manifestation late in life of idiopathic adulthood ductopenia

Abstract: Idiopathic adulthood ductopenia is a chronic cholestasic liver disease of unknown etiology characterized by the loss of interlobular bile ducts. We describe three patients who fulfilled the diagnostic criteria of idiopathic adulthood ductopenia, but differed from the cases reported so far in late manifestation of the disease and a benign clinical course despite histologic evidence of ongoing cholangitis. Treatment with ursodeoxycholic acid in one patient resulted in improvement of biochemical markers of cholestasis, suggesting that chronic cholestasis in idiopathic adulthood ductopenia can be influenced beneficially.     

Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis

Tight junctions (TJ) of biliary epithelial cells (BEC) and hepatocytes prevent bile regurgitation from the biliary tract. Alterations in these TJs may participate in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). We examined the localization of 2 TJ proteins, ZO-1 and 7H6, in these diseases. Frozen sections from livers of PBC, PSC, extrahepatic cholestasis (Ex-C), and hepatitis C-associated cirrhosis (LC-C), as well as histologically normal livers, were processed for double-fluorescence immunohistochemistry. In controls and cirrhosis, 7H6 and ZO-1 colocalized surrounding the luminal space of the bile ducts and outlined the bile canalicular spaces between hepatocytes. In untreated PBC, immunostaining for ZO-1 in BEC of bile ducts 40 to 80 microm in diameter was preserved, but that for 7H6 was diminished to absent. In PBC treated with ursodeoxycholic acid (UDCA), immunostaining for 7H6 was well preserved. In PSC as well as in Ex-C, immunostaining for both 7H6 and ZO-1 was well preserved in bile ducts. In hepatocytes, ZO-1 showed preserved immunoreactivity, but immunostaining for 7H6 frequently disappeared. The percentage of bile ducts with immunostaining for 7H6 in all bile ducts with immunostaining for ZO-1 was significantly reduced in PBC compared with that in control, LC-C, Ex-C, and PSC (all P <.0001). Substantial alteration in the TJ protein occurs predominantly in bile ducts in PBC and in hepatocytes in PSC, suggesting increased paracellular permeability along different paracellular routes for bile regurgitation in these chronic cholestatic liver diseases.     

Idiopathic adulthood ductopenia: case report and review of the literature

The clinical and pathological findings of idiopathic ductopenia were studied in a 30-year-old woman who initially manifested jaundice and pruritus. Serum biochemical tests of liver function indicated severe and progressive cholestasis. Viral hepatitis markers and circulating autoantibodies were absent. The patient had a normal cholangiogram and lacked evidence of inflammatory bowel disease. Histological examination of a liver specimen showed severe cholestasis and absence of interlobular bile ducts. Severe jaundice and intractable pruritus developed in the patient and served as the indications for liver transplantation 4 months after initial examination. Transplantation resulted in prompt and complete resolution of the jaundice and pruritus. Two types of idiopathic adulthood ductopenia associated with different prognoses are recognized. Patients with type 1 idiopathic adulthood ductopenia are asymptomatic or manifest symptoms of cholestatic liver disease. They tend to have less destruction of the intrahepatic bile ducts on liver biopsy specimens. Their clinical course ranges from spontaneous improvement to progression to biliary cirrhosis. In contrast, patients with type 2 idiopathic adulthood ductopenia generally manifest initial symptoms of decompensated biliary cirrhosis, have extensive destruction of the intrahepatic bile ducts on liver biopsy, and frequently require orthotopic liver transplantation.     

Is routine cholangiography useful in men with suspected primary biliary cirrhosis?

The aim of this study was to assess the diagnostic value of cholangiography in men with chronic cholestasis and positive antimitochondrial antibody (AMA) titers who were suspected of having primary biliary cirrhosis (PBC). The authors reviewed retrospectively the records of men who had positive AMA titers over a 16-month period to determine the results of cholangiography. They also reviewed the records of 102 patients with primary sclerosing cholangitis (PSC) from 1989 to 1995 who had undergone cholangiography and testing for AMA. Of 35 men with positive tests for serum AMA, 12 of these patients were referred for cholangiography (11 endoscopic and 1 transhepatic). All completed cholangiograms were normal. A diagnosis of PBC was made in nine patients and atypical autoimmune hepatitis in one. Conversely, only two PSC patients had positive AMA titers (1:20 and 1:80). Both of these patients had coexisting inflammatory bowel disease and cholangiograms diagnostic of PSC. Cholangiography was negative in the male patients with positive AMA titers who were suspected of having PBC. In men with cholestatic liver biochemistries and strongly positive AMA titers, especially in the absence of associated inflammatory bowel disease, routine cholangiography does not add to the diagnostic evaluation.     

Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by inflammatory destruction of small bile ducts. Primary sclerosing cholangitis (PSC) is a different, presumed autoimmune cholestatic liver disease where the bile ducts are also destroyed. In this study, apoptosis and portal triad inflammation in liver tissue from patients with PBC is examined and compared to that from patients with PSC and patients with normal liver. METHODS: Explanted liver tissue from patients with PBC and PSC and normal liver from patients with metastases to liver were examined. The liver samples were stained for apoptosis using the terminal deoxynucleotidyl triphosphate (TdT)-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay. The biliary epithelial cells (BEC) were then scored on the basis of their TUNEL stain and the degree of periductal inflammation. RESULTS: In PBC, apoptosis of BEC, as detected by the TUNEL assay, was significantly increased in the presence of inflammation. Regardless of the presence or absence of inflammation, the small bile ducts in PBC liver tissue exhibited greater evidence of apoptosis than did similar ducts from PSC or control livers. CONCLUSION: These findings suggest that in PBC, unlike PSC, the apoptosis of BEC in PBC is secondary to the invasion of inflammatory cells.     

Are bile duct lesions of primary biliary cirrhosis distinguishable from those of autoimmune hepatitis and chronic viral hepatitis? Interobserver histological agreement on trimmed bile ducts

Background Primary biliary cirrhosis (PBC) is histopathologically characterized by chronic nonsuppurative destructive cholangitis and ductopenia of interlobular bile ducts. Bile duct injury is also often encountered in chronic viral hepatitis (CVH) and in autoimmune hepatitis (AIH).Methods In this study, we performed interobserver agreement analysis on 90 injured bile ducts from liver specimens of PBC (17 cases), CVH (26 cases), and AIH (18 cases), with 30 bile ducts chosen from each disease group. Digital images of bile ducts with minimal periductal elements were recorded in CD-ROM format and sent to 14 observers (six special hepatopathologists, four local hepatopathologists, and four general pathologists). We analyzed the following issues: (1) diagnostic accuracy of PBC, based only on bile duct lesions; (2) classification of bile duct lesions in AIH cases as destructive cholangitis equivalent to PBC-associated injury, or not.Results The diagnostic accuracy of PBC cases with severe bile duct injuries was very high (over 80%), although the accuracy in cases with only mild bile duct injuries was low (50% or less). For AIH, each observer classified 9 of the 30 bile ducts, on average, as destructive cholangitis.Conclusions This study revealed that 66.9% of PBC cases could be diagnosed based on trimmed bile ducts alone. Bile duct injury similar to that in PBC could be encountered in AIH.     

Clinical implications of antimitochondrial antibodies in type 1 autoimmune hepatitis: a longitudinal study

BACKGROUND/AIMS: Autoimmune hepatitis (AIH) is a chronic liver disease characterized by the presence of antinuclear antibodies. However, antimitochondrial antibodies (AMA) and bile duct changes, which are the characteristics of primary biliary cirrhosis (PBC), can be detected in AIH patients. METHODOLOGY: Twenty patients with definite AIH were prospectively followed-up, and the serial changes in AMA profiles were determined. We also examined the correlations between these antibodies and histopathological findings in the liver. RESULTS: Of the 20 patients, 7 (35%) had bile duct injury, and 2 of these 7 patients also showed chronic nonsuppurative destructive cholangitis or ductopenia of interlobular bile ducts histopathologically. Serologically, 7 patients (35%) were positive for AMA at least once by immunoblotting during the follow-up periods. There were no significant differences in biochemical hepatobiliary indices, the presence of bile duct lesions, or the changes in biochemical profiles between AMA-positive and AMA-negative AIH patients during the follow-up periods. CONCLUSIONS: We confirmed that AMA and certain histopathological findings that are characteristics of PBC can be seen in some AIH patients. However, there was no significant correlation between AMA positivity and the histopathological findings in the liver, or biochemical hepatobiliary indices. Thus, the clinical implications of AMA in AIH patients remain unclear.     

Small-duct primary sclerosing cholangitis with hepatocellular carcinoma requiring liver transplantation

BACKGROUND:Primary sclerosing cholangitis(PSC)is a chronic progressive cholestatic liver disease,which usually affects young adults and is diagnosed by cholangiography.On a few occasions,the disease either starts in or exclusively involves the small intrahepatic bile ducts,referred to as small-duct PSC. METHODS:A 31-year-old man presented with severe hematemesis secondary to liver cirrhosis.Over a course of 8 years,his liver decompensated and required an orthotopic liver transplantation. In this report we d...     

Prim?r bili?re Zirrhose

Primary biliary cirrhosis (PBC) is characterized by immune-mediated destruction of small intrahepatic bile ducts and subsequent development of liver fibrosis and cirrhosis, occuring mainly in middle-aged women. PBC is diagnosed on the basis of a cholestatic serum enzyme pattern, elevated serum IgM, the presence of antimitochondrial antibodies (AMA) in serum directed against the E₂ subunit of the pyruvate dehydrogenase complex, and a ?florid bile duct lesion” of mid size intrahepatic bile ducts and bile duct paucity. The cholestatic serum enzyme pattern and serum AMA are mandatory for the diagnosis. PBC is frequently associated with other autoimmune disorders such as Sjögren’s syndrome, Hashimoto’s thyroiditis, and celiac disease. Early diagnosis and medical therapy with ursodeoxycholic acid aim to hinder progression of the disease toward cirrhosis. Additional medical treatments are under evaluation. Liver transplantation is an effective treatment of end-stage PBC.     

Autoimmune liver disease - are there spectra that we do not know?

Autoimmune liver diseases (AILDs) are common leading causes for liver cirrhosis and terminal stage of liver disease. They have variable prevalence among patients with liver disease and have two major clinical and biochemical presentations. Autoimmune hepatitis (AIH) is the typical example of hepatocellular AILD, but it can also be presented under a cholestatic pattern. AIH has a scoring diagnostic system and respond in most cases to the treatment with prednisolone and azathioprine. Primary biliary cirrhosis (PBC) is the second most common AILD, with a cholestatic presentation and characterized by positive antimitochondrial antibody (AMA). It has an excellent response and long term outcome with the administration of ursodeoxycholic acid (UDCA). Another AILD that is thought to be a variant of PBC is the autoimmune cholangitis, being a disease that has biochemical and histological features similar to PBC; but the AMA is negative. Primary sclerosing cholangitis (PSC) is a rare entity of AILD that has a cholestatic presentation and respond poorly to the treatment, with the ultimate progression to advance liver cirrhosis in most patients. Other forms of AILD include the overlap syndromes (OS), which are diseases with mixed immunological and histological patterns of two AILD; the most commonly recognized one is AIH-PBC overlap (AIH-PSC overlap is less common). The treatment of OS involves the trial of UDCA and different immunosuppressants. Here we present three case reports of unusual forms of chronic liver diseases that most likely represent AILD. The first two patients had a cholestatic picture, whereas the third one had a hepatocellular picture at presentation. We discussed their biochemical, immunological and histological features as well as their response to treatment and their outcomes. Then, we compared them with other forms of AILD.     

Overlap syndromes

In hepatology, the term overlap syndrome describes variant forms of the major hepatobiliary autoimmune diseases, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Patients with overlap syndromes present with both hepatitic and cholestatic biochemical and histological features of AIH, PBC, and/or PSC, and usually show a progressive course toward liver cirrhosis and liver failure without adequate treatment. AIH-PBC overlap syndromes have been reported in almost 10% of adults with AIH or PBC, whereas AIH-PSC overlap syndromes were found in 6 to 8% of children, adolescents, and young adults with AIH or PSC. A minority of patients may also show transition from stable PBC to AIH, AIH to PBC, or AIH to PSC, as documented by single case reports and small case series. Single cases of AIH and autoimmune cholangitis (antimitochondrial antibody-negative PBC) overlap have also been reported. Empiric medical treatment of AIH-PBC and AIH-PSC overlap syndromes includes anticholestatic therapy with ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine. In end-stage disease, liver transplantation is the treatment of choice.     

Autoimmune cholangitis within the spectrum of autoimmune liver disease

Autoimmune cholangitis is an idiopathic disorder with mixed hepatocellular and cholestatic findings. Our goal was to characterize the disease prospectively by application of uniform diagnostic criteria. Twenty patients were identified and compared with 242 patients with conventional forms of autoimmune liver disease. Patients with autoimmune cholangitis were distinguished from type 1 autoimmune hepatitis (AIH) by lower serum levels of aspartate transaminase (AST), gamma-globulin, and immunoglobulin G; higher serum levels of alkaline phosphatase; and lower frequencies of autoantibodies. They were distinguished from primary biliary cirrhosis (PBC) by higher serum levels of AST and bilirubin, lower serum concentrations of immunoglobulin M, and greater occurrence of autoantibodies. Their female predominance, lower serum alkaline phosphatase levels, higher frequency of autoantibodies, and absence of inflammatory bowel disease differentiated them from primary sclerosing cholangitis (PSC). Laboratory findings ranged widely and did not characterize individual patients. HLA risk factors were similar to those of type 1 AIH and PBC, and different from those of PSC. Treatment responses to corticosteroids or ursodeoxycholic acid were poor. Composite histological patterns resembled mainly PBC or PSC. We conclude that autoimmune cholangitis diagnosed by prospective analysis cannot be assimilated into a single, conventional, diagnostic category. It may represent variant forms of diverse conditions, a transition stage, or a separate entity with varying manifestations.     

Primär sklerosierende Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic progressive cholestatic disease leading to multiple strictures of the extra- and intrahepatic bile ducts and to biliary cirrhosis. The majority of patients are young men who also suffer from inflammatory bowel disease. The risk of cholangiocarcinoma and of colorectal cancer is significantly increased. PSC is diagnosed based on characteristic cholangiographic patterns with multifocal strictures and intervening segments of normal or dilated ducts, when secondary causes of sclerosing cholangitis have been excluded. The pathogenesis of PSC is elusive, and there is currently no causal therapeutic strategy. Ursodeoxycholic acid may be beneficial for a subgroup of PSC patients, and new innovative therapeutics are currently under evaluation in clinical trials. Endoscopic interventions are used and effective to dilate dominant bile duct strictures and useful to diagnose biliary malignancy. The only definitive therapy is liver transplantation. It offers excellent long-term outcome, when timing is right. However, in a subset of patients biliary strictures and also recurrent PSC can limit the posttransplant prognosis.     

Approaches to the pathogenesis of primary biliary cirrhosis through animal models

Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic liver disease of unknown etiopathogenesis that mainly affects middle-aged women. Patients show non-suppurative cholangitis with damage and destruction of the small- and medium-sized intrahepatic bile ducts. Characteristically, the disease is strongly associated with autoimmune phenomena such as the appearance of serum antimitochondrial autoantibodies (AMA) and portal infiltrating T cells against the inner lipoyl domain in the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Here we review the major characteristics of a series of inducible and genetically modified animal models of PBC and analyze the similarities and differences to PBC features in humans.     

Familial idiopathic adulthood ductopenia: a report of five cases in three generations

BACKGROUND/AIMS: Idiopathic adulthood ductopenia is a cholestatic liver disease of unknown etiology. Although most cases are sporadic, familial cases do occur. METHODS: We describe a series of adult-onset bile duct depletion involving five members of an extended family spanning three generations. The proband, a 49-year-old man, presented in 1989 with asymptomatic elevation of liver enzyme tests. Investigations for chronic liver disease, including endoscopic retrograde cholangiopancreatography, were negative. Findings on liver biopsy progressed from normal in 1989 to striking loss of interlobular bile ducts in 1992. Ursodeoxycholic acid has resulted in improvement of liver enzyme tests. The proband's brother required a liver transplant at age 35 for cryptogenic cirrhosis. The proband's sister, age 42, has had intermittent jaundice and elevation of liver enzyme tests since 1971. Her liver biopsy findings progressed from normal in 1975, to striking bile duct damage by 1997. The proband's 21-year-old son has elevated liver enzyme tests and a liver biopsy consistent with idiopathic adulthood ductopenia. The proband's father had a liver biopsy at age 70 for investigation of a liver mass. It revealed extensive fibrosis and striking bile duct destruction. RESULTS/CONCLUSIONS: This is the largest series of familial idiopathic adulthood ductopenia reported, and the first with multiple generations described. Genetics appears to play a role in some cases of adulthood ductopenia. Ursodeoxycholic acid may be beneficial in the treatment of this condition.     

Cholestatic liver diseases: slow progress in understanding and treating slowly progressive disorders

BACKGROUND: Cholestatic liver diseases are characterized by failure of normal amounts of physiological bile to reach the gastrointestinal tract. Any interference with normal bile flow from the canalicular membrane of the hepatocyte to the distal common bile duct may result in cholestasis. METHODS: Literature review. RESULTS: In primary biliary cirrhosis (PBC), the small intrahepatic bile ducts are destructed, resulting in obstruction of intrahepatic bile flow, whereas extrahepatic and/or intrahepatic biliary strictures block the passage of bile towards the intestine in primary sclerosing cholangitis (PSC). In contrast, the biliary tree is morphologically unaffected in less common cholestatic liver diseases as benign recurrent intrahepatic cholestasis (BRIC) and progressive familiar intrahepatic cholestasis (PFIC1-4). Genetic defects in hepatic canalicular transport mechanisms and bile salt synthesis deficiencies seem to underlie these types of cholestatic disorders. CONCLUSION: Recent advances in understanding and treatment of cholestatic liver diseases may help in better diagnosing and treating the various conditions characterized by cholestasis.     

Pathogenesis of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. The strong clinical association between PSC and inflammatory bowel diseases led to intriguing pathogenetic concepts, in which the inflamed gut with translocation of bacterial products and homing of gut-primed memory T lymphocytes via aberrantly expressed adhesion molecules plays a fundamental role. Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models ("toxic bile concept"). The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.