Chronic Cholestatic Disease Research Articles

P21 Therapeutic Efficacy of Plasmapheresis for the Treatment of Refractory Pruritis of Primary Billiary Cirrhosis: 2 Case Reports.

Primary billiary cirrhosis (PBC), a chronic cholestatic disease of presumed autoimmune aetiology, is characterised by progressive intrahepatic bile duct destruction, liver cirrhosis, failure, and death, unless treated by liver transplantation. Distressing pruritis (skin itch), fatigue and metabolic bone diseases frequently complicate this disease, significantly reducing quality of life. The pathogenesis of pruritis remains uncertain. Some unknown pruritogen(s) produced by the liver have been implicated which accumulate in the plasma as a result of chronic cholestasis. Recent evidence also suggests a central mechanism, with increased neurotransmission/neuromodulation mediated by endogenous opioid agonists. Therapeutic interventions include unabsorbable oral resins, urso‐deoxycholeic acid, opiate antagonists and rifampicin. More experimental therapies include: partial diversion of bile; charcoal haemoperfusion; UVA; plasmapheresis and albumin‐based dialysis (for patients with renal impairment). We used plasma exchange for the treatment of intractable pruritis in two patients with primary billiary cirrhosis. Both were females between ages of 50–60 years, refractory to all medical treatments and severely disabled by intractable pruritis and fatigue. In the first patient, weekly to fortnightly plasmapheresis considerably reduced the intensity of itch and stabilized her condition until her liver transplant. The second patient was treated for a relapse of PBC following her liver transplant. She significantly improved with more than 50% reduction in the intensity of her generalized itch with healing of excoriations, and was able to sleep for 4 h undisturbed after only one procedure. We suggest that plasmapheresis may be helpful for the pruritis of chronic cholestasis refractory to medical management. It could also be considered for the initial treatment of selected patients in combination with other therapies.

Cirrosis biliar primaria: experiencia de trece años en dos centros de referencia

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease, which can progress to hepatic failure. To study the clinical presentation, pathological features, treatment and outcome of a group of patients with PBC. Retrospective review of medical records of 115 patients (110 females, age range 30-76 years) with PBC. Clinical presentation, pathological stage, treatment, outcome and eventual use of liver transplantation, were recorded. Seventy eight percent of patients were symptomatic at presentation (itching in 69% and malaise in 62%). Antimitochondrial antibodies were positive in 56%. No clinical or laboratory differences were observed between symptomatic patients or those with positive antimitochondrial antibodies and the rest of the study group. Sjögren syndrome was present in 38%, hypothyroidism in 13%, scleroderma in 7% and rheumatoid arthritis in 5%. Initially, 61% had fibrosis and/or cirrhosis, and ursodeoxycholic acid was indicated in 94% of the patients. Fifteen patients underwent liver transplantation due to upper digestive bleeding or itching. Survival has been 67% at 36 months after transplantation. In one transplanted liver, PBC recurred. An early diagnosis and treatment of a progressive disease such as PBC will reduce the incidence of complications and the use of costly treatments.

Measurement of parenchymal function and bile duct flow in primary sclerosing cholangitis using dynamic 99mTc‐HIDA SPECT

Primary sclerosing cholangitis is a chronic cholestatic disease characterized by obliterative fibrosis of intrahepatic and/or extrahepatic bile ducts. The unpredictable clinical course of the disease can be relentless, leading to premature death in a large percentage of patients. Prognostic index formulas, the revised Mayo model being the most frequently used, have been developed to predict clinical course and prognosis. The aim of this study was to investigate the potential value of dynamic (99m)Tc-HIDA SPECT in patients with primary sclerosing cholangitis by correlating scintigraphic results with cholangiographic and biochemical findings and prognostic scoring systems used in clinical practice. In 18 patients with primary sclerosing cholangitis, segmental parenchymal and bile duct functions were measured using dynamic (99m)Tc-HIDA SPECT. Quantitative scintigraphic results were compared to cholangiographic findings, as graded by a biliary classification system, the Child-Pugh score and revised Mayo prognostic score, as well as the individual biochemical parameters included in the scoring systems. In individual segments, scintigraphic quantitative parameters indicative of bile flow showed a statistically significant correlation with the state of the bile-flow path for the respective segments as assessed by the biliary classification system. The revised Mayo score correlated with the scintigraphic quantitative parameters indicative of parenchymal function and bile flow as calculated for the whole liver. Dynamic (99m)Tc-HIDA SPECT, capable of assessing different aspects of liver function for the total liver, as well as for individual segments, has potential value in the management of patients with primary sclerosing cholangitis.

Recurrence of Primary Sclerosing Cholangitis in Patients After Liver Transplantation

Background Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease that progresses to end-stage liver disease. There are several specific problems related to the posttransplantation period in these patients. The aim of this study was to analyze a single center experience with 17 orthotopic liver transplantations (OLT) due to PSC. Patients and Methods Seventeen patients were included (10 men, 7 women). Actuarial patient and graft survival rates and the incidence of recurrent sclerosing cholangitis were determined at 1, 5, and 7 years. Results Fifteen patients received single grafts, whereas two patients required retransplants. Patients received either cyclosporine (n = 7) or tacrolimus (n = 10) based immunosuppression. The 1-, 5-, and 7-year patient survival rates were 80%, 60%, and 60%, respectively, whereas the graft survival rates were 88%, 65%, and 65%, respectively. Two patients had cholangiocarcinomas (CCA) diagnosed during OLT; both recurred within 6 months and had a fatal outcome. Two patients (12%) developed recurrent sclerosing cholangitis, as assessed by liver histology and imaging of biliary tree. Conclusions Liver transplantation provides good patient and graft survival rates in cases affected with PSC. CCA is associated with poor recipient survival. Recurrent PSC occurs in approximately 12% of cases but does not significantly affect patient survival.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease characterized by fibrosis leading to progressive stricturing of the biliary system. It was first described in 1874, but more than a century later, fewer than 100 cases had been reported. However, in the last 25 years the development of endoscopic and radiologic techniques allowed the diagnosis of PSC to be made without resort to surgery or postmortem examinations. This led to the realization that PSC was much more common than previously thought. Since 1980, more than 1500 articles on PSC have been published.

The Enigma of Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by a striking predominance in female patients (with most cases diagnosed between ages 40 and 60 yr) as well as serum auto-antibodies to mitochondrial antigens, elevated serum immunoglobulin M,progressive destruction of intrahepatic bile ducts, and, ultimately, liver cirrhosis and failure(1). The precise mechanisms leading to selective destruction of biliary epithelial cells lining intrahepatic bile ducts are still unknown, although numerous immunomediated pathways have been proposed. Genetic background appears to be important in determining susceptibility to the disease (2), but no clear association with alleles in the major histocompatibility complex has been identified. Molecular mimicry either by infections (3) or xenobiotics (4) has been proposed to be capable of breaking tolerance in genetically predisposed individuals, thus leading to onset of PBC. This article describes and discusses the available data regarding the immunomediated pathogenesis of PBC (with particular attention to auto-antibodies and autoreactive T-cells) and presents the recent evidence indicating a role for either xenobiotic chemicals or novel infectious agents in the induction of the disease.

Bupropion for fatigue and as a tumor necrosis factor-α lowering agent in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease which can often be severe, progressive and necessitate liver transplantation. The cause of PBC is not known, and treatments other than liver transplantation are often not effective. Among the more common and troublesome symptoms of PBC is fatigue. The etiology of fatigue in PBC is not well-understood, and there is no known treatment for it. Here, we suggest that for a number of reasons that the safe and commonly used oral antidepressant bupropion might be effective for fatigue in PBC: (1) increased monoaminergic and dopaminergic tone to combat fatigue, (2) treatment of concomitant depression, (3) in general for PBC as a tumor necrosis factor-α (TNF) lowering agent, if TNF is eventually found to play a role in PBC pathogenesis.

Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic inflammatory iver disease most commonly seen in middle—aged women. The cause is unknown but there is much evidence to support an autoimmune process, notably the strong (AMA).The disease has an association with the anti-mitochondrial antibodies insidious onset and patients with very early disease are usually only recognized,or elevated levels of serum alkaline following the incidental discovery of AMA phosphatase during screening for other disease Progression of the disease is slow but eventually many patients develop cirrhosis and ultimately death may of cirrhosis such as bleeding oeso-occur from liver failure or complications phageal varices. PBC was previously considered to be rare but recognition of cases earlier in the evolution of this chronic disease has allowed a more accurate of its incidence to be made. In northern Britain and Scandinavia PBC estimate of between 90 and 150 cases per 1000000 and in Europe it is has a prevalence now the most common indication for liver transplantation

Colchicine or Methotrexate Plus UDCA for Primary Biliary Cirrhosis: 10-Year Results

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease presumed to be of autoimmune origin. Ursodeoxycholic acid (UDCA), the only approved therapy, improves results of biochemical tests of liver function, but its long-term effect on survival is unclear. Initially, the authors of this 10-year, randomized trial intended to compare methotrexate with colchicine monotherapy for PBC, but when data about UDCA's efficacy became available after 2 years, UDCA (12-15 mg/kg per day) was administered to …

Options for Treatment of Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic disease where there is progressive, granulomatous destruction of the middle-sized bile ducts. The disease affects mainly middle-aged women. The association with other autoimmune diseases and the widespread disturbance of the humoral and cellular immune systems has led to the inclusion of PBC as an autoimmune disease. However, there are several lines of evidence that suggest that both host and environmental factors are implicated in triggering the disease. Without a clear aetiology, it is difficult to find a logical approach to treatment. Well constructed clinical trials are difficult to run because of the variable and long natural history of the disease; and suitable endpoints are difficult to define and validated surrogate endpoints have not been defined. The only drug licensed for use is the bile acid, ursodeoxycholic acid. This drug is associated with significant biochemical improvement and improvement in the immunological disturbances (including a reduction in the titre of the diagnostic autoantibody, antimitochondrial antibody), but the effect on survival and histological progression is still controversial. There is little effect on symptoms. Nonetheless, its safety and lack of toxicity have meant that it has become the drug of choice and most studies now assess the effect of additional treatments. Many other agents have been studied. There is some evidence, from prospective, controlled studies, for a beneficial effect of azathioprine and ciclosporin (cyclosporine); evidence for a beneficial effect of corticosteroids and of mycophenolate is limited and there is little firm evidence for a beneficial effect of methotrexate, penicillamine, thalidomide or colchicine. Other treatments being evaluated include fibric acid derivatives (fibrates), NSAIDs and leukotriene antagonists. Liver transplantation remains the only option for end-stage disease but recurrence of disease may be found in the graft. Experimental therapies include antiretroviral therapy. Symptomatic treatment is required for pruritus and the mainstays are the bile acid binding agents such as colestyramine. For those who are intolerant of the drug or where it is ineffective, rifampicin and naltrexone may be effective. There is no effective treatment for the associated lethargy.

540 Extensive homology between the major immunodominant mitochondrial antigen of primary biliary cirrhosis and helicobacter pylori does not lead to immunological crossreactivity

Background: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic disease characterized by the presence of antibodies directed predominantly against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). What provokes tolerance breakdown in PBC remains to be established, though there is evidence to indicate that microbes may induce anti-mitochondrial antibodies (AMA) through a mechanism of molecular mimicry. Methods: Having found that urease beta (UREB)22–36 antigen of Helicobacter pylori (HELPY) shares extensive (87%) similarity with PDCE2212–226, the major mitochondrial autoepitope, it was hypothesized that this would also lead to crossreactivity. The UREB/PDC-E2 mimics were thus constructed and tested by ELISA in 112 PBC patients and 114 controls. Results: Reactivity to PDC-E2212–226 was found in 104 patients but to UREB22–36 in only 2. In these two patients, the double reactivity was not cross-reactive. The lack of surface antibody accessibility to UREB22–36, as demonstrated through three-dimensional model prediction analysis, may explain this unexpected finding. There was some speculation on whether HELPY UREB22–36 might act as a cross-reactive CD4 T-cell epitope. All seven PBC patients, tested in a standard proliferation assay against PDC-E2212–226, gave a positive response. All seven were unresponsive to HELPY UREB22–36. The pattern of reactivity to HELPY antigens by immunoblot was similar between anti-PDC-E2-positive and negative PBC cases, as well as between PBC patients and controls. Conclusion: Contrary to common belief, extensive sequence homology (molecular mimicry) between self and microbe does not necessarily result in cross-reactivity. It is therefore likely that, when present, cross-reactivity between self and microbes is of biological importance.

Extensive homology between the major immunodominant mitochondrial antigen in primary biliary cirrhosis and Helicobacter pylori does not lead to immunological cross‐reactivity

Background: Primary biliary cirrhosis (PBC) is an immune‐mediated chronic cholestatic disease characterized by the presence of antibodies directed predominantly against the E2 subunit of the pyruvate dehydrogenase complex (PDC‐E2). What provokes tolerance breakdown in PBC remains to be established, though there is evidence to indicate that microbes may induce anti‐mitochondrial antibodies (AMA) through a mechanism of molecular mimicry. Methods: Having found that urease beta (UREB)22–36antigen of Helicobacter pylori (HELPY) shares extensive (87%) similarity with PDC‐E2212–226, the major mitochondrial autoepitope, it was hypothesized that this would also lead to cross‐reactivity. The UREB/PDC‐E2 mimics were thus constructed and tested by ELISA in 112 PBC patients and 114 controls. Results: Reactivity to PDC‐E2212–226was found in 104 patients but to UREB22–36in only 2. In these two patients, the double reactivity was not cross‐reactive. The lack of surface antibody accessibility to UREB22–36, as demonstrated through three‐dimensional model prediction analysis, may explain this unexpected finding. There was some speculation on whether HELPY UREB22–36might act as a cross‐reactive CD4 T‐cell epitope. All seven PBC patients, tested in a standard proliferation assay against PDC‐E2212–226, gave a positive response. All seven were unresponsive to HELPY UREB22–36. The pattern of reactivity to HELPY antigens by immunoblot was similar between anti‐PDC‐E2‐positive and negative PBC cases, as well as between PBC patients and controls. Conclusion: Contrary to common belief, extensive sequence homology (molecular mimicry) between self and microbe does not necessarily result in cross‐reactivity. It is therefore likely that, when present, cross‐reactivity between self and microbes is of biological importance.

Liver transplantation for primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease that progresses to end-stage liver disease. This report is a retrospective analysis of a Canadian centre experience with liver transplantation (LT) for PSC. Of 1107 LTs performed between 1984 and 2002, 132 were performed on 111 patients with PSC. Patient survival at 1, 3, 5, and 10 years was 84.5%, 84.5%, 83.4%, and 68.9%, respectively. Graft survival at 1, 3, 5, and 10 years was 80.8%, 79.8%, 72.7%, and 55.3%. These were not significantly different from overall patient survival ( P = .91) or graft survival ( P = .28) in non-PSC patients transplanted over the same time period. Early mortality was predominantly related to primary nonfunction and multi-organ failure; late mortality was predominantly related to malignancy. No patient with known cholangiocarcinoma (CCA) underwent LT, but three patients had an incidental CCA noted on explant pathology. All three died of widespread metastatic disease (10.8, 38.0, and 39.8 months after LT). Nineteen patients lost their primary grafts requiring retransplantation, and two of these patients required a third transplant. Recurrent PSC was detected in six patients and suspected in another six. Four patients have been retransplanted for recurrent PSC. Chronic rejection was detected in nine patients. Eight have required retransplantation. The incidence of biliary complications was 16.2%. Conclusions LT is effective therapy for PSC. Patient and graft survival is comparable to that seen in patients transplanted for indications other than PSC, but long-term graft survival may be lower. Recurrent PSC and chronic rejection are the major determinants of graft loss.

The management of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic hepatobiliary disease that usually progresses to biliary cirrhosis and liver failure; it also predisposes to cholangiocarcinoma. The cause of PSC is unknown, although evidence suggests that the tissue damage is mediated by the immune system. There is an unexplained close association between PSC and inflammatory bowel disease, particularly in ulcerative colitis, which coexists in the majority of patients with PSC. No medical therapy has been proven to halt or reverse disease progression; however, recent preliminary evidence suggests that ursodeoxycholic acid (UDCA) in a high dose of 20 to 25 mg/kg may slow the disease process. Evidence from a pilot study suggests that the combination of UDCA and immunosuppressive therapy, such as prednisolone or azathioprine, may also increase efficacy. For patients with end-stage PSC, liver transplantation remains the only effective therapy, although there is clear evidence that PSC may recur in the liver allograft.

Primary Biliary Cirrhosis and Fat-Soluble Vitamin Levels

Patients with chronic cholestatic liver disease, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis have decreased bile acid delivery

Sclerosing cholangitis

Primary sclerosing cholangitis is a chronic cholestatic disease that may have an autoimmune basis. Most patients have a circulating antineutrophil cytoplasmic antibody that appears to be targeted against a 50-kD nuclear envelope protein. The clinical applications of this antibody have not yet been defined. Other autoantibodies directed against antigens, such as cathepsin G, elastase, and anticardiolipin, may also be detected in some patients. It is suggested that primary sclerosing cholangitis may have a bacterial cause. Helicobacter gene sequences have been detected in liver tissues in primary sclerosing cholangitis. The role of Helicobacter spp and other bacteria in the etiopathogenesis of primary sclerosing cholangitis remains to be determined. Primary sclerosing cholangitis may overlap with autoimmune hepatitis in some cases, although the real prevalence of this association remains to be determined. Many prognostic models have been created, but they lack cross-validation, and their clinical usefulness remains limited. Endoscopic retrograde cholangiography remains the gold standard for diagnosis, but magnetic resonance imaging may be a viable alternative in many cases. Clinical trials with cladibrine, pentoxifylline, and budesonide have failed to demonstrate benefits. Orthotopic liver transplantation remains the only effective treatment.

Health-related quality of life in chronic liver disease: the impact of type and severity of disease.

The type and severity of chronic liver disease may have different effects on health-related quality of life (HRQL). The aim of our study was to determine whether HRQL in patients with chronic liver disease differs by type and severity of disease and to identify which clinical and physiological factors affect this impairment. In this study, HRQL was measured with a generic (Short Form 36) and a liver disease-specific (Chronic Liver Disease Questionnaire) questionnaire. Clinical, demographic, and laboratory data were collected at office visits. Patient's HRQL scores were compared with the published norms and to the chronically ill populations. A total of 353 patients (mean age 50 yr, 51% men) with chronic liver disease, either viral disease (hepatitis B and C), cholestatic disease (primary biliary cirrhosis or primary sclerosing cholangitis), or hepatocellular disease were enrolled in the study. In general, HRQL in patients with chronic liver disease was lower than the normal population and was similar to that of patients with chronic obstructive pulmonary disease or congestive heart failure. In cirrhotic patients, some dimensions of HRQL were less impaired in patients with cholestatic disease than in those with hepatocellular diseases. More severe disease (higher Child's class) was associated with a lower Chronic Liver Disease Questionnaire score and the Short Form 36's physical component summary scores. Older age had a weak negative association with the physical aspects of HRQL. We conclude that chronic liver disease substantially reduces HRQL, and this impact does not differ markedly by type of disease. Older age and measures of disease severity were associated with poorer HRQL.

Health-related quality of life in chronic liver disease: the impact of type and severity of disease

OBJECTIVE: The type and severity of chronic liver disease may have different effects on health-related quality of life (HRQL). The aim of our study was to determine whether HRQL in patients with chronic liver disease differs by type and severity of disease and to identify which clinical and physiological factors affect this impairment. METHODS: In this study, HRQL was measured with a generic (Short Form 36) and a liver disease-specific (Chronic Liver Disease Questionnaire) questionnaire. Clinical, demographic, and laboratory data were collected at office visits. Patient’s HRQL scores were compared with the published norms and to the chronically ill populations. A total of 353 patients (mean age 50 yr, 51% men) with chronic liver disease, either viral disease (hepatitis B and C), cholestatic disease (primary biliary cirrhosis or primary sclerosing cholangitis), or hepatocellular disease were enrolled in the study. RESULTS: In general, HRQL in patients with chronic liver disease was lower than the normal population and was similar to that of patients with chronic obstructive pulmonary disease or congestive heart failure. In cirrhotic patients, some dimensions of HRQL were less impaired in patients with cholestatic disease than in those with hepatocellular diseases. More severe disease (higher Child’s class) was associated with a lower Chronic Liver Disease Questionnaire score and the Short Form 36’s physical component summary scores. Older age had a weak negative association with the physical aspects of HRQL. CONCLUSIONS: We conclude that chronic liver disease substantially reduces HRQL, and this impact does not differ markedly by type of disease. Older age and measures of disease severity were associated with poorer HRQL.

Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man

Background/Aims/Methods: Since in rat experiments, activation of progenitor cells is seen in conditions associated with hepatocyte injury or inhibited replication, we compared the activation and fate of human putative progenitor cells in regenerating liver versus chronic cholestatic disease, using immunohistochemistry, rat oval cell marker OV6 and a panel of bile ductular rat models: the choline-deficient acetylaminofluorene (CDAAF)- and alpha-napthylisothiocyanate (ANIT)-model, using immunohistochemistry and electron microscopy. Results: In very early stages of human liver regeneration, putative progenitor cells in the vicinity of portal tracts were immunoreactive for OV6, CK7, CK19 and chrom-A. In later stages of regeneration and in chronic cholestasis, reactive bile ductules (immunoreactive for OV6, CK7, CK19, chrom-A, NCAM) and intermediate hepatocyte-like cells (immunoreactive for OV6, CK7, chrom-A), became apparent, suggesting bidirectional differentiation of the putative progenitor cells. In regenerating human liver, intermediate hepatocyte-like cells became more numerous with time and extended far into the lobule. In advanced cholestasis, intermediate hepatocyte-like cells were less numerous and formed periportal rosettes and small clusters. In the CDAAF rat model (associated with inhibited hepatocyte replication), but not in the ANIT model, gradual differentiation of oval cells into hepacytes wa seen after stopping the diet. Conclusions: Our results in human liver suggest that reactive ductules and intermediate hepatocyte-like cells originate at least partly from activation and differentiation of “progenitor cells”. In regeneration after submassive necrosis, in analogy with what is seen in rat models, differentiation towards hepatocytes is more pronounced than in chronic cholestasis.

LIPIDS AND LIPID-ACTIVATED VITAMINS IN CHRONIC CHOLESTATIC DISEASES

Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangiopathy are cholestatic liver diseases of unknown cause. Destruction of small to medium bile ducts (in primary biliary cirrhosis and autoimmune cholangiopathy) and large bile ducts (in primary sclerosing cholangitis) leads to progressive cholestasis, liver failure and end-stage liver disease. A variety of abnormalities in lipid metabolism have been described in primary biliary cirrhosis, and range from alterations in serum lipid levels and lipoprotein subsets to deranged metabolism of cholesterol. Progressive cholestasis and, consequently, decreased small intestinal bile acid concentrations in these cholestatic liver disease can also lead to impaired absorption of fats and fat-soluble vitamins, resulting in steatorrhea and deficiencies in vitamins A, D, E, and K. This article focuses on abnormalities in lipid metabolism in primary biliary cirrhosis and primary sclerosing cholangitis, and on lipid-activated vitamin deficiencies in these disorders.