Biomedical subjects

Keith Lindor

Publications and source records attributed to Keith Lindor.

13 recordsLinked to original sources

PubMed2006

Clinical predictors for hepatocellular carcinoma in patients with primary biliary cirrhosis.

BACKGROUND & AIMS: Although hepatocellular carcinoma (HCC) occurs with increased frequency in patients with primary biliary cirrhosis (PBC), the exact frequency is relatively low. Optimal selection of PBC patients for HCC screening needs to be determined for effective screening. In this study, we aimed to explore clinical predictors of HCC in PBC patients. METHODS: We performed a case-control study using 17 PBC patients with HCC identified from 1976 to 2002 at the Mayo Clinic. Control PBC patients who had no evidence of HCC were selected for each case by matching the first year of their visit to the Mayo Clinic. All medical information was collected within 2 years from when the cases were diagnosed with HCC. Logistic regression models were used for the analyses. RESULTS: Age, sex, history of blood transfusion, current smoking, histologic stage at PBC diagnosis, any signs of portal hypertension, Mayo score, hemoglobin level, platelet count, aspartate aminotransferase level, and albumin level were associated with the presence of HCC (P < .05 for each). In multivariable analysis, older age (OR, 1.7; 95% confidence interval [CI], 1.1-2.5 for 5 years), male sex (OR, 9.7; 95% CI, 1.4-68.3), history of blood transfusion (OR, 5.0; 95% CI, 1.0-24.3), and any signs of portal hypertension (OR, 22.9; 95% CI, 3.4-155.3) were associated significantly with increased odds of HCC and yielded an excellent diagnostic performance (area under the receiver operating characteristics curve rate, 0.91). CONCLUSIONS: Older age, male sex, history of blood transfusion, and any signs of portal hypertension or cirrhosis indicate higher likelihood of HCC and should be considered for HCC screening. Further studies in larger patient cohorts are required to verify the diagnostic model.

Adult↗

PubMed2006

Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis.

BACKGROUND/AIMS: Choosing endpoints in nonalcoholic steatohepatitis (NASH) trials is challenging because of the lack of validated surrogates and the trade-off between accuracy and invasiveness. In this study, we assessed diagnostic accuracy of serum aminotransferase changes in predicting histological changes in NASH trials. METHODS: We conducted a longitudinal cohort study by using 102 participants in ursodeoxycholic acid-NASH trial who had both baseline and 2-year liver biopsy and multiple measurements of serum aminotransferases. We calculated rates of alanine aminotransferase (ALT) [or aspartate aminotransferase (AST)] change as slopes of linear regression over 2 years (IU/l/month) and changes in each histological feature as differences in Brunt's scores of two biopsies in each individual. RESULTS: Rate of aminotransferase change correlated with changes in inflammation and fibrosis, but not steatosis and only with change in inflammation in multivariable analysis. In each histological feature, changes were inversely correlated with baseline histological grade. In predicting improvement of inflammation, areas under the receiver-operating characteristic curve of aminotransferase information alone were 0.72 for ALT and 0.73 for AST and were improved to 0.88 and 0.89, respectively, when baseline histology were taking account of. CONCLUSIONS: Serum aminotransferase changes could be useful as surrogates in screening therapies for NASH in clinical trials with appropriate consideration of baseline aminotransferase and histology.

Adult↗

PubMed2005

Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease.

BACKGROUND/AIMS: The effects of lifestyle modifications in nonalcoholic fatty liver disease (NAFLD) are incompletely defined. We aimed at determining the association of changes in body weight and lifestyle with changes in serum ALT levels. METHODS: We analyzed annual health checkup data from 1546 employees. Of 469 subjects with elevated ALT, we selected 348 male subjects by excluding those who had other causes of liver disease. They were followed for one year to assess the association of change in lifestyle with change in serum ALT. The 136 subjects who had ALT normalization were followed for two years to assess the association between lifestyle management and persistently normal ALT. RESULTS: In adjusted analysis, weight loss and regular exercise were significantly associated with improvement in serum ALT and increased the odds of ALT normalization, while starting smoking was significantly associated with deterioration in serum ALT. Subjects achieving > or = 5% weight reduction showed improvement in serum ALT. Reduction in alcohol consumption was not associated with changes in serum ALT. Maintaining reduced weight (<5% gain) was significantly associated with persistently normal ALT. CONCLUSIONS: Reducing weight by at least 5% with subsequent weight control and exercising regularly may be beneficial in treating NAFLD.

Adult↗

PubMed2005

Chronological development of elevated aminotransferases in a nonalcoholic population.

The incidence and risk factors of nonalcoholic fatty liver disease (NAFLD) have never been prospectively determined. To determine the frequency and risk factors of NAFLD and chronological ordering between NAFLD, weight gain, and features of insulin resistance, a historical cohort study was conducted in a Japanese workplace. A cohort free of previous liver injury, alcohol consumption of more than 140 g/wk, and hepatitis B or C infection (529 of 1537 subjects), and a subcohort of 287 subjects free of insulin resistance-related features were identified. Elevated aminotransferases in nonalcoholics were used as a surrogate for NAFLD. High aminotransferases together with weight gain of more than 2 kg and insulin resistance-related features in the subcohort were sought for up to 5 years. The incidence of high aminotransferases was 31 per 1000 person-years (71 events). A significant interaction occurred between age and sex in the development of high aminotransferases. In subjects younger than age 40 years, male sex (hazard ratio [HR]: 4.6), elevated body mass index (HR: 2.1), hypertension (HR: 2.6), and low high-density lipoprotein cholesterol (HR: 2.8) increased the risk of high aminotransferases, whereas age (HR: 0.6 for each 5 years) decreased the risk. In subjects older than age 40 years, glucose intolerance (HR: 5.3) was the only significant risk factor. In the subcohort, weight gain preceded high aminotransferases and other insulin resistance-related features, which appeared sequentially in order of low high-density lipoprotein cholesterol, hypertriglyceridemia/hypertransaminasemia/hypertension, and glucose intolerance. In conclusion, this cohort study clearly showed chronological ordering and an association between development of elevated aminotransferases and risk factors of NAFLD.

Adult↗

PubMed2005

Diagnostic model of esophageal varices in alcoholic liver disease.

Esophageal varices may cause life-threatening bleeding with attendant high hospital cost. Since effective preventive modalities for variceal hemorrhage have been established, early detection of esophageal varices is critical for prevention of bleeding. Currently, endoscopic screening is widely recommended to patients who have the diagnosis of cirrhosis. However, the diagnosis of cirrhosis relies on histological evaluations, which is costly and invasive, and endoscopic screening also burdens medical resources. Recent cost-effectiveness studies suggested that empiric prophylaxis with beta-blockers may be viable in comparison with endoscopic screening in patients with cirrhosis. However, this issue need to be also evaluated taking account of societal and patient perspectives and is not yet decided. An accurate non-invasive diagnostic model to predict the presence of esophageal varices may reduce unnecessary endoscopic procedures and prophylactic medication and improve cost-benefit of these approaches. Use of an accurate serum marker for severe hepatic fibrosis may also improve accuracy of non-invasive diagnostic models. Hyaluronic acid, a serum marker for severe hepatic fibrosis, has been reported to have a high diagnostic performance in assessing the severity of hepatic fibrosis in patients with alcoholic liver disease. In this issue, a non-invasive diagnostic model including hyaluronic acid was shown to have excellent performance in excluding the presence of medium to large esophageal varices in severe alcohol abusers. Based on current evidence, the strategy of using a non-invasive diagnostic model together with a serum marker for severe hepatic fibrosis may improve cost-benefit in the prevention of variceal hemorrhage among patients with alcoholic liver disease. The independent verification of such diagnostic models is needed.

Biomarkers↗

PubMed2005

Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease.

AIM: To determine whether serum hyaluronic acid reliably predicts the severity of hepatic fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: We studied 79 patients with histologically confirmed NAFLD. Hyaluronic acid was measured in serum obtained at the time of liver biopsy. Severity of fibrosis was staged based on Brunt's classification. The prediction levels for fibrosis were determined by area under the receiver operating characteristic curve (AUC). RESULTS: The logarithm of serum hyaluronic acid was significantly different among the stages of fibrosis (P<0.0001, analysis of variance) and had a significant positive correlation with the degrees of fibrosis after adjusting for age and serum albumin (partial r=0.44, P<0.0001). AUCs were 0.67, 0.87, 0.89, and 0.92 for any levels of fibrosis, > or =moderate fibrosis, > or =severe fibrosis, and cirrhosis, all of which were significantly higher than 0.5 (P<0.05). The cut-off value of serum hyaluronic acid of 46.1 mug/l was associated with the highest AUC for severe fibrosis, yielding a sensitivity of 85% and a specificity of 80%. The corresponding positive and negative predictive values were 51% and 96%, when assuming prevalence of severe fibrosis in NAFLD patients of 20% at referral centers. CONCLUSIONS: Measurement of serum hyaluronic acid is useful to identify NAFLD patients with severe fibrosis.

Adult↗

PubMed2004

Do antinuclear antibodies in primary biliary cirrhosis patients identify increased risk for liver failure?

BACKGROUND & AIMS: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease with a variable clinical course. Identification of serologic markers associated with increased risk of liver failure would assist in management of PBC patients. The objective of this study was to identify antinuclear antibody (ANA) markers that may be used to predict PBC outcome. METHODS: Indirect immunofluorescence was used to identify ANAs in 492 PBC patients. chi2 and Kaplan-Meier analyses were used to examine the association between ANAs and liver failure. RESULTS: A greater percentage of ANA-positive, compared to ANA-negative, PBC patients developed liver failure (41% vs 25%, P = .005). The presence of anti-centromere antibodies was associated with liver failure (anti-centromere antibody positive vs negative, 58% vs 33%, P = .001). The time to liver failure was shorter in ANA-positive, compared with ANA-negative, patients (log rank score 5.8, P = .02). After 8.9 years (the median follow-up for patients without liver failure), 68% of ANA-positive and 81% of ANA-negative patients were free of liver failure. Anti-centromere antibodies were also associated with a shorter time to liver failure (log rank score 8.4, P = .004). After 8.9 years, 52% of anti-centromere antibody positive and 74% of anti-centromere antibody negative patients were without liver failure. CONCLUSIONS: ANAs in general, and anti-centromere antibodies in particular, are associated with liver failure in PBC. PBC patients with ANAs may be candidates for treatment with experimental therapies to prolong the interval between diagnosis and liver failure. ANA-negative patients, who appear to have a relatively benign clinical course, should perhaps be treated with ursodeoxycholic acid alone.

Antibodies, Antinuclear↗

PubMed2003

Recurrent idiopathic hepatitis: a new entity?

Our goals were to describe a new clinical entity, which we termed recurrent idiopathic hepatitis. We provide a case report of this entity and conclude that this is perhaps a new entity somewhat analogous to recurrent idiopathic cholestasis.

Acute Disease↗

PubMed2003

Association of primary biliary cirrhosis and rheumatoid arthritis.

Primary biliary cirrhosis (PBC) and rheumatoid arthritis (RA) are chronic medical conditions in which, although the etiology is uncertain, autoimmune features predominate. These two conditions are, in fact, multisystemic diseases, with a multitude of manifestations that are not limited to their target end organ. It has been well established that patients with PBC may have musculoskeletal complaints and patients with RA may have evidence of hepatic dysfunction. Both of these conditions are fairly rare, with RA being found in approximately 1% of the population and PBC being found in approximately 20/100,000 women and 2/100,000 men.The likelihood of these uncommon conditions occurring in the same patient is very rare and unusual. We have identified a unique group of 25 patients who have met disease-defining criteria for both RA and PBC. Awareness of this combination should prompt rheumatologists to assess for PBC with antimitochondrial antibody testing in patients with abnormal liver tests and also to raise awareness that abnormal liver tests in RA patients are not always due to drugs.

Journal Article↗

PubMed2002

Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis.

BACKGROUND AND AIMS: The pathogenesis of primary biliary cirrhosis (PBC) is unknown. The role of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), and the effect of ursodeoxycholic acid (UDCA) in modifying the cytokine environment in patients with PBC has remained largely unstudied. Our aims were to determine: (i) the relationship between serum levels of TNF-alpha and TGF-beta and the severity of PBC; and (ii) the effects of UDCA therapy on TNF-alpha and TGF-beta levels in patients with PBC. METHODS: We studied 90 patients who had been treated with UDCA (53 patients) or placebo (37 patients) for 2 years as part of a randomized, double-blind, controlled trial. Patients were divided into histological stage I/II or stage III/IV disease. Serum TNF-alpha and TGF-beta levels were quantified by enzyme-linked immunoabsorbent assay. RESULTS: Baseline levels of TNF-alpha were significantly greater in patients with stage III/IV compared to stage I/II disease. After 2 years of treatment with UDCA, patients showed a significantly greater decrease in TNF-alpha levels and progression risk score compared to placebo-treated patients. TNF-alpha and TGF-beta levels were significantly reduced compared to baseline levels in the UDCA-treated group after 2 years, while there was no significant change in the levels of placebo-treated patients. CONCLUSIONS: Serum TNF-alpha and TGF-beta levels may reflect severity of disease in patients with PBC. The beneficial effects of UDCA therapy may be explained by lowering serum levels of these two cytokines.

Adult↗

PubMed2002

Apolipoprotein synthesis in nonalcoholic steatohepatitis.

The pathophysiology of hepatic steatosis, a prerequisite of nonalcoholic fatty liver disease, is poorly understood. Because very-low-density lipoprotein (VLDL) formation is the chief route of hepatic lipid export, we hypothesized that the synthesis of apoB-100, a rate-determining step in hepatic VLDL formation, may be altered in patients with nonalcoholic steatohepatitis (NASH). This study evaluated the relative synthesis rates of apolipoprotein B-100 (apoB-100) in patients with NASH and in lean and body mass index (BMI)-matched (obese) controls without NASH. A primed continuous infusion of L-[1-(13)C] leucine was used to measure the absolute synthesis rates (ASR) of apoB-100 and fibrinogen in 7 patients with NASH and compared them with 7 lean and 7 obese (BMI-matched) controls without NASH. The ASRs of fibrinogen and albumin also were measured. The mean ASR of apoB-100 in patients with NASH was lower (31.5 +/- 3.4 mg/kg/d) than that of obese (115.2 +/- 7.2 mg/kg/d, P <.001) and lean controls (82.4 +/- 4.1 mg/kg/d, P =.002). In contrast, the mean ASR of fibrinogen was greater in subjects with NASH than in both control groups. These data indicate that NASH is associated with markedly altered hepatic synthesis of apoB-100. The finding that albumin synthesis was not similarly decreased in patients with NASH shows that the attenuation of apoB-100 synthesis is not on the basis of globally impaired hepatic protein synthesis. In conclusion, because apoB-100 synthesis is a rate-determining step in hepatocyte lipid export, decreased synthesis of this protein may be an important factor in the development of hepatic steatosis, a prerequisite for NASH.

Adult↗

PubMed2002

Oral tolerance and pyruvate dehydrogenase in patients with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the immunological destruction of intralobular bile ducts and serum anti-mitochondrial antibodies (AMA). Based upon previous work of oral tolerance and autoimmunity, we hypothesized that feeding the mitochondrial autoantigens of PBC would alter the clinical course and the level of antimitochondrial antibodies. The bovine pyruvate dehydrogenase complex (PDC) was purified and 5 mg fed in gelatin capsules to 6 patients with early stage PBC for 6 months. Antimitochondrial antibodies and liver biochemistries were measured at every 3 months for 12 months. The clinical trial was completed for all patients except for 1 who showed deterioration of pre-existing skin rash during treatment, which disappeared within 2 weeks after treatment was discontinued. However, after 1 year, neither the titers of AMAs nor liver biochemistries were significantly changed by this treatment. This is the first trial to test the efficacy of oral tolerance induction in PBC. However, the data, which limited in scope, did not demonstrate efficacy and further highlights the difficulties in showing continuing evidence of tolerance induction in autoimmunity.

Administration, Oral↗

PubMed2002

Antimitochondrial antibody profiles: are they valid prognostic indicators in primary biliary cirrhosis?

OBJECTIVE: Retrospective studies have reported that subtypes of antimitochondrial antibodies (AMAs) discriminate between a benign and a progressive course in patients with primary biliary cirrhosis (PBC). Four AMA profiles (A-D) were defined: profiles A and B associated with a benign course and C and D with a progressive course. We aimed to confirm whether AMA profiles predict prognosis in a large sample of North American patients with PBC. METHODS: Stored pretreatment sera from patients with PBC from two centers were tested for AMA profiles using standard techniques. Proportions of patients in each profile group reaching the endpoints of liver transplantation or death from liver disease were compared. Kaplan-Meier curves were constructed comparing AMA profiles. RESULTS: All 472 patients studied had AMA positive, biopsy-confirmed PBC. Mean age at diagnosis was 53 yr, 90% were female, mean follow-up was 7.6 yr (range = 0.5-23), and 51% received ursodeoxycholic acid for >6 months. Profile A was not detected; 16.7% had profile B; 51.1%, profile C; and 32.2%, profile D. Duration of follow-up was comparable among the different profile groups. The proportions of patients reaching endpoints of death from liver disease or transplantation did not differ among the AMA profiles. No difference in the Kaplan-Meier curves between the different profile groups was observed (p > 0.05). CONCLUSION: AMA profiles do not predict prognosis in patients with PBC.

Autoantibodies↗