Biomedical subjects

Keith D Lindor

Publications and source records attributed to Keith D Lindor.

At least 55 records · Page 3Linked to original sources

PubMed2003

Drug-induced cholestasis.

Drug-induced cholestasis is a common entity, seen with numerous classes of pharmacological agents. A high index of suspicion is required for the correct diagnosis. Different clinical syndromes may be recognized, with variable degrees of hepatitis in association with cholestasis. The most important aspect of treatment is prompt discontinuation of the offending drug. Several agents have been used for symptomatic relieve of the pruritus associated with cholestasis, including cholestyramine, ursodeoxycholic acid, and opiate antagonists, with limited results. Prognosis is usually good, with few cases of prolonged cholestasis leading to vanishing bile duct syndrome. Liver failure may rarely occur if diagnosis goes unrecognized and the inciting drug is not withdrawn.

Animals↗

PubMed2003

Management of osteoporosis, fat-soluble vitamin deficiencies, and hyperlipidemia in primary biliary cirrhosis.

Osteoporosis is several times more common in patients with PBC compared with the general population. Maintaining adequate intake of calcium and vitamin D is important for prevention of bone loss. The use of bisphosphonates or vitamin K to improve bone mineral density in osteopenic patients seems promising and needs to be further evaluated. Patients with PBC may develop fat-soluble vitamin deficiencies, especially vitamins A and D; serum levels should be investigated in patients considered at risk with the aim of recommending appropriate replacement therapy. Finally, hyperlipidemia in PBC does not seem to be associated with an increased risk of atherogenesis. New therapies in this patient population are currently under investigation.

Avitaminosis↗

PubMed2003

When is liver biopsy needed in the diagnosis of primary biliary cirrhosis?

BACKGROUND & AIMS: Liver biopsy has been largely replaced by less invasive measurements applied to mathematical models in defining the prognosis of patients with primary biliary cirrhosis (PBC). The need for liver biopsy in the diagnosis of patients with positive antimitochondrial antibodies (AMAs) in the setting of biochemical cholestasis remains uncertain. This study was undertaken to determine which variables indicate the need for liver biopsy in patients with positive AMA and suspected PBC. METHODS: A total of 3198 patients that were tested for AMA in 1999 and 2000 were identified. Of these, 198 (6.2%) were AMA positive. Forty-two patients were excluded because of unavailable laboratory data or liver biopsy specimens. Data on the remaining 156 patients were analyzed to determine which variables among patients with positive AMA with and without a histopathologic diagnosis of PBC indicate the need for liver biopsy. RESULTS: In 131 of 156 (84.6%) patients, a diagnosis of PBC was established by liver biopsy. The histological diagnosis of PBC was associated with a cholestatic biochemical profile (alkaline phosphatase [AP] >1.5 times the upper limits of normal [ULN] and aspartate aminotransferase [AST] <5 times ULN) in 112 of 131 (85.5%) patients. The combination of AP >1.5 times the ULN and AST <5 times the ULN yielded a 98.2% positive predictive value of PBC diagnosis on liver biopsy in AMA-positive subjects. These results were corroborated by cross-validation in an independent set of patients. CONCLUSIONS: In patients with positive AMA, a cholestatic biochemical profile (AP >1.5 times the ULN), and absence of markedly elevated AST (<5 times the ULN), liver biopsy is rarely required to establish the diagnosis of PBC. Liver biopsy would be beneficial to establish the diagnosis of PBC in only a minority of AMA-positive patients with AP <1.5 times the ULN or AST >5 times the ULN.

Alkaline Phosphatase↗

PubMed2003

Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) has shown effectiveness as a colon cancer chemopreventive agent in preclinical studies. In addition, a recent report suggests that it also may decrease the risk for developing colorectal dysplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We sought to evaluate the effect of UDCA on colorectal neoplasia in a group of patients with UC and PSC enrolled in a randomized, placebo-controlled trial. METHODS: From a prior, randomized, placebo-controlled trial of UDCA therapy in PSC at our center, we followed-up patients with concomitant UC to assess the effect of UDCA on the development of colorectal dysplasia and cancer as compared with placebo. RESULTS: Fifty-two subjects were followed-up for a total of 355 person-years. Those originally assigned to receive UDCA had a relative risk of 0.26 for developing colorectal dysplasia or cancer (95% confidence interval, 0.06-0.92; P = 0.034). Many of the patients originally assigned to the placebo group eventually received open-label UDCA. Assigning these patients to the UDCA group from the time they began active therapy did not change the magnitude of the protective effect (relative risk, 0.26; 95% confidence interval, 0.07-0.99; P = 0.049). CONCLUSIONS: UDCA significantly decreases the risk for developing colorectal dysplasia or cancer in patients with UC and PSC.

Adult↗

PubMed2003

Primary sclerosing cholangitis in children: a long-term follow-up study.

Primary sclerosing cholangitis (PSC) is increasingly diagnosed in children and adolescents, but its long-term prognosis remains uncertain. The aim of this longitudinal, cohort study was to determine the long-term outcome of children with PSC. Fifty-two children with cholangiography-proven PSC (34 boys and 18 girls; mean age 13.8 +/- 4.2 years; range, 1.5-19.6 years) who were seen at our institution over a 20-year period were followed-up for up to 16.7 years. Two thirds presented with symptoms and/or signs of PSC and 81% had concomitant inflammatory bowel disease (IBD). Twenty-five percent had total alkaline phosphatase activity within the normal range for the age group, but all of them had elevated gamma-glutamyl transpeptidase levels. Autoimmune hepatitis overlapping with PSC was present in 35% of children. A positive but transient clinical and/or biochemical response occurred under therapy with ursodeoxycholic acid, alone or in combination with immunosuppressive medications. During follow-up, 11 children underwent liver transplantation for end-stage PSC and 1 child died. The median (50%) survival free of liver transplantation was 12.7 years. Compared with an age- and gender-matched U.S. population, survival was significantly shorter in children with PSC (P <.001). In a Cox regression model, lower platelet count, splenomegaly, and older age were associated with shorter survival. Presence of autoimmune hepatitis overlapping with PSC (P =.2) or medical therapy (P =.2) did not affect survival. In conclusion, PSC significantly decreases survival in this child population. Although pharmacologic therapy may improve symptoms and liver test results initially, it does not seem to impact the long-term outcome.

Adolescent↗

PubMed2003

Treatment with ursodeoxycholic acid is associated with weight gain in patients with primary biliary cirrhosis.

BACKGROUND: Ursodeoxycholic acid (UDCA) is the established treatment of primary biliary cirrhosis (PBC) and is a safe and well-tolerated medication. Nevertheless, patients often anecdotally complain of weight gain while on this drug. GOALS: We compared weight changes in patients treated with UDCA and those on placebo to characterize this potential side effect. STUDY: One-hundred eighty patients with PBC who were enrolled into a randomized, controlled trial received either UDCA (13-15 mg/kg/d) or an identical placebo. Changes from baseline weight were calculated at 12, 24, 36, and 48 months. Other markers of disease activity, including liver biochemistries, serum lipids, histologic stage, and Mayo Risk Score were evaluated in both groups. RESULTS: The proportion of patients who gained weight during the first 12 months of therapy was significantly greater in the UDCA than placebo group (67/86 [78%] versus 43/73 [57%] respectively, P = 0.005). Patients in the UDCA group gained an average of 3.6 +/- 6.5% kg (2.2 +/- 5.1 kg) which was significantly greater than the average of 0.6 +/- 6.9% kg (0.6 +/- 4.9 kg) gained in the placebo group (P = 0.04). The biggest change in weight occurred in the first 12 months of treatment (P < 0.001); after this, weight was maintained for the 4-year duration of treatment. There was no significant correlation between initial body mass index (BMI) and weight change or changes in disease activity and weight. CONCLUSION: UDCA treatment in patients with PBC is associated with a significant weight gain that occurs in the first 12 months of treatment, persists for the duration of treatment, and occurs independent of baseline BMI. Discussions with PBC patients beginning UDCA treatment should include the beneficial effects this medication has on disease outcome, but should also mention weight gain as a possible side effect.

Body Mass Index↗

PubMed2003

Methotrexate therapy for primary biliary cirrhosis.

OBJECTIVE: Preliminary data suggested possible benefits of methotrexate in primary biliary cirrhosis. We assessed the effectiveness of methotrexate use in primary biliary cirrhosis and its tolerance in patients with this disease. METHODS: A total of 110 primary biliary cirrhosis patients began methotrexate 15 mg/wk; for most, ursodeoxycholic acid was added during the study. We analyzed data from patients completing 5 yr of treatment with methotrexate to assess its effect on biochemical and histologic parameters after 5 yr of therapy. Based on an intent to treat analysis, we also compared survival of our patients (n = 110) with that of patients in a previously published, placebo-controlled trial of ursodeoxycholic acid (n = 180). RESULTS: Only half of the study group completed 5 yr of methotrexate therapy. Therapy did not prevent progression of disease, as indicated by a rising Mayo risk score. Portal fibrosis tended to remain the same. Methotrexate did not diminish the risk of death or liver transplantation when compared with ursodeoxycholic acid or placebo; however, ursodeoxycholic acid use decreased the risk of death or transplant (p = 0.006). CONCLUSIONS: Methotrexate is not well tolerated in primary biliary cirrhosis. The toxicity of methotrexate and its inability to prevent complications of progressive liver disease or improve survival and the need for liver transplantation limits its utility. The benefits of ursodeoxycholic acid were again confirmed.

Adult↗

PubMed2003

Safety and efficacy of estrogen therapy in preventing bone loss in primary biliary cirrhosis.

OBJECTIVE: Estrogen therapy has been found to be useful in the treatment of postmenopausal osteoporosis. However, concern about its potential for worsening cholestasis has limited its use in postmenopausal women with primary biliary cirrhosis. The aim of the present study was to determine the safety as well as the efficacy of estrogen replacement therapy with respect to bone mass in postmenopausal women with primary biliary cirrhosis. METHODS: Bone mineral density of the lumbar spine (measured using dual energy x-ray absorptiometry) of 46 unselected postmenopausal women with primary biliary cirrhosis receiving estrogen replacement therapy was compared with 46 age-matched women with primary biliary cirrhosis not receiving estrogen replacement therapy, and with the expected normal bone mineral density adjusted for age and ethnic group. RESULTS: The mean duration of follow-up was 4.8 +/- 0.4 yr. Treatment with estrogens resulted in a significantly lower rate of bone loss (0.002 g/cm(2)/yr +/- 0.028 vs 0.009 g/cm(2)/yr +/- 0.020, p = 0.05). Worsening cholestasis attributable to estrogen replacement therapy did not occur in any patient. One patient (2%) discontinued therapy because of side effects. CONCLUSIONS: Estrogen replacement therapy in postmenopausal patients with primary biliary cirrhosis is safe and may be effective in decreasing the rate of bone loss.

Adult↗

PubMed2003

Is there a role for liver biopsy in primary sclerosing cholangitis?

OBJECTIVE: Liver biopsies are performed in patients with primary sclerosing cholangitis (PSC) to stage disease and to rule out coexisting liver disease. The purpose of this study was to examine how often routine liver biopsies provide important information in patients with PSC. METHODS: We reviewed the charts of 138 patients with a cholangiographic diagnosis of PSC to determine whether information from liver biopsy had an impact on clinical management. RESULTS: A total of 30 patients did not have a liver biopsy, whereas 29 patients had a biopsy before cholangiography. In 79 patients the liver biopsy was performed after the diagnosis of PSC was established by cholangiography (median time from cholangiography to liver biopsy, 21 days). In 78 of 79 patients (98.7%) the liver biopsy revealed no atypical findings and did not affect clinical management. In one patient the liver biopsy revealed findings of an overlap syndrome with autoimmune hepatitis, and the patient was treated with corticosteroids and azathioprine. This patient had biochemical features consistent with autoimmune hepatitis. One patient developed a bile leak after liver biopsy, requiring hospitalization (complication rate 0.9%). CONCLUSIONS: Liver biopsies rarely contribute new information that affects the management of patients with PSC. Given the risks of the procedure, liver biopsies for patients with a diagnosis of PSC established by cholangiography may not routinely be necessary.

Adolescent↗

PubMed2003

Value of determining carbohydrate-deficient transferrin isoforms in the diagnosis of alcoholic liver disease.

OBJECTIVE: To determine whether isoform separation of carbohydrate-deficient transferrin (CDT) is of value in the diagnosis of alcoholic liver disease (ALD) and is specific to ALD when compared with other liver diseases. PATIENTS AND METHODS: During 1995 and 1996, 47 patients with ALD were evaluated with CDT at the Mayo Clinic in Rochester, Minn. The diagnosis of ALD was based on biochemical and histological analyses and on a history of drinking that exceeded 5 years with an average alcohol intake of more than 60 g/d. Disease controls included nonalcoholic steatohepatitis (NASH) (n = 26) and other liver disease (n = 22). Normal controls (n = 21) were healthy individuals without liver disease. Transferrin isoforms were quantified by densitometry of Coomassie-stained transferrins after affinity purification and isoelectric focusing. The pentasialo, tetrasialo, trisialo, disialo, monosialo, and asialo isoforms were quantified as percentages of total band densities. RESULTS: Receiver operating characteristic (ROC) curves were constructed for each isoform. The curves for total desialated isoforms (sum of disialo, monosialo, and asialo) displayed the best relationship between sensitivity and specificity with an ROC-area under the curve (AUC) of 0.922. The ROC-AUC values for individual transferrin isoforms in ALD vs NASH for pentasialo, tetrasialo, trisialo, disialo, monosialo, and asialo were 0.806, 0.917, 0.885, 0.933, 0.804, and 0.785, respectively. Only 58% of patients with ALD were detected at a specificity that excluded ALD in 84% of those who did not have it. CONCLUSION: Within alcohol ingestion times reported to us, no associations with recent drinking were observed. Alcohol as a cause of liver disease is not perfectly established by CDT analysis, although a high total CDT value favors ALD over NASH.

Adult↗

PubMed2003

Natural history of pruritus in primary biliary cirrhosis.

The natural history of pruritus in primary biliary cirrhosis (PBC) remains poorly defined. The aim of this investigation was to evaluate outcomes of pruritus in clinical trials for ursodeoxycholic acid (UDCA). In a UDCA-placebo trial begun in 1988 (n = 180), a 55% prevalence rate for pruritus was observed. Serum alkaline phosphatase level and Mayo risk score were independent risk factors for pruritus (P < 0.0001). Among placebo-treated patients (n = 91), the annual risks for development or improvement/resolution of pruritus were 27% and 23%, respectively. For UDCA-treated patients (n = 89), a trend toward improvement in pruritus was observed after 1 year compared to placebo (30% vs. 23%, P = 0.08) but not at 2 or 3 years. In a 3-dose UDCA trial begun in 1995 (n = 155), the overall prevalence of pruritus was significantly lower at 37% when compared to UDCA-placebo participants (P < 0.001). Baseline serum alkaline phosphatase level and Mayo risk score were again independent risk factors for pruritus (P < 0.0001). Among 13 (3.9%) patients with refractory pruritus, symptom resolution (n = 5) or improvement (n = 8) was associated with the use of oral rifampin (300 or 600 mg daily). Two patients treated with rifampin developed biochemical evidence for hepatotoxicity necessitating drug withdrawal. Although less prevalent among recently diagnosed individuals, more than one third of PBC patients develop pruritus. No significant risk reduction in developing pruritus with UDCA therapy was observed compared to placebo-treated patients. The long-term administration of rifampin for refractory pruritus is associated with occasional hepatotoxicity.

Adult↗

PubMed2002

A novel incentive system for faculty in an academic medical center.

The need to contain health care costs has led some physicians to become salaried employees of health care organizations. However, the use of nonfinancial incentives for physicians in such an environment has not been broadly explored. The authors describe a novel incentive system that is designed to promote continuing high-quality care and to increase patient access to health care while enhancing clinical and academic productivity and physician satisfaction. Key components of this system include annual targets, flexibility in meeting these targets, and ability to convert clinical productivity generated in excess of what was necessary to meet the target to support scholarly activities. This system led to increased faculty productivity, improved patient access, enhanced scholarly activity, and overall enhanced career satisfaction.

Academic Medical Centers↗

PubMed2002

Human leukocyte antigen Class II associations in serum antimitochondrial antibodies (AMA)-positive and AMA-negative primary biliary cirrhosis.

BACKGROUND/AIMS: An association of Class II HLA-DR8 antigen is reported in patients with serum antimitochondrial antibodies (AMA)-positive primary biliary cirrhosis (PBC); no information exists as to an association with AMA-negative PBC. We compared the frequency of HLA Class II genes in AMA-positive and AMA-negative PBC patients and healthy controls. METHODS: Genomic DNA was extracted from the blood of 154 AMA-positive and 26 AMA-negative Caucasian PBC patients and from 216 healthy Caucasian controls and tested for the alleles at two HLA Class II loci, DRbeta1 and DQbeta1. RESULTS: Higher allele frequencies of HLA-DRbeta1*08 and DQbeta1*04 were found in the AMA-positive PBC patients versus controls (14.9% vs. 6.5%, odds ratio (OR)=3.3, global P=0.03 and 14.4% vs. 6.5%, OR=2.6, global P=0.002). All patients positive for DRbeta1*0801 were positive for the DQbeta1*0402 allele, delta score=22 for AMA-positive patients, 11 for controls. In AMA-negative PBC, the frequency of DRbeta1*08 and DQbeta1*04 was 0%, significantly different from the AMA-positive patients (P=0.05, P=0.05). CONCLUSIONS: AMA response may identify a group of PBC patients with a distinctive expression of the disease with the response associated with a gene(s) in the class II region of the major histocompatibility complex on the short arm of chromosome 6.

Adult↗

PubMed2002

Pirfenidone in the treatment of primary sclerosing cholangitis.

Our aim was to evaluate the safety and assess the efficacy of pirfenidone, an antifibrotic drug, in patients with primary sclerosing cholangitis (PSC). Twenty-four patients with PSC were enrolled in this pilot study. Oral pirfenidone, 2400 mg daily, was given for one year. Liver biochemistries were determined at three-month intervals. The Mayo risk score was calculated, and liver biopsy and endoscopic cholangiography were performed at entry and at one year of treatment. No significant changes in liver biochemistries were noted at the end of the treatment period or at any of the three-month intervals. The Mayo risk score did not change significantly, and no significant changes were noted in the degree of inflammation, fibrosis, histologic stage of disease, or cholangiographic findings at the end of the treatment period. Adverse events occurred in 20/24 (83%) patients, but disappeared shortly after pirfenidone was discontinued. Pirfenidone did not benefit patients with PSC, and it was frequently associated with adverse events. The results of this pilot study discourage further trials of pirfenidone in patients with PSC.

Administration, Oral↗

PubMed2002

Non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects a high proportion of the world's population. Insulin resistance and oxidative stress play a critical role in the pathogenesis of NAFLD. Clinical, biochemical and imaging studies are of value in the diagnostic evaluation of patients with NAFLD, but liver biopsy remains the most sensitive and specific means of providing important diagnostic and prognostic information. Simple steatosis has the best prognosis within the spectrum of NAFLD, but NAFLD has the potential to progress to steatohepatitis, fibrosis and even cirrhosis. No effective medical therapy is currently available for all patients with NAFLD. In patients with diabetes mellitus and hyperlipidemia, appropriate metabolic control is always recommended, but rarely effective in resolving the liver disease. Weight reduction, when achieved and sustained, may improve the liver disease, although the results with weight loss have been inconsistent. Pharmacological therapy aimed at the underlying liver disease holds promise. Several medications with different mechanisms of action and potential benefit are currently being evaluated in clinical trials. Liver transplantation is a life-extending therapeutic alternative for patients with end-stage NAFLD, but NAFLD may recur after liver transplantation.

Biopsy↗

PubMed2002

Treatment of non-alcoholic steatohepatitis.

Treatment of patients with non-alcoholic steatohepatitis (NASH) has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipidaemia. NASH associated with obesity may resolve with weight reduction, although the benefits of weight loss have been inconsistent. Appropriate control of glucose and lipid levels is always recommended, but is not always effective in reversing the liver condition. Results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, alpha-tocopherol, metformin and thiazolidinedione derivatives suggest that these medications may be of potential benefit for patients with NASH. These medications, however, need first to be tested in well-controlled trials with clinically relevant end-points and extended follow-up. A better understanding of the pathogenesis and natural history of NASH will help to identify the subset of patients at risk of progressing to advanced liver disease and, hence, those patients who should derive the most benefit from medical therapy.

Diabetes Mellitus, Type 2↗

PubMed2002

Primary biliary cirrhosis with additional features of autoimmune hepatitis: response to therapy with ursodeoxycholic acid.

Patients with primary biliary cirrhosis (PBC) may have additional features of autoimmune hepatitis (AIH). Corticosteroids usually contraindicated in PBC have been advocated for these patients. Patients with antimitochondrial antibody (AMA)-positive PBC from two previous randomized, controlled trials were assessed for features of AIH. Their biochemical, immunologic, and histologic responses to ursodeoxycholic acid (UDCA) versus placebo were compared with those without AIH features. The survival of patients testing positive or negative for antinuclear antibodies (ANA) was also examined. Features of AIH were defined by the presence of 2 or more of the following: 1) alanine transaminase (ALT) > 5 x the upper limit of normal (ULN); 2) immunoglobulin G (IgG) > 2 x ULN or positive anti-smooth muscle antibody (ASMA); and 3) moderate to severe lobular inflammation on pretreatment liver biopsy. Testing for AMA, ASMA, and ANA was done by immunofluorescence. The change in serum bilirubin, alkaline phosphatase (ALP), transaminases, IgM, and IgG from baseline to 2 years was compared. Of the 331 patients randomized, 16 (4.8%) had features of AIH (12 UDCA, 4 placebo). The median percent change in serum biochemistry and immunoglobulin values were similar in patients with PBC +/- features of AIH after 2 years of therapy with UDCA. Over 2 years, little change in histologic features of AIH was observed. Survival was similar for patients with PBC with and without ANA. In conclusion, features of AIH in PBC may be transient and response to UDCA therapy similar to patients with PBC without features of AIH.

Adult↗

PubMed2002

Small-duct primary sclerosing cholangitis: a long-term follow-up study.

Some patients with inflammatory bowel disease (IBD) have chronic cholestasis and hepatic histology compatible with primary sclerosing cholangitis (PSC) but normal findings on cholangiography. These patients with small-duct PSC have remained largely unstudied. Our aim was to determine the prevalence and long-term outcomes of patients with small-duct PSC. Eighteen patients with small-duct PSC (7 female and 11 male patients; mean age, 39.9 +/- 15.3 years [range, 13-68 years]) seen over a 4-year period were matched blindly by age and sex to 36 patients with classic PSC and followed up for 32.5 years. Small-duct PSC represented 5.8% of patients (18 of 309) with sclerosing cholangitis. Subsequent endoscopic retrograde cholangiography (ERC) performed in 5 patients with small-duct PSC showed progression to typical PSC in 3 patients at 4, 5.5, and 21 years of follow-up. None of the patients with small-duct PSC but 4 of the patients with classic PSC developed hepatobiliary malignancy. There were 3 deaths (17%) or liver transplantations in patients with small-duct PSC (2 after progressing to classic PSC) and 15 (42%) in the classic PSC group. Survival free of liver transplantation was significantly greater in the small-duct than in the classic PSC group (P =.04). Compared with the general U.S. population, survival in patients with small-duct PSC was similar (P =.4) but significantly lower in patients with classic PSC (P <.001). In conclusion, small-duct PSC may represent an earlier stage of PSC associated with a significantly better long-term prognosis. Some patients, however, progress to classic PSC and/or end-stage liver disease with the consequent necessity of liver transplantation.

Adolescent↗