Biomedical subjects

Keith D Lindor

Publications and source records attributed to Keith D Lindor.

At least 19 recordsLinked to original sources

PubMed2006

Abnormal hepatic biochemistries in patients with inflammatory bowel disease.

OBJECTIVES: The relationship between abnormal hepatic biochemistries and inflammatory bowel disease (IBD) is unclear. We determined the prevalence of abnormal hepatic biochemistries and chronic liver disease in a cohort of IBD patients, and we compared patients with normal and abnormal liver biochemistries. METHODS: Patients with IBD evaluated at our institution between January 1, 2000 and December 31, 2000 were identified. Data on gender, age, IBD subtype, extent and activity, medications, liver disease history, liver biochemistries, and vital status were collected. The chi(2) test, Student's t-test, and Cox proportional regression were used. RESULTS: We identified 544 patients with available hepatic biochemistries. Abnormal hepatic biochemistries were found in 159 (29%). Defined chronic liver disease was present in 5.8% of patients (primary sclerosing cholangitis in 4.6%). The prevalence of abnormal hepatic biochemistries was 27% for those with active IBD and 36% for those in remission (P= 0.06). Patients with abnormal hepatic biochemistries were less frequently on 5-aminosalicylates (35%vs 51%, P < 0.001), and a smaller proportion was alive at last follow-up (90.4%vs 98.5%, P < 0.0001). The age-adjusted risk of death was 4.8 times higher in patients with abnormal hepatic biochemistries, after excluding patients with any diagnosis of liver disease. CONCLUSIONS: Abnormal hepatic biochemistries were present in nearly one-third of our patients, and surprisingly, they were not associated with IBD activity. Abnormal hepatic biochemistries and chronic liver disease appeared to have a negative impact on vital status. Persistently abnormal hepatic biochemistries should be evaluated, and not attributed to IBD activity.

Adolescent↗

PubMed2006

Fluoxetine for the treatment of fatigue in primary biliary cirrhosis: a randomized, double-blind controlled trial.

Fatigue is a common symptom in primary biliary cirrhosis (PBC). In animal models of cholestasis, abnormalities in serotonin neurotransmission are observed with fatigue. The role of selective serotonin reuptake inhibitors in fatigue-related PBC, however, is unknown. A double-blind, placebo-controlled study design was conducted to determine the safety and efficacy of fluoxetine for the treatment of fatigue in PBC. Patients were randomized to fluoxetine, 20 mg daily, or matched placebo for 8 weeks' duration. Fatigue was assessed by the Fisk Fatigue Impact Scale (FFIS). The primary study endpoint was a > or =50% reduction in overall FFIS score at the end of treatment. Health-related quality of life (HRQL) was assessed as a secondary endpoint. Among 220 consecutively screened patients, only 18 (9%) eligible individuals were randomized to fluoxetine (n=10) or placebo (n=8) for 8 weeks. Baseline variables including median FFIS scores (52 vs 42; P=0.21) were similar between treatment arms (P > 0.05). After 8 weeks of therapy, no statistically significant change in median FFIS score was observed in the fluoxetine group. Median FFIS score in the placebo group was reduced (42 to 28), but not statistically significant. No difference in HRQL was observed between treatment arms after 8 weeks. Fourteen (78%) patients completed therapy, while four (22%) individuals withdrew from the trial. Three of the four patients had drug-related adverse events with fluoxetine. In this study, fluoxetine did not improve fatigue in PBC and was associated with adverse events.

Adolescent↗

PubMed2006

Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis.

OBJECTIVES: Biliary strictures, similar to primary sclerosing cholangitis (PSC), have been reported in patients with autoimmune pancreatitis, which is characterized by elevated serum IgG4 levels and responsiveness to corticosteroids. We sought to determine the frequency of elevated IgG4 in patients with PSC and to clinically compare PSC patients with elevated and normal IgG4 levels. METHODS: We measured serum IgG4 in 127 patients with PSC and 87 patients with primary biliary cirrhosis, as disease controls. Demographic, clinical, and laboratory characteristics were compared between the PSC groups with normal and elevated IgG4 (>140 mg/dL). RESULTS: Elevated IgG4 was found in 12 PSC patients (9%) versus one PBC patient (1.1%) (p= 0.017). Patients with elevated IgG4 had higher total bilirubin (p= 0.009), alkaline phosphatase (p= 0.01), and PSC Mayo risk score (p= 0.038), and lower frequency of IBD (p < 0.0001). Importantly, the time to liver transplantation was shorter in patients with elevated IgG4 (1.7 vs 6.5 yr, p= 0.0009). The type of biliary involvement (intrahepatic, extrahepatic, or both) and pancreatic involvement were similar in both groups. CONCLUSIONS: A small proportion of PSC patients had elevated serum IgG4. In these patients parameters of liver disease severity were more pronounced and time to liver transplantation was shorter, suggesting a more severe disease course. It is possible that this subset of patients behaves similarly to autoimmune pancreatitis patients with biliary strictures, and could potentially respond to corticosteroids. Testing PSC patients for IgG4 and treating those with elevated levels with corticosteroids in clinical trials should be considered.

Adult↗

PubMed2006

Primary sclerosing cholangitis: diagnosis and management.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease caused by progressive inflammatory destruction of intrahepatic and extrahepatic bile ducts, and ultimately cirrhosis. PSC occurs primarily in patients with underlying ulcerative colitis and affects primarily young to middle-aged men. PSC is believed to be an autoimmune disease mediated by immune dysregulation in patients with genetic susceptibility. One possible mechanism for the development of PSC is the homing of memory lymphocytes to the biliary tract. Cholangiography is the gold standard for diagnosis of PSC. The typical radiologic findings include multifocal strictures and dilation involving the intrahepatic or extrahepatic biliary tract, or both. Although no medical therapy has proved beneficial, a variety of agents have been tested, some of which appear promising and deserve further study. High-dose ursodeoxycholic acid may have benefit in slowing disease progression; a multicenter placebo-controlled trial is ongoing. Liver transplantation is a good option for patients with advanced PSC, although the disease can recur after successful transplantation.

Autoimmune Diseases↗

PubMed2006

Primary sclerosing cholangitis: epidemiology, natural history, and prognosis.

Primary sclerosing cholangitis is a progressive disease associated with significant morbidity and mortality that continues to draw attention from investigators worldwide. Epidemiologic studies indicate that its annual incidence remains stable, although more asymptomatic cases are being diagnosed. Nevertheless, even asymptomatic cases can progress to end-stage liver disease, albeit at a highly variable rate. Moreover, patients are predisposed to several malignancies, especially cholangiocarcinoma, which contributes to their decreased survival. On the other hand, a subgroup of patients with the so-called small-duct variant may have a better prognosis, and those with overlap syndromes with autoimmune hepatitis may respond well to immunosuppressants. Otherwise, efficient treatment is not available for patients with primary sclerosing cholangitis. Thus, even though it occurs rarely, this disease is commonly an indication for liver transplantation. Fortunately, transplantation outcomes are excellent, with overall 5-year survival rates of approximately 80%.

Cholangitis, Sclerosing↗

PubMed2005

Nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is emerging as the most common chronic liver condition in the Western world. It is associated with insulin resistance and frequently occurs with features of the metabolic syndrome. Disease presentation ranges from asymptomatic elevated liver enzyme levels to cirrhosis with complications of liver failure and hepatocellular carcinoma. Current treatment recommendations are limited to weight loss and exercise, although several promising medications are on the horizon. In this article we discuss the etiology, pathogenesis and diagnosis of nonalcoholic fatty liver disease as well as approaches to its management.

Biopsy↗

PubMed2005

Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial.

Bone loss is a well-recognized complication of primary biliary cirrhosis (PBC). Although it has been suggested that alendronate might improve bone mineral density (BMD) in PBC, no randomized placebo-controlled trial has been conducted. The primary aim of this study was to compare the effects of alendronate versus placebo on BMD and biochemical measurements of bone turnover in patients with PBC-associated bone loss. We conducted a double-blinded, randomized, placebo-controlled trial. Patients with a PBC and BMD t score of less than -1.5 were randomized to receive 70 mg per week of alendronate or placebo over 1 year. BMD of the lumbar spine and proximal femur were measured at entry and at 1 year. Changes from baseline in BMD and biochemical measurements of bone turnover were assessed. Thirty-four patients were enrolled. Seventeen patients were randomized to each arm. After 1 year, a significantly larger improvement (P = .005) in spine BMD was observed in the alendronate group (0.09 +/- 0.03 g/cm2 SD from baseline) compared with the placebo group (-0.003 +/- 0.02 g/cm2 SD from baseline). A larger improvement (P = .046) was also observed in the femoral BMD of alendronate patients versus placebo. BMD changes were independent of concomitant estrogen therapy. The rate of adverse effects was similar in both groups. In conclusion, in patients with PBC-related bone loss, alendronate significantly improves BMD compared with placebo. Although in this study oral alendronate appears to be well tolerated in patients with PBC, larger studies are needed to formally evaluate safety.

Aged↗

PubMed2005

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.

Aged↗

PubMed2005

Living donor liver transplantation using a right lobe graft in an adult with situs inversus.

Situs inversus totalis is a rare anatomic variant in which there is a complete mirror image of the thoracic and abdominal viscera. The common association of situs inversus and biliary atresia has led to a variety of modifications of surgical techniques utilizing both living donor and deceased donor liver grafts, with mixed results in the pediatric liver transplant population. The use of a living donor liver graft in an adult with situs inversus has not yet been described. However, living donor liver transplantation (LDLT) has produced excellent results in the adult population, particularly in the cholestatic population, which may be disadvantaged by the model for end-stage liver disease system. This is the first report of a successful living donor right liver graft in an adult with end-stage liver disease secondary to primary sclerosing cholangitis and situs inversus totalis.

Anastomosis, Surgical↗

PubMed2005

The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis.

CA 19-9 has been used with questionable accuracy to aid diagnosis of cholangiocarcinoma complicating primary sclerosing cholangitis. We aimed to characterize the test properties of CA 19-9 and of a change in CA 19-9 over time in predicting cholangiocarcinoma. Charts of 208 patients were reviewed. Fourteen patients had cholangiocarcinoma. Median CA 19-9 was higher with cholangiocarcinoma (15 vs. 290 U/ml, p < 0.0001). A cutoff of 129 U/ml provided: sensitivity 78.6%, specificity 98.5%, adjusted positive predictive value 56.6% and negative predictive value 99.4%. The median change over time was 664 U/ml in cholangiocarcinoma compared to 6.7 U/ml in primary sclerosing cholangitis alone (p < 0.0001). A cutoff of 63.2 U/ml for change in CA 19-9 provided: sensitivity 90%, specificity 98% and positive predictive value 42%. Only 2 patients with cholangiocarcinoma were the candidates for curative therapy. In conclusion, the positive predictive value of an elevated CA 19-9 was 56.6%; only advanced cases were detected by this method.

Bile Duct Neoplasms↗

PubMed2005

The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies.

BACKGROUND/AIMS: The histological course of nonalcoholic fatty liver disease (NAFLD) remains undescribed. Therefore, we examined the liver histology of NAFLD patients who had undergone sequential liver biopsies. METHODS: Data on 103 patients who underwent serial liver biopsies in the absence of effective treatment were reviewed, and biopsies scored in a blind fashion. RESULTS: Mean interval between biopsies was 3.2+/-3.0 years (range 0.7-21.3). Fibrosis stage apparently progressed in 37%, remained stable in 34% and regressed in 29%. Severity of steatosis, inflammation, hepatocyte ballooning and Mallory's hyaline improved significantly. Aminotransferases decreased significantly between biopsies, paralleling improvement in steatosis and inflammatory features but not fibrosis stage. The rate of fibrosis change ranged from -2.05 to 1.7 stages/year. By multivariate analysis, diabetes (P = 0.007) and low initial fibrosis stage (P < 0.001) were associated with higher rate of fibrosis progression, as was higher body mass index (P = 0.008) when cirrhotics were excluded. CONCLUSIONS: Fibrosis in NAFLD progresses slowly over time with considerable variability in the rate of changes among patients. Changes of aminotransferases do not parallel changes in fibrosis stage. Diabetic patients with elevated BMI and low fibrosis stage are at risk for higher rates of fibrosis progression.

Adult↗

PubMed2005

The natural history of nonalcoholic fatty liver disease: a population-based cohort study.

BACKGROUND & AIMS: The natural history of nonalcoholic fatty liver disease (NAFLD) in the community remains unknown. We sought to determine survival and liver-related morbidity among community-based NAFLD patients. METHODS: Four hundred twenty patients diagnosed with NAFLD in Olmsted County, Minnesota, between 1980 and 2000 were identified using the resources of the Rochester Epidemiology Project. Medical records were reviewed to confirm diagnosis and determine outcomes up to 2003. Overall survival was compared with the general Minnesota population of the same age and sex. RESULTS: Mean (SD) age at diagnosis was 49 (15) years; 231 (49%) were male. Mean follow-up was 7.6 (4.0) years (range, 0.1-23.5) culminating in 3192 person-years follow-up. Overall, 53 of 420 (12.6%) patients died. Survival was lower than the expected survival for the general population (standardized mortality ratio, 1.34; 95% CI, 1.003-1.76; P = .03). Higher mortality was associated with age (hazard ratio per decade, 2.2; 95% CI, 1.7-2.7), impaired fasting glucose (hazard ratio, 2.6; 95% CI, 1.3-5.2), and cirrhosis (hazard ratio, 3.1, 95% CI, 1.2-7.8). Liver disease was the third leading cause of death (as compared with the thirteenth leading cause of death in the general Minnesota population), occurring in 7 (1.7%) subjects. Twenty-one (5%) patients were diagnosed with cirrhosis, and 13 (3.1%) developed liver-related complications, including 1 requiring transplantation and 2 developing hepatocellular carcinoma. CONCLUSIONS: Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis. Liver-related death is a leading cause of mortality, although the absolute risk is low.

Adult↗

PubMed2005

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the intra- and extrahepatic bile ducts. An estimated 80% of patients in North America and Europe have coexistent inflammatory bowel disease (IBD). The underlying pathophysiology of PSC remains poorly understood. As a result, there is currently no effective medical therapy to halt disease progression. Important complications from PSC include metabolic bone disease, colorectal neoplasia, and cholangiocarcinoma. Liver transplantation remains the only successful treatment option for patients with advanced liver disease from PSC. A diagnosis of PSC should be considered among individuals with IBD and elevated serum liver biochemical tests.

Adult↗

PubMed2005

Raloxifene improves bone mass in osteopenic women with primary biliary cirrhosis: results of a pilot study.

BACKGROUND/AIMS: Bone disease is common in patients with primary biliary cirrhosis (PBC). Our aim was to evaluate safety and efficacy of raloxifene in this population. METHODS: Nine postmenopausal women with PBC were enrolled and seven completed the study. Subjects received raloxifene 60 mg daily for 1 year. Each patient on raloxifene was age-matched to three controls. Liver biochemistries were monitored periodically; bone mineral density (BMD) of the lumbar spine (LS) and femoral neck (FN) was measured at baseline and at 1 year. RESULTS: No significant adverse effects were reported. Liver biochemistries remained unchanged. Baseline LS-BMD was similar in the treatment group and controls [median 0.720 g/cm(2) (range 0.620-0.867) vs. 0.740 g/cm(2) (0.570-1.040), P=0.5]. CONCLUSION: Compared with baseline, LS-BMD improved significantly with 1 year of therapy [0.72 g/cm(2) (0.62-0.87) vs. 0.74 g/cm(2) (0.63-0.97), P=0.02]. FN-BMD remained stable [0.53 g/cm(2) (0.50-0.60) vs. 0.54 g/cm(2) (0.49-0.63), P=0.6]. Improvement in LS BMD was seen in patients on raloxifene but not in matched controls [0.02 g/cm(2) (0.01-0.10) vs. 0.00 g/cm(2) (-0.120-0.040), P=0.06)]. In conclusion, raloxifene appears safe and of benefit in preventing bone loss in patients with PBC. Larger studies with longer follow-up are warranted.

Administration, Oral↗

PubMed2005

Mycophenolate mofetil for the treatment of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology. Despite advances in understanding the pathophysiology underlying this disorder, no effective medical therapy has been identified for halting disease progression. The aim of this investigation was to determine the safety and estimated efficacy of mycophenolate mofetil (MMF) for the treatment of PSC. Thirty patients with PSC received MMF 1 g daily to a maximum of 3 g daily for 1 yr. Liver tests were determined at 3-month intervals with the Mayo risk score calculated at baseline and at the end of therapy. Twenty-three (77%) patients completed 1 yr of therapy. Significant but clinically marginal improvement in serum alkaline phosphatase level after 1 yr of therapy was observed (1135 +/- 581 U/L vs 912 +/- 463 U/L, p= 0.02). No other significant changes in liver biochemistries or Mayo risk score was observed. Seven patients (23%) discontinued MMF due to adverse events possibly related to therapy. Adverse reactions resolved spontaneously or with dose reduction in 10 (33%) patients. One patient developed pancreatitis, bacterial cholangitis, and sepsis during the eighth month of MMF therapy. No patient developed cytopenia on therapy. In conclusion, MMF does not appear to have clinically important benefits for PSC despite being tolerated by most patients. The results of this pilot study do not support further study of MMF as a single agent in the treatment of PSC.

Adult↗

PubMed2005

Secondary sclerosing cholangitis: a comparison to primary sclerosing cholangitis.

OBJECTIVES: The natural history of secondary sclerosing cholangitis (SSC) is ill-defined. In order to better determine the natural history of this condition, we retrospectively reviewed data from the Mayo Clinic in Rochester, Minnesota. We also compared the natural history of patients diagnosed with SSC to a cohort with a diagnosis of primary sclerosing cholangitis (PSC). METHODS: We used a computer-assisted search to identify patients with a diagnosis of SSC seen from 1992 to 2002. The diagnosis was confirmed by chart review and information about age, gender, etiology, therapy, and clinical course was sought. We excluded those presumed SSC patients who had a history of inflammatory bowel disease, those with malignancy at the time of diagnosis, and those who had undergone liver transplantation prior to the diagnosis of SSC. Patients with PSC matched for age, gender, and serum bilirubin level served as disease controls. RESULTS: We identified 31 patients, average age 57, (range 28-79). The causes of SSC included surgical trauma from cholecystectomy (13 patients), intraductal stones (12 patients), recurrent pancreatitis (4 patients), and abdominal injury (2 patients). Nine patients with SSC ultimately required liver transplantation and 4 patients have died. When compared to matched patients with PSC, the survival free of transplant was significantly shortened (p<0.03). CONCLUSIONS: When the long-term outcome of SSC patients was compared to matched PSC controls, the SSC patients had a poorer outcome. The natural history of SSC is characterized by a shortened life expectancy.

Abdominal Injuries↗

PubMed2005

Recent advances in the treatment of non-alcoholic fatty liver disease.

Non-alcoholic steatohepatitis is a liver disease strongly associated with features of the metabolic syndrome. It is part of the disease spectrum of non-alcoholic fatty liver disease, which is now thought to be the most common cause of chronic liver disease in the US and other Western countries. Initially this condition was considered innocuous but it is now recognised as having the potential to progress to cirrhosis and its complications. The role of insulin resistance and oxidative stress in its pathogenesis is increasingly accepted. Current investigations are directed towards a better understanding of the natural history, pathogenesis and development of treatment strategies. Several therapeutic modalities, including antioxidants, insulin-sensitising agents and lipid-lowering agents, have been evaluated for the treatment of these patients, mostly in small clinical trials. Despite promising results, no therapy has demonstrated a proven benefit.

Clinical Trials as Topic↗

PubMed2005

Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid.

BACKGROUND & AIMS: Despite evidence for therapeutic efficacy with ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC), only 30-50% of patients achieve complete biochemical remission within 1 year of therapy. Mycophenolate mofetil (MMF) is an immunosuppressive medication that inhibits T and B lymphocyte proliferation. The aim of this investigation was to determine the safety and estimated efficacy of MMF in patients with PBC. METHODS: Twenty-five patients with incomplete responses to UDCA (defined as persistent elevation of serum alkaline phosphatase > or =2 times the upper limit of normal) received MMF 1 g daily to a maximum of 3 g daily with UDCA (13-15 mg/kg per day) for 1 year. Liver biochemistries were determined at 3-month intervals with Mayo Risk Score calculated at baseline and end of therapy. RESULTS: Nineteen (76%) patients completed 1 year of therapy. Despite improvements in serum alkaline phosphatase (920 +/- 308 vs. 709 +/- 242 IU/L, P = 0.001) and AST (65 +/- 31 vs. 51 +/- 19 IU/L, P = 0.007) levels, these findings were clinically insignificant. Exploratory analysis revealed a strong correlation between advanced PBC defined by higher Mayo Risk Score and reduction in serum alkaline phosphatase levels (r = -0.74, P = 0.006). Six patients (24%) did not complete therapy; adverse drug events were responsible for study withdrawal in 3 individuals. Adverse reactions that resolved spontaneously or by dose reduction occurred in 13 patients. CONCLUSIONS: MMF is not associated with important clinical benefits in PBC based on the results of this pilot investigation.

Administration, Oral↗