The role of macrophage migration inhibitory factor in autoimmune liver disease.

UNLABELLED: The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional -794 CATT5-8 microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the proinflammatory and high-expression -794 CATT7 allele in AIH, compared to PBC, whereas lower frequency was found in PBC, compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by enzyme-linked immunosorbent assay in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC versus healthy controls. We also identified a truncated circulating form of the MIF receptor, CD74, that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls. CONCLUSIONS: These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in pathogenesis and as biomarkers of these diseases.

Colchicine or methotrexate, with ursodiol, are effective after 20 years in a subset of patients with primary biliary cirrhosis.

BACKGROUND & AIMS: The combination of ursodeoxycholic acid (UDCA), colchicine, and methotrexate (MTX) is effective therapy for a subset of patients with primary biliary cirrhosis (PBC) who do not respond to UDCA. However, the durability of the response is unclear. We investigated whether the response to combination therapy was durable. METHODS: We followed, for 10 additional years (range 9-13 years), 29 patients with PBC who had been treated with the combination of UDCA and MTX or UDCA and colchicine in a randomized controlled trial that began in 1988 and lasted 10 years. RESULTS: Of the 11 patients given MTX plus UDCA, 9 were still alive and well, whereas 2 died from causes unrelated to liver disease at the ages of 79 and 70. Of the 18 patients given the combination of colchicine and UDCA, 12 were alive and well 20 years after the trial ended. Three had progressive liver disease; 2 of these had liver transplantation and 1 died of pneumonia. Three died of unrelated causes at the ages of 73, 76, and 76 years, respectively. CONCLUSIONS: Treatment with the combination of UDCA and MTX or UDCA and colchicine led to sustained clinical remission in a subset of patients with PBC. The response to the combination of UDCA and MTX appeared to be more durable than to UDCA and colchicine.

Prevalence of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome.

BACKGROUND & AIMS: The prevalence of and the most appropriate way to diagnose the primary biliary cirrhosis (PBC)-chronic autoimmune hepatitis (AIH) overlap syndrome are uncertain. We investigated the prevalence of PBC and AIH and their level of overlap at a tertiary referral center, along with clinical, biochemical, and serologic characteristics. METHODS: We reviewed data from all patients with PBC (n = 609) and/or AIH (n = 15) examined at the Tufts Medical Center (Boston, MA) from January 1, 2000, to June 20, 2006. PBC was diagnosed based on 2 of the following 3 results: 6 months of positive results in tests for cholestatic liver enzymes, a positive result in a test for antimitochondrial antibodies, or a liver biopsy that indicated PBC. AIH was defined as an alanine aminotransferase level of 200 U/L or greater (≥ 5-fold above normal), a liver biopsy that indicated severe interface hepatitis, and levels of immunoglobulin G 2-fold or greater than that of normal. RESULTS: Only 6 patients with PBC (1%) met the Paris criteria for the overlap syndrome. If we included 9 patients with PBC who did not meet the Paris criteria, but had results from liver enzyme tests and liver biopsy analyses that indicated improvement after treatment with prednisone, the prevalence was 15 (2.8%). This is at the low end of previously reported prevalence values for overlap of PBC and AIH (2%-20%). CONCLUSIONS: The prevalence of the PBC-AIH overlap syndrome varies among medical centers. We propose that if the definition of PBC-AIH overlap syndrome be modified to include patients with unequivocal responses to prednisone despite not meeting the Paris criteria, this would improve treatment of patients.

Methotrexate in patients with primary biliary cirrhosis who respond incompletely to treatment with ursodeoxycholic acid.

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.

Risk of non-melanoma skin cancer in autoimmune hepatitis.

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.

Statins in primary biliary cirrhosis: are they safe?

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

Modafinil in the treatment of debilitating fatigue in primary biliary cirrhosis: a clinical experience.

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.

Quality of life and everyday activities in patients with primary biliary cirrhosis.

UNLABELLED: Primary biliary cirrhosis (PBC) is generally a slowly progressive disease that may lead to cirrhosis and liver failure. However, patients with PBC often suffer from a variety of symptoms long before the development of cirrhosis that include issues of daily living that have an impact on their work environment and their individual quality of life. We therefore examined multiple parameters by taking advantage of the database of our cohort of 1032 patients with PBC and 1041 matched controls. The data were obtained from patients from 23 tertiary referral centers throughout the United States and from rigorously matched controls by age, sex, ethnicity, and random-digit dialing. The data showed that patients with PBC were more likely than controls to have significant articular symptoms, a reduced ability to perform household chores, and the need for help with routine activities. Patients with PBC rated their overall activity similar or superior to that of controls; however, more of them reported limitations in their ability to carry out activities at work or at home and difficulties in everyday activities. PBC cases also more frequently reported limitations in participating in certain sports or exercises and pursuing various hobbies; however, they did not report significant limitations in social activities. In a multivariable analysis, household income, a diagnosis of systemic lupus erythematosus, limitations in work activities, a reduction in work secondary to disability, and church attendance were independently increased in PBC cases with respect to controls. CONCLUSION: Our data indicate that the quality of life of patients with PBC in the United States is generally well preserved. Nevertheless, patients with PBC suffer significantly more than controls from a variety of symptoms that are beyond the immediate impact of liver failure and affect their lifestyle, personal relationships, and work activities.

Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients.

Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology, often associated with other autoimmune conditions. Controlled studies have so far provided conflicting data on risk factors and comorbidity rates in PBC. We enrolled patients with PBC (n = 1032) from 23 tertiary referral centers for liver diseases in the United States and random-digit-dialed controls (n = 1041) matched for sex, age, race, and geographical location. Patients and controls were administered a modified version of the US National Health and Nutrition Examination Study (NHANES III) questionnaire by trained personnel to evaluate associations between PBC and social, demographic, personal and family medical histories, lifestyle, and reproductive factors and the rates of comorbidity in affected individuals. Data indicate that having a first-degree relative with PBC (adjusted odds ratio [AOR] 10.736; 95% confidence interval 4.227-27.268), history of urinary tract infections (AOR 1.511, 95% CI 1.192-1.915), past smoking (AOR 1.569, 95% CI 1.292-1.905), or use of hormone replacement therapies (AOR 1.548, 95% CI 1.273-1.882) were significantly associated with increased risk of PBC. The frequent use of nail polish slightly increased the risk of having PBC. Other autoimmune diseases were found in 32% of cases and 13% of controls (P<0.0001). In conclusion, environmental factors, possibly including infectious agents through urinary tract infections or chemicals contained in cigarette smoke, may induce PBC in genetically susceptible individuals. Exogenous estrogens may also contribute to explain the female predominance of the disease.

The natural history of PBC: has it changed?

The prognosis and natural history of primary biliary cirrhosis (PBC) have improved significantly during the last few decades. Patients are diagnosed at earlier stages, are more likely to be asymptomatic at diagnosis, and are more likely to receive medical treatment. The survival of asymptomatic patients is longer than the median survival of symptomatic patients. The natural history of PBC has been assessed in the presence of effective therapy, ursodeoxycholic acid (UDCA). Evidence suggests that UDCA delays histological progression in PBC and decreases the risk of development of esophageal varices. Survival of UDCA-treated patients is better than that of untreated patients and also is better than that predicted by the Mayo model. For patients in early stages of PBC, UDCA treatment may normalize survival. However, patients with stage III and IV PBC do not respond as well to UDCA. Therefore, there is a continued need for additional treatment in patients with advanced disease.

Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis.

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 coli). 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.