Liver transplantation for primary sclerosing cholangitis versus primary biliary cirrhosis: A comparison of complications and outcome

Abstract Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are the most common cholestatic disorders in adulthood requiring hepatic transplantation. Although they run similar courses, they may have different problems before and after transplantation. The aim of this study was to compare pre- and post-transplant complications and outcomes in these two similar but distinct patient groups. One hundred and seventeen adult patients underwent liver transplantation at our institution over a 6 year period, including 19 with PSC and 20 with PBC. Pre-transplant there were no significant differences in age, liver biochemistry, haematology or Child-Pugh scores between the two groups. The mean duration of disease before transplant was longer in PSC patients (11.7 vs 6.5 years; P < 0.05). The prevalence of septic cholangitis was greater in PSC (58 vs 5%; P < 0.01) as was the requirement for surgical or radiological interventional procedures, excluding cholecystectomy (53 vs 0%; P < 0.01). At transplantation, four patients with PSC had previously unrecognized cholangiocarcinoma. In the pre-transplant period these four patients had uncontrolled biliary sepsis at the time of transplant vs five of 15 PSC patients without cholangiocarcinoma. Postoperatively, PSC patients had a greater prevalence of intra-abdominal sepsis requiring surgical or radiological intervention (42 vs 5%; P < 0.05). In comparison, patients with PBC had a high prevalence of skeletal complications (30 vs 10%; P < 0.05) particularly avascular necrosis (15 vs 0%). The prevalence of chronic rejection was similar in both groups (15%). Overall survival was higher in PBC patients (85 vs 63%; P < 0.05). The prevalence of postoperative intra-abdominal sepsis requiring surgical or radiological intervention was higher in those patients with PSC who died (six of seven) compared to survivors (two of 12), (P < 0.001). Postoperative uncontrolled intra-abdominal sepsis directly contributed to more deaths in PSC patients (four of seven vs 0%). In conclusion, despite many similarities with PBC, PSC patients have higher prevalence of pre- and postoperative intra-abdominal sepsis that may contribute to poorer survival. In contrast PBC patients have excellent survival rates after a liver transplant, although bony complications are increased.     

Urinary bile acid sulfate levels in patients with primary biliary cirrhosis

Aim: Urinary bile acids are mainly conjugated with sulfuric acid. In a previous work, we demonstrated that the levels of urinary sulfated bile acids (USBA) and serum total bile acids (TBA) were correlated very well and also that USBA was considered to be a more useful indicator of hepatic fibrosis than TBA in patients with hepatitis C virus (HCV)‐related liver diseases. In the current study we aimed to confirm these finding in patients with primary biliary cirrhosis (PBC), a prototypic cholestatic liver disease. Methods: Urinary sulfated bile acids were measured using an automatic assay kit in 50 patients with PBC, of whom 11 were diagnosed as having cirrhosis. We obtained specimens before ursodeoxycholic acid (UDCA) administration in four patients, and during UDCA in 46 patients. The correlations between USBA and various laboratory tests were studied. Results: The median USBA level was 67.9 µmol/g creatinine in PBC; 27.7 without cirrhosis and 210.3 with cirrhosis (P = 0.001). The number of PBC patients with elevated USBA was significantly higher than those with elevated TBA (82% vs. 56%). This significance was remarkable especially in early stages, non‐cirrhotic patients (77% vs. 49%). USBA level was well correlated with TBA (r_s = 0.72), and negatively correlated with platelet (r_s = ?0.34) and albumin (r_s = ?0.31). Conclusion: Urinary sulfated bile acids and TBA are well correlated, and together with the findings that USBA is not affected by meals, USBA is considered to be more beneficial and convenient than TBA for earlier detection of fibrosis in PBC.     

Thyroid dysfunction in primary biliary cirrhosis,primary sclerosing cholangitis and non‐alcoholic fatty liver disease

Background/Aims: Primary biliary cirrhosis (PBC) is frequently associated with autoimmune diseases, including thyroid disease, although it is uncertain that this association is higher than in other liver diseases. Methods: We compared the prevalence and incidence of thyroid dysfunction (TD) in a series of patients with PBC (n=67) with patients with primary sclerosing cholangitis (PSC) (n=79) and non‐alcoholic fatty liver disease (NAFLD) (n=97) seen in a tertiary referral centre who had previously participated in clinical trials. Results: At initial evaluation, prevalence of TD in PBC was 13% compared with 11% in PSC (P=0.71) and 25% in NAFLD (P=0.08). Incidence of TD was 2.9 patients per 100 person‐years in PBC compared with 2.1 patients per 100 person‐years in PSC (P=0.57) and 1.8 patients per 100 person‐years in non‐alcoholic liver disease (P=0.45). Older age, female gender, biochemical abnormalities and concurrent autoimmune disorders were not predictive of the development of TD. Conclusions: TD was unexpectedly as common in patients with PBC as in patients with PSC and NAFLD, yet significantly more common than expected in the general population. Further investigation of thyroid disease in PSC and NAFLD is warranted.     

Aminoterminal propeptide of type III procollagen and hyaluronan in patients with primary biliary cirrhosis: Markers of fibrosis in primary biliary cirrhosis

The aminoterminal propeptide of type III procollagen (PIIINP) and hyaluronan have previously been studied in different liver diseases. The results of these studies are controversial. The aim of the present study was to examine the relationship between PIIINP and hyaluronan levels and the clinical, biochemical and histological features of primary biliary cirrhosis (PBC) and its prognosis. Fifty-five PBC patients were studied at the time of diagnosis of PBC and were followed up for a mean of 58 months. During the follow-up period 21 patients died. In addition, 30 healthy subjects were examined in the present study. Hyaluronan and PIIINP were measured by radioimmunoassay and the levels of both PIIINP and hyaluronan were higher in PBC patients than in healthy volunteers (P< 1.8 times 10^-6 and 1.6 times 10^-9, respectively). Hyaluronan and PIIINP levels were above normal values in 82 and 84% of PBC patients, respectively. There were correlations between PIIINP and hyaluronan and the histological stage of PBC (r=0.44, P< 0.004 and r=0.56, P< 0.00001, respectively). The correlation between PIIINP and hyaluronan was 0.46 (P< 0.0035). In symptomatic patients, both PIIINP and hyaluronan values were higher than in controls (P< 0.002 and P< 0.006, respectively). The levels of PIIINP correlated significantly with bilirubin (r=0.43, P< 0.006), while hyaluronan was correlated with age (r=0.33, P< 0.015), pruritus (r=0.32, P< 0.02), fatigue (r=0.41, P< 0.003), hepatomegaly (r=-0.46, P< 0.0008), the presence of oesophageal varices (r=0.34, P< 0.002), weight loss (r=0.29, P< 0.05), bilirubin (r=0.54, P< 0.0001), albumin (r=-0.30, P< 0.04), extent of fat excretion (r=0.53, P< 0.009) and length of symptomatic period before diagnosis of PBC (r=0.43, P< 0.002). Using Cox's logistic regression analysis, survival was found to be influenced by bilirubin concentration but not by hyaluronan, PIIINP, age, albumin or histological stage. Therefore, hyaluronan is a more sensitive marker for predicting advanced PBC than is PIIINP. However, neither hyaluronan nor PIIINP gave any indication of prognostic outcome.     

Lack of evidence for involvement of fetal microchimerism in pathogenesis of primary biliary cirrhosis

Microchimerism may be involved in the etiopathogenesis of autoimmune diseases such as scleroderma. Primary biliary cirrhosis (PBC) shares some features with scleroderma, including a female predominance and a histologic picture reminiscent of chronic graft-versus-host disease. Our aim was to detect Y-chromosome-specific sequences as a marker for microchimerism in liver tissue of female patients with PBC. Liver biopsies of 105 female patients were investigated (28 patients with primary biliary cirrhosis, 25 patients with chronic hepatitis C, 6 patients with chronic hepatitis B, 9 with autoimmune hepatitis, and 37 patients with other liver diseases) by a sensitive Y-chromosome-specific polymerase chain reaction and/or fluorescence in situ hybridization (FISH) technique for the detection of the Y chromosome on a single cell level. In the liver of 9 (8.6%) female patients Y-chromosome-specific sequences were detected by PCR. Five of the patients had PBC as underlying disease, 2 had chronic hepatitis C, and 2 other liver diseases. No significant difference in the positivity rate for Y-specific sequences in females with PBC and patients with other liver diseases was found (P > 0.05). By FISH, single cells with one Y chromosome were detected in liver specimens from 3 of 21 patients suffering from PBC and from 1 of 13 patients with other liver diseases. In summary, microchimerism can be detected in livers of patients with hepatic diseases. However, in our study we found no evidence for an increased prevalence of microchimerism in the livers of patients with primary biliary cirrhosis. Our data suggest that microchimerism does not play a significant role in the development of PBC.     

The gut microbial influence on cholestatic liver disease

Patients with cholestatic liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) have a different gut microbiome composition than healthy controls. In contrast with PBC, PSC has a strong association with inflammatory bowel disease and is the prototypical disease of the gut‐liver axis. Still, there are some distinct overlapping microbial features in the microbiome of patients with PSC and PBC suggesting similarities in cholestatic diseases, although the possible pathogenetic involvement of these shared microbial changes is unknown. Herein, we present an overview of the available data and discuss the relevance for potential disease relevant host‐microbiota interactions. In general, the microbiome interacts with the host via the immunobiome (interactions between the host immune system and the gut microbiome), the endobiome (where the gut microbiome contributes to host physiology by producing or metabolizing endogenous molecules) and the xenobiome (gut microbial transformation of exogenous compounds, including nutrients and drugs). Experimental and human observational evidence suggest that the presence and functions of gut microbes are relevant for the severity and progression of cholestatic liver disease. Interestingly, the majority of new drugs that are currently being tested in PBC and PSC in clinical trials act on bile acid homeostasis, where the endobiome is important. In the future, it will be paramount to perform longitudinal studies, through which we can identify new intervention targets, biomarkers or treatment‐stratifiers. In this way, gut microbiome‐based clinical care and therapy may become relevant in cholestatic liver disease within the foreseeable future.     

Increased intercellular adhesion molecule-1 serum concentration in cholestasis

Background/Aims: Increase of serum levels of the soluble intercellular adhesion molecules in patients with the cholestatic liver diseases primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are known and have been thought to indicate activation of the immune system and the grade of the inflammatory process. In hepatitis and cholestatic diseases, expression of adhesion molecules was found on the surface of bile duct epithelia and hepatocytes.Materials and Methods: Serum levels of sICAM-1 in patients with intrahepatic cholestasis in PBC (n=42) and extrahepatic cholestasis (n=18) due to choledocholithiasis were investigated. sICAM-1 levels and “classical” cholestasis parameters as alkaline phosphatase (ALP), γ-glutamyl-transpeptidase (γ-GTP) and bilirubin levels were compared. Furthermore, sICAM-1 concentrations and “classical” cholestasis parameters were analysed before and after therapy with ursodeoxycholic acid (UDCA). In addition, sICAM-1 was detected in serum and bile fluid of four patients with cholestasis due to choledocholithiasis. Soluble ICAM-1 levels in sera and, if accessible, in bile fluids were determined using a commercially available ELISA system. Statistics were done by Wilcoxon's signed rank exact test and Spearman's rank correlation test. Sensitivity and specificity of cholestasis parameters and sICAM-1 concentrations was analysed by receiver operating characteristic (ROC) curves.Results: Increased sICAM-1 serum concentrations in a similar range were found in patients with PBC (range 251–2620 μg/l; median 966 μg/l) as well as in patients with extrahepatic cholestasis (257–2961 μg/l; median 760 μg/l) compared to healthy controls (n=12; 220–500 gmg/l; median 318 μg/l). sICAM-1 levels correlated significantly to histological stage I to IV (p<0.001), ALP (range 107–1877 U/l; median 545 U/l; r=0.496, p=0.0008), bilirubin (range 0.3–26 mg/dl; median 0.8 mg/dl; r=0.52; p<0.0004) and γ-GTP levels (range 43–705 U/l; median 221 U/l; r=0.36; p=0.02) in PBC patients. In PBC patients a histological stage III or IV (n=21) could be predicted with high sensitivity (95%) and specificity (85%) if sICAM-1 levels were above 840 μg/l. After treatment of PBC patients with UDCA, sICAM-1 levels decreased significantly with decline of other “classical” cholestasis parameters. Increased sICAM-1 levels (range 257–2961, median 745 μg/l) in extrahepatic cholestasis correlated also significantly with serum concentrations of bilirubin (r=0.8; p<0.01; range 0.3–19.7, median 1.6 mg/dl), γ-GTP (r=0.55; p=0.03; range 33–1401, median 179 U/l) and ALP (r=0.61; p=0.1; range 110–1378, median 562 U/l). sICAM-1 2as detectable in bile fluid (264–919 μg/l) of four patients with extrahepatic cholestasis and nose-biliary catheterisation.Conclusions: sICAM-1 concentrations were found to discriminate between histological stage I/II and stage III/IV of PBC with higher sensitivity and specificity than “classical” cholestasis parameters. Increased serum concentrations for sICAM-1 in intra- and in extrahepatic cholestasis and detection of sICAM-1 in the bile may indicate that sICAM-1 is eliminated through the bile. In other words, not only increased synthesis but also decreased elimination may be responsible for increased sICAM-1 serum levels in patients with cholestatic liver diseases.     

Single or multiple dose ursodeoxycholic acid for cholestatic liver disease: biliary enrichment and biochemical response

Background: Ursodeoxycholic acid (UDCA) improves liver biochemistry in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Since UDCA acts partly by reducing the intestinal absorption of hydrophobic endogenous bile salts and is poorly absorbed from the intestine, a multiple dose regimen has been advocated. Single dose treatment, on the other hand, may improve compliance.Aim: The effects of a single or multiple dose regimen on liver enzymes and serum and biliary bile salts composition were evaluated.Methods: Twenty-seven patients (19 PSC, 8 PBC), most with early stage disease, received UDCA (10 mg kg⁻¹ day⁻¹) in a single dose at bed time (n=13) or in three divided gifts with meals (n=14) over 3 months. Five patients had both treatment regimens in random order with a 1-month wash-out period in between.Results: Liver biochemistry equally improved in both groups. Biliary enrichment (% UDCA of total bile salts, mean±SEM) was 40.1±2.4 in the single dose group vs 40.8±2.8 in the multiple dose group (p=NS) and was positively correlated with biochemical improvement (AP: r=0.47, p=0.02; GGT: r=0.58, p=0.002; ASAT: r=0.67, p=0.002; ALAT: r=0.52, p=0.01). Biochemical improvement was not correlated with the concentration or %UDCA in serum. Patients participating in the cross-over design had comparable biochemical response and biliary %UDCA during both regimens.Conclusion: Single and multiple dose UDCA have similar effects on liver biochemistry and biliary enrichment in cholestatic liver disease. Biochemical improvement appears to be related to biliary (but not serum) enrichment with UDCA.     

Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic progressive cholestatic diseases that frequently lead to biliary cirrhosis. The exact pathogenesis of these diseases remains elusive but is likely immunologically based. Complications range from fatigue and pruritus to end-stage liver disease. The risk of developing hepatocellular carcinoma is low for patients with PBC, whereas cholangiocarcinoma is common in PSC and carries an ominous prognosis. Although ursodeoxycholic acid is effective in slowing the progression of PBC, no effective medical therapy exists for PSC. Liver transplantation is the only option for patients with end-stage liver disease and yields excellent long-term survival in both groups.     

Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic progressive cholestatic diseases that frequently lead to biliary cirrhosis. The exact pathogenesis of these diseases remains elusive but is likely immunologically based. Complications range from fatigue and pruritus to end-stage liver disease. The risk of developing hepatocellular carcinoma is low for patients with PBC, whereas cholangiocarcinoma is common in PSC and carries an ominous prognosis. Although ursodeoxycholic acid is effective in slowing the progression of PBC, no effective medical therapy exists for PSC. Liver transplantation is the only option for patients with endstage liver disease and yields excellent long-term survival in both groups.     

Natural history and prognostic factors of primary biliary cirrhosis in Taiwan: a follow‐up study up to 18 years

Purpose: The natural history of primary biliary cirrhosis (PBC) has been little studied in Asia. We conducted a Taiwanese cohort study on the natural history of PBC and analysed the prognostic factors. Methods: This study enrolled 96 consecutive PBC patients between 1985 and 2006 to evaluate the baseline characteristics and outcomes. Results: There were 74 females and 22 males. Eighty‐five were positive for antimitochondrial antibodies in sera, and 11 were negative. The clinical manifestations and prognosis were similar between these two groups. In a median follow‐up of 47.5±55.8 months, 27 patients died. Multivariate analysis indicated that the independent prognostic factors were serum albumin (P=0.021), creatinine (P=0.033) and ursodeoxycholic acid treatment (P=0.008). Besides, 42 patients developed adverse outcomes. Albumin (P<0.001), bilirubin (P=0.019) and prothrombin time (PT) (P=0.010) were significant factors. Moreover, a Mayo risk score <5, a Model for End‐Stage Liver Disease (MELD) score <6, a Child–Pugh stage A and early liver histology were associated with favourable outcomes. Conclusion: Serum albumin, bilirubin and PT were independent prognostic factors of adverse outcomes for Taiwanese PBC patients. Besides, the Mayo risk score, the MELD score, the Child–Pugh stage and liver histology were also validated to predict survival.     

Duplication of MER115 on chromosome 4 in patients with primary biliary cirrhosis

Background: Primary biliary cirrhosis (PBC) is a complex disease with genetic and environmental influences. The disease is more prevalent in families with PBC and candidate gene case–control studies have linked PBC with DRB1^*08 human leucocyte antigen class II alleles. Aims: The goal of this study was to characterize a MER115 intergenic region on chromosome 4 as a putative genetic variant associated with PBC. Methods/Results: This region was incidentally identified during investigations to discover candidate microbial agents using representational difference analysis (RDA) with liver samples from patients with PBC and primary sclerosing cholangitis (PSC). blast search analysis of all the RDA products from the PBC liver revealed genomic sequences, whereas Escherichia coli, mycoplasma and hepatitis B virus DNA were found in the PSC liver. We identified one of the PBC RDA products as an ancestral repeat, referred to as MER115. Southern blot analysis with the PBC product uncovered a restriction fragment length polymorphism in PBC patients' liver. Southern blot hybridization signal showed increased signal intensity in PBC vs. control patients' DNA (P<0.005) and slot blot hybridization studies confirmed a copy number variation of the MER115 in hepatic DNA of PBC vs. control patients (P=0.02). Conclusions: Further comparative genetic studies will be required to determine the extent of genomic duplication associated with MER115 and provide data on the possible copy number variants of genes close to this intergenic region in patients with PBC.     

Primary biliary cirrhosis is associated with oxidative stress and endothelial dysfunction but not increased cardiovascular risk

Aim: Primary biliary cirrhosis (PBC) is a chronic cholestatic disease which is associated with hypercholesterolaemia. Further, cholestatic diseases are associated with deficiencies of anti‐oxidant vitamins. Despite these associations PBC is not associated with an increase in cardiovascular mortality. The aim of this study is to assess if primary biliary cirrhosis is associated with oxidative stress, endothelial dysfunction and alteration of vascular compliance which is a surrogate marker for cardiovascular risk. Methods: Fifty‐one PBC patients and 34 control subjects were studied. Lipid soluble vitamins A, and E in addition to ascorbate and carotenoids were measured to assess anti‐oxidant status. C‐reactive protein, hydroperoxides and adhesion molecules sICAM‐l/sVCAM‐l were assessed as serological measures of endothelial function. Finally, measures of vascular compliance were assessed by applanation tonometer. Results: CRP, sICAM and sVCAM were all significantly higher in PBC patients (469.14 vs 207.13, P < 0.001; 768.12 vs 308.03,P < 0.001; 708.40 vs 461.31, P < 0.001) whilst anti‐oxidant vitamin levels were lower in PBC patients, with ascorbate, vitamin E and vitamin A all significantly lower in PBC patients (39.91 vs 72.68, P < 0.001; 2.63 vs 3.14, P = 0.02; 1.08 vs 1.81, P < 0.001). Despite these findings PBC patients have a lower pulse wave velocity than control subjects (8.22 m/s vs 8.78 m/s, P = 0.022). Conclusion: PBC patients appear to have reduced vascular risk as assessed by pulse wave velocity but concurrently have evidence of endothelial dysfunction, inflammation and anti‐oxidant deficiency.     

Platelet function rather than plasmatic coagulation explains hypercoagulable state in cholestatic liver disease

BACKGROUND/AIMS: As compared to other chronic liver diseases, cholestatic disorders are associated with a better outcome of variceal bleeding and less blood loss at transplantation, suggesting the presence of a hypercoagulable state. We have assessed plasmatic coagulation and platelet function in patients with cholestatic and non-cholestatic liver disease. METHODS: Thirty-seven patients with chronic cholestatic liver disease (primary biliary cirrhosis (PBC)/primary sclerosing cholangitis (PSC)), 53 patients with chronic hepatitis C (HCV) or alcoholic cirrhosis (C2), and 62 healthy controls were studied. RESULTS: Thrombelastography revealed a hypercoagulable state in non-cirrhotic patients with PBC/PSC, but not in those with HCV (ma-value: 6.54[6.25-6.92, 95%CI] vs. 5.39[5.11-5.58], P < 0.05) possibly due to higher fibrinogen levels in PBC/PSC patients (369[329-418]mg/dl vs. 263[250-275]mg/dl, P < 0.05). PFA-100 closure time was prolonged in HCV/C2 patients with advanced cirrhosis, but not in cirrhotic patients with PBC/PSC (Child B; epinephrine stimulation: 192[161-229]s vs. 132[105-158]s, P < 0.05). Flow cytometric studies of platelet receptors and granules revealed a higher surface expression of CD42b (112[105-119]% vs. 100[95-104]%, P < 0.05) and LIBS-1 (261[184-348]% vs. 121[92-145]%, P < 0.05) in patients with PBC/PSC than in those with HCV/C2. CONCLUSIONS: These results indicate that platelet function differs between patients with cholestatic and non-cholestatic liver disease and is stable or even hyperactive in patients with PBC and PSC.     

Fatigue measurements in patients with primary biliary cirrhosis and the risk of mortality during follow‐up

Background: Fatigue was recently suggested to predict an increased risk of mortality in a primary biliary cirrhosis (PBC) cohort during follow‐up. Aims: To analyse the impact of fatigue on prognosis in PBC. Methods: Patients with PBC who had earlier completed the fatigue impact scale (FIS) were identified. Prognosis in terms of death and liver transplantation (Tx) was determined. Results: FIS values at baseline were analysed from 208 patients (192 females; median age 59 years (interquartile range 51–67), median follow‐up of 5 years. Overall, 181 patients were alive at follow‐up, 22 (12%) died and five (2.4%) underwent transplantation. FIS at baseline was 28 (12–47) and FIS at follow‐up was 25 (8–64) (P<0.001; r=0.69). Among survivors, FIS at baseline was 27 (12–43), 36 (12–72) in those who died (P=0.059) and 99 (41–102) in those who underwent transplantation (P=0.0008). FIS at baseline was 44 (12–88) in patients with death and/or Tx vs. 27 (12–43) in survivors (P=0.003). Age [hazard ratio (HR) 1.1 (confidence interval (CI) 1.0–1.2)] and aspartate aminotransferase [HR 2.0 (CI 1.3–3.0)] were independently associated with decreased survival on multivariate analysis. FIS scores over 40 [HR 9.6 (CI 2.3–39.7)] and bilirubin [HR 4.8 (CI 2.8–8.2)] were independently associated with a poor outcome in patients who underwent Tx or had a liver‐related death. Conclusions: Fatigue seems to change little over time in PBC. Fatigue levels were higher at baseline in those who died or underwent Tx. High fatigue levels seem to be a predictor of risk of liver‐related mortality and need for transplantation over time but not a predictor of non‐liver‐related mortality.     

Localisation and semiquantitative assessment of hepatic procollagen mRNA in primary biliary cirrhosis

Background—Chronic liver disease ischaracterised by excessive deposition of collagen and otherextracellular matrix proteins, produced mainly, but not exclusively, byactivated hepatic stellate cells in the perisinusoidal space. Inprimary biliary cirrhosis (PBC) fibrosis is concentrated mainly aroundthe portal tracts.
Aims—To examine the hypothesisthat, in addition to hepatic stellate cells, portal tract fibroblastsmight play a significant role in the deposition of collagen in PBC.
Methods—Fifty liver biopsyspecimens from patients with PBC were studied. An in situ hybridisationtechnique was adapted to localise and measure semiquantitatively type Iprocollagen mRNA in formalin fixed, paraffin wax embedded sections,using an ³⁵S labelled cRNA probe specific for theα₁ chain of rat type I procollagen. Hepatic fibrogenicactivity was also assessed using serum type III procollagen peptide (PIIINP).
Results—In PBC, type I procollagengene expression was significantly increased. Signal was localisedmainly in and around inflamed portal tracts, to cells which had theappearances of portal fibroblasts. Signal activity in these cellscorrelated with the degree of portal fibrosis and inflammation and alsowith serum PIIINP concentrations.
Conclusions—Results are consistentwith the hypothesis that the excessive extracellular matrix, depositedwithin the liver in PBC, is synthesised not only by hepatic stellatecells but also by portal tract fibroblasts. The semiquantitativeassessment of procollagen mRNA in liver biopsy specimens may provide auseful method of evaluating the rate of synthesis of collagen andtherefore disease activity in patients with PBC.

Keywords:in situ hybridisation; procollagen peptide; primarybiliary cirrhosis; hepatic fibrosis

     

Antimitochondrial antibody‐negative primary biliary cirrhosis: a subset of primary biliary cirrhosis

Objective: Antimitochondrial antibodies (AMA) are the hallmark in primary biliary cirrhosis (PBC); nevertheless, it has long been recognized that 5–10% patients with typical features compatible with PBC do not have detectable AMA, and they were referred to as ‘AMA‐negative PBC’. This study aimed to evaluate whether AMA‐negative/positive PBC represents different clinical entities. Methods: We compared the clinical, laboratory, percentage of regulatory T cells (Tregs) in peripheral blood, liver biopsy features and response to treatment of the two groups of patients. The first group was comprised of 12 patients with ‘AMA‐negative PBC’. The second was made up of another 12 PBC patients with positive AMA. Results: Antimitochondrial antibodies‐negative/positive patients were remarkably similar in terms of clinical manifestations, liver biochemistries and histological findings. The frequency of anti‐nuclear antibodies, anti‐smooth‐muscle antibody, anti‐gp210 and anti‐sp100 antibody showed no significant difference between the two groups. A significantly lower mean percentage of CD4⁺CD25^high T cells was observed in peripheral blood mononuclear cells of AMA‐negative/positive PBC patients compared with that of the 12 control subjects (5.8±1.8 and 5.4±1.4% vs. 7.6±1.7% respectively; P=0.014 and 0.004). However, no difference could be found between AMA‐negative and AMA‐positive PBC patients (P=0.599). After 1 year treatment with ursodeoxycholic acid, the two groups showed similar response. Conclusion: Antimitochondrial antibody‐negative/positive PBC patients are similar in clinical, laboratory, percentage of Treg in peripheral blood, liver biopsy features and response to treatment. This suggests that AMA‐negative PBC may be a variant of AMA‐positive PBC rather than a separate clinical entity.     

Deposition of C3, the terminal complement complex and vitronectin in primary biliary cirrhosis and primary sclerosing cholangitis

ABSTRACT— Characteristics of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are bile duct destruction and portal inflammation. Increased levels of circulating complement activation products are also present. This raises the possibility of involvement of complement-dependent cytotoxic mechanisms in the pathogenesis. Therefore, we investigated liver biopsy specimens from 21 patients with PBC, six patients with PSC and six controls for complement deposits by immunohistochemistry using polyclonal and monoclonal antibodies against C3d, the terminal complement complex (TCC) and vitronectin (S-protein). We found C3d, TCC and vitronectin deposits only in the portal tracts. C3d and TCC were present in the walls of the hepatic arteries and in the connective tissue stroma but never around the bile ducts. We found vitronectin deposits throughout the connective tissue, often independent of the TCC deposits. When vitronectin and TCC were co-localized, the staining patterns were inverse; that is, intense staining for TCC accompanied weak staining for vitronectin and vice versa. Occasionally complete dissociation between TCC and vitronectin staining was observed. Deposits of TCC and vitronectin showed a focal distribution leaving many portal tracts free of TCC. Our results question whether complement-dependent cytotoxic mechanisms take part in the bile duct destruction in PBC and PSC.     

Clinical features of symptomatic primary biliary cirrhosis initially complicated with esophageal varices

Background Esophageal varices (EV), one feature of portal hypertension, have been regarded as a late complication of liver diseases. However, accumulating evidence indicates that EV sometimes develop early during the course of primary biliary cirrhosis (PBC). The prognosis is usually poorer for patients with symptomatic PBC than for those with asymptomatic PBC. Nevertheless, the clinical features and prognosis of patients with PBC whose initial symptoms are EV have not been clarified. Methods The clinical features and the prognosis of patients who initially developed EV without other symptoms (v-PBC) were retrospectively investigated in 54 patients with symptomatic PBC. Results The leukocyte and platelet counts were lower in patients with v-PBC than in those with PBC accompanied by other symptoms (s-PBC). Liver function tests, autoantibodies, and histological stage did not differ between patients with v-PBC and those with s-PBC. Although the prognosis did not differ, the incidence of hepatocellular carcinoma was significantly higher in v-PBC than in s-PBC (P = 0.0037). Conclusions These data indicate that v-PBC is a hypercarcinogenic state and constitutes a new subgroup of PBC.     

Estrogen-progestogen therapy for low bone mineral density in primary biliary cirrhosis

Abstract: Aims/Background: Patients with primary biliary cirrhosis (PBC) often have osteoporosis of the high-turnover type, suggesting that estrogen could have a beneficial effect. However, the cholestatic potential of estrogen could imply a risk of increased cholestasis in a disease characterized by cholestasis. The aim of the present study was to test whether hormone replacement therapy (HRT) could be used to increase bone mineral density (BMD) in PBC patients with osteoporosis, without causing deterioration of the liver function. Methods: Nine female PBC patients with osteoporosis and one with osteopenia were offered HRT for two years. The change in BMD was compared to the change in ten age-matched female PBC patients who had less severe or no osteopenia and who did not receive HRT. Liver function tests were checked at six-month intervals. Results: HRT patients showed a statistically significant increase in lumbar spine BMD and total body BMD whereas control patients showed a significant decrease in lumbar and total body BMD. In contrast to the controls, HRT patients also showed a decrease in truncal fat (–3.8%). Neither of the groups showed any statistically significant changes in the liver function tests. Conclusions: HRT is safe and effective in female PBC patients with osteoporosis.