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Background: Approximately 35% of PBC patients have progressive disease despite treatment with UDCA.Aims: We offered treatment with methotrexate and colchicine to PBC patients who had not responded fully to UDCA, after at least 1 year of treatment.Methods: A total of 91 PBC patients failed to respond adequately to UDCA, defined as patients whose liver biopsies showed persistent interface hepatitis and whose serum alkaline phosphatase levels remained more than 50% above normal after at least 12 months on UDCA. We added colchicine (0.6 mg orally twice daily) for 6 months. If there was no decrease in alkaline phosphatase, methotrexate (0.25 mg/kg lean body weight orally per week) was added. Liver biopsies were performed at least three times: at diagnosis, after a patient had been on UDCA for at least 1 year (mean 3.4 years), and after a patient had been on methotrexate for at least 6 months (mean 2.2 years). A fourth liver biopsy was performed in 51 patients after they had been on methotrexate for at least another year (mean 3.5 years).Results: From the time that methotrexate was begun until the final visit, there were significant decreases in the mean levels of alkaline phosphatase, 323 to 151, ALT, 73 to 39, fibrosis, 2.5 to 2.0, and inflammation scores, 2.0 to 1.0, (p < 0.0001 for all). Based on pre-specified definitions, 73 patients (80%) responded to methotrexate while 18 (20%) did not.Conclusions: In 91 PBC patients who responded incompletely to UDCA, colchicine and methotrexate significantly improved liver enzyme tests and liver histology. [ABSTRACT FROM AUTHOR]

: ObjectiveApproximately 20–30% of patients with primary biliary cirrhosis (PBC) respond fully to treatment with ursodeoxycholic acid (UDCA). The rest have progressive disease and eventually develop cirrhosis and liver failure. More effective treatment is needed. Methotrexate improved biochemical tests of liver function and liver histology in patients with PBC who had failed to respond to UDCA in one report and induced sustained biochemical and histological remission in another. The role of colchicine in PBC is unclear. We describe three patients with symptomatic PBC who responded very well to the addition of colchicine after they had failed to respond to UDCA alone and in combination with methotrexate. We suggest that colchicine should be tried in PBC patients who clearly fail to respond to UDCA.: MethodsThree patients with symptomatic biopsy-proven, antimitochondrial antibody-positive PBC failed to respond to UDCA and then to the addition of methotrexate. Colchicine was eventually added to the regimen. Symptoms, biochemical tests of liver function, and percutaneous liver biopsies were done at baseline, after treatment with UDCA, UDCA plus methotrexate, and UDCA plus methotrexate plus colchicine.: ResultsAll three patients responded after colchicine was added to UDCA and methotrexate. Symptoms, biochemical tests of liver function, and liver histology improved in all, and blood tests normalized in two.: ConclusionsColchicine may be effective treatment in some symptomatic patients with PBC who respond incompletely to UDCA alone or in combination with methotrexate. Colchicine may be tried in such patients. [Copyright &y& Elsevier]

PREAMBLEGuidelines for clinical practice are intended to indicate preferred approaches to medical problems as established by scientifically valid research. Double blind, placebo-controlled studies are preferable, but reports and expert review articles are also utilized in a thorough review of the literature conducted through the National Library of Medicine’s MEDLINE. When only data that will not withstand objective scrutiny are available, a recommendation is identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject, without regard to specialty training or interests, and are intended to indicate the preferable but not necessarily the only acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care that are inflexible and rarely violated. Given the wide range of specifics in any health care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision.Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the Board of Trustees. Each has been intensely reviewed and revised by the Committee, other experts in the field, physicians who will use them, and specialists in the science of decision of analysis. The recommendations of each guideline are therefore considered valid at the time of their production based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at an established time and indicated at publication to assure continued validity. [Copyright &y& Elsevier]

Chronicles the history of urban policy making between 1960 and 1994. U.S. President John F. Kennedy's commitment to defining and carrying out urban policies; Enactment of programs for every category of urban and rural problems from 1963 to 1968; Administration of U.S. President Richard Nixon's emphasis on Title VII New Communities program.

Compares the community development program of the United States called Model Cities with Israel's Project Renewal. Features of the programs; Differences in the implementation process of the projects; Fundamental changes in the U.S. brought by the program.

Focuses on the role of traditional American values in developing consensus concerning complex public policy issues. Diversity in the American spirit and culture; Higher expectations and equal opportunity as part of the American way of life; Variables that separate individuals at birth and affect the odds of success in life; Ambivalence about leadership; Beliefs that guide civic and personal behavior.

Evaluates the response of primary biliary cirrhosis to low-dose oral methotrexate therapy. Positive response on some patients; Remission of primary biliary cirrhosis in response to methotrexate or in combination with colchicine or ursodiol; Progressive histologic improvement observed on the serial liver biopsy specimens; Side effects of the therapy.

Presents case studies of sclerosing cholangitis in patients who responded to low-dose methotrexate treatment. Clinical history of the patients; Laboratory examination findings; Discussion on the disease.

Background and Aim: Although cholesterol levels are elevated in patients with primary biliary cirrhosis (PBC), most PBC patients are not at increased risk of dying from atherosclerotic heart disease. There is, however, a subgroup, approximately 10%, who have additional disorders of lipid metabolism. They might benefit from a cholesterol-lowering agent. However, there is concern about using statins in patients with pre-existing liver disease. We therefore reviewed our experience with statins in a large cohort of PBC patients who were seen at Tufts Medical Center during the past decade.Methods: From January 1, 1996, until June 30, 2006, 603 patients with PBC were seen by one of us (M.M.K.). Fifty-eight were on statins and five were on ezetimibe. The mean duration of usage was 41 months (range 3-125 months). Alanine aminotransferase (ALT) levels were measured at 3-month intervals.Results: Statins were well tolerated. No patient complained of muscle pain or weakness. There was no increase in ALT levels. ALT levels were slightly elevated at the time that statins were begun (41.7 +/- 25.1 U/l), and were normal at the last time these patients were seen (39.0 +/- 21.0 U/l) (P Conclusion: Statins are safe in PBC patients who might benefit from their use. [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PBC) is characterized by a T-cell-mediated destruction of bile duct epithelial cells that line the small intrahepatic bile ducts. The targets of activated T-lymphocytes are the dihydrolipoamide acetyltransferase components of the 2 oxo acid dehydrogenases, enzyme complexes that are important in oxidative energy metabolism. Pyruvate dehydrogenase is the best known of these. Its dihydrolipoamide acetyltransferase component is referred to as PDC-E2. A major question in understanding the pathogenesis of PBC is why PBC patients lose their tolerance to antigens that are found in virtually every cell in the body. A possible cause is molecular mimicry between microbial agents and self-antigens. Infection with or exposure to a microorganism whose PDC-E2 bears close homology with human PDC-E2 could act as an immunological trigger that initiates the development of PBC. Emerging data suggest that there is a microorganism that may initiate the onset of PBC. Novosphingobium aromaticivorans is a gram negative strictly aerobic bacteria that is found worldwide in soil, water, and coastal plain sediments. Its PDC-E2-like proteins have a higher degree of homology with the immunodominant region of human PDC-E2 than any microorganism thus far studied (100-1,000 times greater than that of Escherichia coil). In addition, N. aromaticivorans can metabolize xenobiotics that are similar to the chemical compounds that react with sera from PBC patients. Some of these xenobiotics are immunologically related to lipoic acid, the cofactor that is at the active center of PDC-E2. Thus, N. aromaticivorans can theoretically break down self-tolerance in two ways: by molecular mimicry due to subclinical infection and by the metabolism of xenobiotics that are present in the environment In an initial study, investigators found that antibodies against N. aromaticivorans were found in 77 of 77 PBC patients from Milan, Italy, who had antibodies to PDC-E2 and that the titers to N. aromaticivorans proteins were similar to those to human PDC-E2. The report in this issue of The American Journal of Gastroenterology confirms these earlier findings and demonstrates that exposure to N. aromaticivorans occurs in genetically different PBC patients from other regions. Thirteen of 14 Icelandic PBC patients who were AMA positive reacted against at least one of the 2 oxo acid dehydrogenase-E2 complexes. These observations provide additional evidence that exposure to N. aromaticivorans may trigger the development of PBC. [ABSTRACT FROM AUTHOR]

Editorial. Comments on sensitivity of alanine aminotransferase (ALT) to liver cell injury. Identification of the types of liver disease; Measurement of serum ALT levels; Detection of nonalcoholic steatohepatitis.

Examines the efficacy and safety of low-dose oral pulse methotrexate therapy in patients with idiopathic granulomatous hepatitis who had complications or refused glucocorticoid therapy. Mode of action of methotrexate; Positive response to low-level methotrexate therapy.

Describes cases of primary biliary cirrhosis treated with low-dose oral pulse methotrexate.

Presents a letter to the editor related to the treatment of fatigue in primary biliary cirrhosis.

Discusses the reversal of portal hypertension in a patient with primary biliary cirrhosis (PBC). Facts about PBC; Case of a patient with PBC who developed thrombocytopenia and esophageal varices; Observations noted from the patient.

Presents a commentary on the study in this issue concerning research into primary biliary cirrhosis. Belief that PBC is an autoimmune disease; Questions on why PBC patients lose the tolerance to antigens that are found in every cell of the body and why women are so more often sufferers; Study finding that women with PBC had a higher rate of monosomy X; Role of fetal cell microchimerism; How this research may be a stop in finding the specific gene or genes on the X chromosome whose loss accounts for the increased prevalence of autoimmune diseases in women.

The article discusses iron-chelation therapy in patients with homozygous thalassemia major. Red-cell transfusions can prolong life in patients with thalassemia major but can cause iron overload due to the body's inability to expel iron. Iron overload in patients with thalassemia major and hemochromatosis can manifest as cirrhosis, cardiac failure, and hypopituitarism. Iron chelation therapy depletes iron, increasing life expectancy. Deferoxamine prevents iron overload but must be administered through continuous infusion and can cause side effects such as hearing loss and neurotoxicity. Deferiprone is an oral iron-chelating agent licensed for use in India. It has been suggested that deferiprone could cause hepatic fibrosis.

A response by Marshall M. Kaplan and M. Eric Gershwin to several letters to the editor about their article concerning primary biliary cirrhosis, which appeared in the September 22, 2005 issue, is presented.

Provides information about primary biliary cirrhosis, a slowly progressive autoimmune disease of the liver that primarily affects women. Description of the disease and its symptoms; Medical treatment; How this condition leads to liver failure; Assertion that primary biliary cirrhosis is diagnosed earlier in its clinical course than it was in the past.

A response by Daniel S. Pratt and Marshall M. Kaplan to several letters to the editor about their article "Evaluation of Abnormal Liver-Enzyme Results in Asymptomatic Patients," in the April 27, 2000 issue is presented.

Presents an evaluation of abnormal liver-enzyme results in asymptomatic patients. Description of aminotransferable levels; Causes of elevated aminotransferable levels; Reasons for elevated alkaline phosphate levels; Factors involved with elevated y-glutamylatransferase levels.

The article presents a letter to the editor about research by Olivieri and others concerning iron chelation with oral deferiprone in patients with thalassemia that was published in the August 13, 1998 issue.

A response by Otto Friedrich to a letter to the editor about his article "Primary Biliary Cirrhosis," which was published in the November 21, 1996 issue, is presented.

Editorial. Offers suggestions for a miltifaceted approach to the treatment of primary sclerosing cholangitis. The work of Lindor for the Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid (PSC-UDCA) Study Group; Primary sclerosing cholangitis as most likely caused by multiple factors; Why early diagnosis is difficult; Goals of treatment; Few data supporting the hypothesis of chronic bile-duct infection.

Presents a review article dealing with primary biliary cirrhosis. Its prevalence, epidemiology, and genetics; Pathological features; Immunologic abnormalities; Clinical features; Treatment of underlying disease; References.

A letter to the editor is presented outlining the case of a patient who was treated with methotrexate and developed liver disease.

Focuses on primary sclerosing cholangitis, a chronic cholestatic liver disease. Characteristics; Pathological features; Pathogenesis; Primary sclerosing cholangitis and liver transplantation; Diagnostic criteria; Clinical features; Other aspects.

A letter to the editor about a 58-year-old woman suffering from primary biliary cirrhosis is presented.

The article comments on primary biliary cirrhosis in middle-aged women. The author observes that severe cholestasis is due to relentless destruction of small and medium-sized bile ducts mediated by activated T lymphocytes, both CD4 and CD8 cells. He argues that Ursodiol, a dihydroxy bile acid that is a stereoisomer of chenodiol, can reduce the deleterious effects of cholestasis in many ways.

A response by David E. Johnston and Marshall M. Kaplan to several letters to the editor about their article "Pathogenesis and Treatment of Gallstones," in the February 11, 1993 issue, is presented.

A letter to the editor about the use of ursodiol to treat chronic cholestatic liver diseases is presented.

A photograph concerning medical examination of primary biliary cirrhosis is presented.

Summarizes the current knowledge of the pathogenesis, diagnosis and treatment of gallstone disease. Gallstones as a major cause of morbidity and mortality throughout the world; Composition of gallstones; Proposed origin of cholesterol gallstones; Statistics on the incidence of gallstones in adults; Treatment for acute cholecystitis; More.

Background: Most patients with autoimmune hepatitis (AIH) require long-term immunosuppressive therapy (IS). While it is well established that solid organ transplant recipients have a high risk of developing non-melanoma skin cancer (NMSC) as a result of immunosuppression, little is known about the risk of NMSC associated with IS in patients with AIH.Objectives: The aim of this study is to determine the incidence and risk factors for NMSC in patients on IS for AIH.Methods: We reviewed the medical records of all patients with AIH seen at a tertiary care medical center between 1998 and 2008. We compared the incidence of NMSC to an age- and sex-matched control population and analyzed risk factors for NMSC.Results: A total of forty-five patients with AIH were identified. Twenty NMSC lesions were found in eight patients. Compared to the age and sex-matched general population, the risk of SCC and BCC were increased as quantified by elevated standardized incidence ratios (28.5 and 5.0, respectively). Patients who developed NMSC were on average 24 years older (78.4 vs. 54.2 years old, p < 0.0001) and had AIH diagnosed at a more advanced age (66.0 vs. 45.4 years old, p = 0.0003).Conclusion: The risk of NMSC is significantly increased in patients with AIH on immunosuppression. Independent risk factors include current age and age at diagnosis of AIH. [ABSTRACT FROM AUTHOR]

Modafinil may be a potentially effective treatment for primary biliary cirrhosis (PBC)-related fatigue. About 42 patients were given a 3-day trial of 100-200 mg modafinil. Response was defined as increased energy, decreased somnolence and sleep requirements, and improved daily function. Patients with positive responses were continued indefinitely on the medication. During the initial trial period, 31 (73%) patients had complete response and continued to take the medication. Eleven (26%) had no response. In long-term follow-up (average 17.7 months), 25 (81%) patients continued to take 100-200 mg modafinil daily. Some required an increased dosage and some took the medication as needed. Four (12%) patients stopped the medication because of side-effects or reduced efficacy; one patient (3%) stopped due to medication cost and one (3%) due to resolution of fatigue. Side-effects included insomnia, nausea, nervousness, and headaches. Modafinil appears to be a safe, effective treatment for PBC-related fatigue. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the persistent cholestatic jaundice after endoscopic retrograde cholangiopancreatography.

The article presents a medical case on two women sisters with decompensated liver disease due to primary biliary cirrhosis (PBC) associated with a hypercoagulable state that resolved with anticoagulation. Their clinical courses suggest that intrahepatic thrombosis contributed to their worsening liver disease. The remarkable clinical response to anticoagulation suggests that intrahepatic thrombosis should be considered as a potential contributor to hepatic deterioration in patients with PBC.

There is a considerable database on the effector mechanisms for CD8 recognition of PDC-E2 in primary biliary cirrhosis (PBC). In particular, the specific roles of MHC class I, the mitochondrial autoepitope, and the liver-specific T cell precursor frequency, are defined for HLA-A2.1 patients. There is evidence for a role of MHC class I-mediated presentation of exogenous antigens, or cross-presentation, in the development of the antimitochondrial response and a contributory role of Fcγ receptor-mediated uptake of autoantigen–autoantibody complexes for the induction of a PDC-E2 specific autoreactive CTL response. Based on this background, we examined potential intracellular pathways for processing the immunodominant mitochondrial autoantigen, PDC-E2, by dendritic cells (DC). In particular, we studied the effects of the proteasome inhibitor lactacystin and the endosomal acidification inhibitor bafilomycin on the induction of PDC-E2-specific CTL response in PBC. Importantly, our data indicate that pre-treatment with either lactacystin or bafilomycin inhibits the PDC-E2 immune complex-induced CTL response. The processing and presentation of PDC-E2 by CD8+T cells is mediated by proteasomes and facilitated by Fcγ receptor-mediated endocytosis. This data reflects another layer of interaction between components of the immune system in the development of autoimmunity. Further characterization of autoantigen uptake and processing may lead to potential therapeutic intervention. [Copyright &y& Elsevier]

While the pathologic mechanisms responsible for organ-specific tissue damage in primary biliary cirrhosis (PBC) remain an enigma, it has been suggested that the pathology is mediated by autoreactive T cells infiltrating the intrahepatic bile ducts. Previously, we have documented that there is 100-fold enrichment in the frequency of CD4(+) autoreactive T cells in the liver that are specific for peptides encoded by the E2 components of the pyruvate dehydrogenase complexes (PDC-E2). We have also recently characterized the first MHC class I-restricted epitope for PDC-E2, namely amino acid 159-167, a region very similar to the epitope recognized by MHC class II-restricted CD4(+) cells and by autoantibodies. The effector functions of these PDC-E2(159-167)-specific CD8(+) cytotoxic T lymphocytes (CTLs) are not well understood. We have taken advantage of tetramer technology and report herein that there is tenfold increase in the frequency of PDC-E2(159-167)-specific CTLs in the liver as compared with the blood in PBC. In addition, the precursor frequency of the CTLs in blood was significantly higher in early-stage PBC. Of interest was the fact that, upon stimulation with the peptide, the response of PDC-E2(159-167) tetramer-positive cells is heterogeneous with respect to IFN-gamma synthesis. These data, we believe for the first time, document the enrichment of autoantigen-specific CD8(+) T cells in the PBC liver, suggesting that CD8(+) T cells play a significant role in the immunopathogenesis of PBC. [ABSTRACT FROM AUTHOR]

Discusses the possibility of the reversal of liver fibrosis, which usually progresses to cirrhosis in chronic liver disease. Discussion of a study published in this issue which implies that liver fibrosis can regress in patients who undergo surgical decompression of an obstructed biliary system; Limitations of the study; Progress in the understanding of the cellular and molecular regulation of hepatic fibrosis; Implications.

Objective: To study the effect of cytomegalovirus immune globulin (CMVIG) on prevention of cytomegalovirus (CMV) disease and its complications in patients receiving liver transplants.Design: Randomized, multicenter, placebo-controlled, double-blind trial.Setting: Four university-affiliated transplant centers in Boston (Boston Center for Liver Transplantation).Patients: One hundred forty-one liver transplant recipients completed the study.Intervention: CMVIG or placebo (1% albumin) given in a dose of 150 mg/kg body weight within 72 hours of the transplant, then at weeks 2, 4, 6, and 8, and at 100 mg/kg at weeks 12 and 16.Measurements: Patients were observed for 1 year after transplantation for the development of CMV infection, disease, pneumonia, as well as for opportunistic fungal infections, graft survival, and mortality. Weekly cultures were taken of urine, buffy coat, and throat wash for CMV for 2 months, then monthly, and at any clinical illness.Results: Using a Cox proportional hazards model, CMVIG was shown to reduce severe CMV-associated disease (multi-organ CMV disease, CMV pneumonia, or invasive fungal disease associated with CMV infection) from 26% to 12% (relative risk, 0.39; 95% CI, 0.17 to 0.89). When we controlled for the use of monoclonal antibodies to T cells (OKT3), CMVIG use was still protective (relative risk, 0.39; CI, 0.17 to 0.90). Rates of CMV disease were reduced from 31% to 19% (relative risk, 0.56; CI, 0.3 to 1.1) in CMVIG recipients although no effect on rates of CMV infection, graft survival, or patient survival at 1 year were shown. When we controlled for the urgency of transplantation and OKT3 use, a reduction in CMV disease (relative risk, 0.22; CI, 0.06 to 0.81) was shown for globulin recipients for all serologic groups except for the highest risk group (the CMV-seropositive donor, CMV-seronegative group).Conclusion: CMVIG reduced the rate of severe CMV-associated disease in patients undergoing orthotopic liver transplantation. No effect of CMVIG on CMV donor-positive, recipient-negative liver transplant recipients was shown, suggesting a need for additional prophylactic strategies. [ABSTRACT FROM AUTHOR]

Examines the case of a patient with mixed cryoglobulinemia responsive to interferon-alpha. Clinical manifestations; Laboratory findings; Pathophysiology; Treatment.