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Biomedical subjects

K D Lindor

Publications and source records attributed to K D Lindor.

At least 19 recordsLinked to original sources
PubMed2002

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic syndrome of unknown etiology frequently associated with inflammatory bowel disease and characterized by diffuse inflammation and fibrosis of the intra and/or extrahepatic bile ducts. Recent studies seem to favor autoimmunity in the context of a genetic predisposition as the most likely underlying mechanism for the development of the disease, however our knowledge on the pathogenesis of PSC is still incomplete and further work is needed. The most common manifestations are fatigue, pruritus, jaundice and abdominal pain; however, the increasing use of invasive cholangiography has led to diagnosing this condition in a high proportion of asymptomatic patients. PSC usually follows a progressive course leading to biliary cirrhosis with complications of portal hypertension and hepatic failure. Patients with PSC also may develop a number of other complications, including bacterial cholangitis, dominant biliary strictures, conditions of chronic cholestasis, colorectal cancer and cholangiocarcinoma. Currently, no medical therapy aimed at disrupting disease progression is available, although high-dose ursodeoxycholic acid and other medicines are being evaluated in clinical trials. A better understanding of the pathogenesis of the disease will serve as a guide for evaluating new medical approaches. Liver transplantation is the only therapeutic alternative that improves survival in patients with end-stage PSC. Prognostic models are useful in determining the timing of liver transplantation.

Journal Article↗
PubMed2001

Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'.

UDCA exerts its beneficial effect in liver diseases through a diverse, probably, complementary array of mechanisms. The clinical use and efficacy of UDCA in PBC have been evident. UDCA may also have a place in the management of PSC, ICP, cystic fibrosis, PFIC and GVHD involving the liver, although, more studies are needed to further determine its therapeutic potential in these diseases and in other hepatobiliary disorders such as liver allograft rejection, drug and TPN-induced cholestasis, NASH, and alcoholic liver disease.

Animals↗
PubMed2001

Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.

BACKGROUND/AIMS: To identify indicators of osteoporosis and to determine the rate of bone loss in patients with primary biliary cirrhosis (PBC). METHODS: Bone mineral density of the lumbar spine and hip was measured at annual intervals over 7 years of follow-up in 176 patients with PBC. RESULTS: Osteoporosis (t-score below -2.5) was found in 20% of patients and occurred 32.1 times more frequently in patients with PBC than expected. Patients with histologic stage 3 or 4 disease had a 5.4-fold increased risk of osteoporosis compared to patients with stage 1 or 2. Age, body mass index, advanced stage (3 or 4), and history of fractures were the only independent indicators of osteoporosis. After 3 years of follow up, the rate of bone loss in patients with stage 1 or 2 increased and equaled that seen in patients with stage 3 or 4. Serum bilirubin level was the only variable independently associated with the rate of bone loss over time. CONCLUSIONS: Severity of the liver disease contributes significantly to the severity of bone disease in PBC. PBC patients who are older, thinner and have more advanced liver disease may have the most benefit from bone density measurements and treatment for their osteoporosis.

Adult↗
PubMed2001

Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis.

The aim of this study was to determine if a relationship exists between nonalcoholic steatohepatitis (NASH) and serum levels of free fatty acids, choline deficiency, or celiac disease. Forty-seven patients with liver biopsy proven NASH were enrolled. Total serum free fatty acids and anti-endomysial antibodies were determined in all patients, while plasma free and phospholipid-bound choline were determined in 29 patients. Total serum free fatty acid concentration correlated significantly with female gender and serum albumin concentration. Patients with severe fibrosis on liver biopsy had significantly greater serum concentration of free fatty acids than patients without severe fibrosis. Plasma free and phospholipid-bound choline levels were normal and no significant correlation was found between the concentration of plasma free or phospholipid bound choline, and the severity of liver damage. Only one of the 47 patients with NASH had a positive titer for the anti-endomysial antibody. In conclusion, increased serum concentrations of free fatty acids were found in NASH and were associated with development of more severe liver disease. Neither choline deficiency nor celiac sprue by anti-endomysial antibody testing was associated with NASH.

Celiac Disease↗
PubMed2001

Natural history and prognostic models in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the intra- and extra-hepatic bile ducts. Despite the recognition of immunological and genetic alterations cited as factors in its pathogenesis, the exact cause for PSC remains unknown. Observational cohort studies, however, have demonstrated that PSC is a progressive disease culminating in liver failure or death. Natural history assessment in PSC, however, has been complicated by variable rates of disease progression and the impact of clinical symptoms upon initial presentation. The development of mathematical models by multivariable regression techniques (most notably Cox proportional hazards regression) has allowed for an improved description of overall survival on an individual basis among patients with PSC. Additionally, these models have also been employed for determining the optimal selection and timing for liver transplantation when advanced disease is imminent.

Cholangitis, Sclerosing↗
PubMed2001

Treatment of nonalcoholic fatty liver: present and emerging therapies.

Treatment of patients with nonalcoholic fatty liver has typically been focused on the management of associated conditions such as obesity, diabetes mellitus, and hyperlipidemia as well as discontinuation of potentially hepatotoxic drugs. Nonalcoholic fatty liver associated with obesity may resolve with weight reduction, although the benefits of weight loss have been inconsistent. Appropriate metabolic control for patients with diabetes mellitus or hyperlipidemia is always recommended but not always effective in reversing nonalcoholic fatty liver. Promising results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, and alpha-tocopherol suggest that these medications may be of potential benefit in the treatment of patients with nonalcoholic fatty liver. 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 this condition will help to identify the subset of patients with nonalcoholic fatty liver at risk of progressing to advanced liver disease and, hence, the subgroup of patients who should derive the most benefit from medical therapy. In this article, we review (1) the existing medical therapy for patients with nonalcoholic fatty liver, (2) the emerging data from clinical trials evaluating potentially useful medications, and (3) the potential therapeutic implications of recent studies on the pathogenesis of this liver disease.

Diabetes Mellitus, Type 2↗
PubMed2001

Dysphagia without endoscopically evident disease: to dilate or not?

OBJECTIVES: It is not known whether patients with symptoms of dysphagia but normal upper endoscopy benefit from empiric esophageal dilation. The aim of this prospective study was to determine whether patients with solid food dysphagia and normal upper endoscopy have symptomatic benefit from empiric dilation using a through-the-scope balloon. METHODS: Patients who were seen for complaints of solid food dysphagia and who had normal endoscopic examinations at our institution from 1998 through 1999 were identified. Those patients who had agreed before sedation to participate in the study, if eligible, were randomized to either sham or balloon dilation using an 18-mm through-the-scope balloon at the time of esophagogastroduodenoscopy. All potentially eligible patients who had given provisional consent completed a dysphagia questionnaire and a 10-cm visual analog dysphagia scale before endoscopy. Follow-up questionnaires were completed on day 1 and at 3 months and 6 months after the procedure. The primary endpoint of the study was the patient's self-assessment of difficulty swallowing, based on the questionnaires. RESULTS: A total of 83 patients met the study criteria and were randomized to balloon dilation (n = 43) or sham (n = 40). The two groups were comparable in age, sex, severity of baseline dysphagia. and use of antireflux medication. Improvement in dysphagia comparing sham to balloon on day 1 was 66% versus 67% (p = 0.99); at 3 months it was 82% versus 76% (p = 0.56); and at 6 months it was 84% versus 73% (p = 0.38). There were no reported complications in either group. CONCLUSION: The data from this prospective randomized, controlled study do not support the practice of empiric dilation in patients with symptoms of dysphagia without an endoscopically evident cause of dysphagia.

Catheterization↗
PubMed2001

Balloon dilation compared to stenting of dominant strictures in primary sclerosing cholangitis.

OBJECTIVE: In some patients with primary sclerosing cholangitis (PSC), a localized, high-grade (dominant) stricture may be the principal cause of symptoms and hyperbilirubinemia. The aim of this retrospective study was to compare the beneficial effects and risk of balloon dilation alone versus dilation followed by stenting in PSC patients with dominant strictures. METHODS: Charts from a group of 1009 patients with PSC seen over 10 yr were reviewed to identify those patients who had undergone endoscopic or percutaneous therapeutic intervention. Procedural and clinical data were recorded. RESULTS: A total of 71 PSC patients, median age of 49 yr (range 18-78 yr) were identified. Thirty-four patients were treated with endoscopic balloon dilation alone, and 37 patients were treated with balloon dilation plus stent placement. Stents were placed percutaneously (n = 19), endoscopically (n = 14), or using both interventions (n = 4). Both groups were comparable at baseline with regards to age, symptoms, and bilirubin level. The median duration of follow-up after intervention was similar in both groups. The number of intervention-related complications (30 vs 6, p = 0.001) as well as the incidence of acute cholangitis (p = 0.004) were more common in the stent group compared to the balloon dilation group. There were more complications related to percutaneous stent placement than endoscopic placement (23 vs 7. p = 0.001). There was no significant difference between the two groups with regards to improving cholestasis. CONCLUSIONS: There was no additional obvious benefit from stenting after balloon dilation in the treatment of dominant strictures in PSC patients. Stenting was associated with more complications, and its role after dilation should be assessed in a randomized trial rather than being accepted as routinely indicated in this setting.

Adult↗
PubMed2001

Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience.

OBJECTIVES: The aims of this retrospective study were to assess the frequency with which we used different treatment modalities for patients with primary sclerosing cholangitis (PSC) and cholangiocellular carcinoma (CCA). METHODS: A total of 41 patients with known CCA complicating PSC with a median age of 49 yr (range, 27-75 yr) were identified from a group of 1009 patients (4%) with PSC seen over 10 yr at the Mayo Clinic. RESULTS: These patients received mainly five forms of treatment: 10 patients were treated with radiation therapy (RT) with or without 5-fluorouracil (5-FU) (seven with palliative and three with curative intent), nine with stent placement for cholestasis, 12 with conservative treatment, four with surgical resection (one of four received RT and 5-FU), and three patients with orthotopic liver transplantation and RT, with or without 5-FU. One patient was treated with 5-FU alone, one with photodynamic therapy, and one patient with somatostatin analog. A total of 36 patients died, whereas four (10%) patients survived (two with surgical resection, one with orthotopic liver transplantation and RT, and one with stent placement) during a median follow-up of 5.5 months (range, 1-75 months). One patient was lost to follow-up. CONCLUSIONS: In highly selective cases, resective surgery seems to be of benefit in PSC patients with CCA. However, these therapies are rarely applied to these patients because of the advanced nature of the disease at the time of diagnosis. Efforts should be directed at earlier identification of potential surgical candidates.

Adult↗
PubMed2001

High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis.

OBJECTIVES: To assess the tolerability and efficacy of high-dose (25-30 mg/kg per day) ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). METHODS: Thirty patients with PSC were enrolled in this pilot study and treated for 1 yr. Changes in the Mayo risk score at 1 yr of treatment and projected survival at 4 yr were compared with that observed in patients randomized to placebo (n = 52) or UDCA (n = 53) at a dose of 13-15 mg/kg per day. RESULTS: A marked improvement in serum alkaline phosphatase activity (1265+/-172 vs 693+/-110 U/L, p < 0.001), AST (161+/-037 vs 77+/-13 U/L, p = 0.001), albumin (4.0+/-0.1 vs 4.2+/-0.1 g/dl, p = 0.03), and total bilirubin (1.6+/-0.3 vs 1.3+/-0.2 mg/dl, p = 0.1) occurred at 1 yr of therapy with high-dose UDCA. Changes in the Mayo risk score after 1 yr of treatment were significantly different among the three groups (p < 0.001), and these changes would be translated into a significantly different expected survival at 4 yr (p = 0.05). This expected survival at 4 yr was significantly different between placebo and the dose of 25-30 mg/kg per day (p = 0.04), but not between placebo and the dose of 13-15 mg/kg per day (p = 0.4). High-dose UDCA was well tolerated. CONCLUSIONS: UDCA at a dose of 25-30 mg/kg per day may be of benefit for patients with PSC, and this regimen deserves further evaluation in a long-term, randomized, placebo-controlled trial.

Adult↗
PubMed2001

Severe cholestatic hepatitis from troglitazone in a patient with nonalcoholic steatohepatitis and diabetes mellitus.

Troglitazone is currently approved for the treatment of diabetes mellitus. Hepatic abnormalities have been reported in up to 1.9% of patients receiving the drug. Severe hepatotoxicity, including the need for liver transplantation, has also been reported in patients treated with troglitazone. Troglitazone has been reported to be beneficial in a small group of patients with nonalcoholic steatohepatitis (NASH). We present a patient with nonalcoholic steatohepatitis and diabetes mellitus who developed severe cholestasis after treatment with troglitazone. The exact mechanism of troglitazone toxicity is unknown, and whether preexisting liver abnormalities increase the incidence of toxicity is speculative. Further data are needed before more widespread use of troglitazone can be recommended for patients with nonalcoholic steatohepatitis.

Adult↗
PubMed2001

Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study.

OBJECTIVES: No effective therapy currently exists for patients with nonalcoholic steatohepatitis (NASH). Betaine, a naturally occurring metabolite of choline, has been shown to raise S-adenosylmethionine (SAM) levels that may in turn play a role in decreasing hepatic steatosis. Our aim was to determine the safety and effects of betaine on liver biochemistries and histological markers of disease activity in patients with NASH. METHODS: Ten adult patients with NASH were enrolled. Patients received betaine anhydrous for oral solution (Cystadane) in two divided doses daily for 12 months. Seven out of 10 patients completed 1 yr of treatment with betaine. RESULTS: A significant improvement in serum levels of aspartate aminotransferase (p = 0.02) and ALAT (p = 0.007) occurred during treatment. Aminotransferases normalized in three of seven patients, decreased by >50% in three of seven patients, and remained unchanged in one patient when compared to baseline values. A marked improvement in serum levels of aminotransferases (ALT -39%; AST -38%) also occurred during treatment in those patients who did not complete 1 yr of treatment. Similarly, a marked improvement in the degree of steatosis, necroinflammatory grade, and stage of fibrosis was noted at 1 yr of treatment with betaine. Transitory GI adverse events that did not require any dose reduction or discontinuation of betaine occurred in four patients. CONCLUSIONS: Betaine is a safe and well tolerated drug that leads to a significant biochemical and histological improvement in patients with NASH. This novel agent deserves further evaluation in a randomized, placebo-controlled trial.

Adult↗
PubMed2001

Fat-soluble vitamin levels in patients with primary biliary cirrhosis.

OBJECTIVE: To determine the occurrence of fat-soluble vitamin deficiencies and to identify clinical factors that may predict vitamin deficiency in patients with primary biliary cirrhosis (PBC). METHODS: Review of our data from a randomized, placebo-controlled trial that evaluated the efficacy of UDCA in 180 patients with PBC. We use the first available measurements of vitamin levels in each study participant. Vitamin levels for A, D, and E were measured in serum. The prothrombin time (PT) was used as a surrogate marker for vitamin K. RESULTS: The proportion of patients with fat-soluble vitamin deficiencies in the treatment and placebo groups was similar and the data sets were combined. The proportion with vitamin A, D, E or K deficiency was 33.5%, 13.2%, 1.9%, and 7.8%, respectively. In multivariate analysis, the Mayo risk score, advanced histological stage, and total cholesterol were independently associated with vitamin A deficiency whereas serum albumin levels was independently associated with vitamin D deficiency. No factors were associated with vitamin E or K deficiency in multivariate analysis owing to the few vitamin E and K deficient patients. Factors predictive of vitamin K deficiency by univariate analysis included Mayo risk score, advanced histological stage, HDL, total bilirubin, AST, and albumin. The cut-off value of the Mayo risk score with the highest sensitivity and specificity for vitamin A deficiency was 5.0. CONCLUSION: Other than deficiency of vitamin A, deficiency of fat-soluble vitamins occurs uncommonly in patients with PBC. A Mayo risk score > or = 5 helps in selecting patients with PBC for surveillance for vitamin A deficiency.

Adult↗
PubMed2001

Development of autoimmune hepatitis in the setting of long-standing primary biliary cirrhosis.

Primary biliary cirrhosis and autoimmune hepatitis, the most common autoimmune liver diseases in adults, are frequently easily differentiated by a combination of clinical, biochemical, and histological features along with the presence of highly sensitive and characteristic serum autoantibodies. Patients presenting with "overlapping" features of both conditions simultaneously are not uncommon. However, patients who switch over time from one disease to another have remained largely unrecognized. We report here two cases from the spectrum of autoimmune liver disease, patients who had well-defined primary biliary cirrhosis for a number of years and then developed the classic picture of superimposed autoimmune hepatitis. The importance of its recognition and the appropriate management modifications are discussed.

Adult↗
PubMed2001

Incomplete response to ursodeoxycholic acid in primary biliary cirrhosis: is a double dosage worthwhile?

OBJECTIVE: The aim of this study was to assess the safety and efficacy of high-dose ursodeoxycholic acid (UDCA, 28-32 mg/kg/day) in patients with primary biliary cirrhosis (PBC) who had shown an incomplete response to the standard dose (13-15 mg/kg/day). METHODS: A total of 25 patients with PBC who had been on UDCA (13-15 mg/kg/day) therapy for 24-141 months and had shown persistent elevation of ALP activity at least two times the upper limit of normal were enrolled. The dose of UDCA was increased to 30 (28-32) mg/kg/day and given for 1 yr. RESULTS: A significant but marginal improvement in serum ALP activity (707+/-52 vs 571+/-32, p = 0.001) was noted at 1 yr of treatment with high-dose UDCA. However, levels of total bilirubin (1.1+/-0.2 vs 1.0+/-0.2, p = 0.1), AST (58+/-9 vs 54+/-1, p = 0.1), albumin (4.1+/-0.7 vs 4.0+/-0.08, p = 0.1), or Mayo risk score (4.13+/-0.3 vs 4.12+/-0.3, p = 0.2) remained essentially unchanged. Normalization of liver tests did not occur in any patient, and adverse events were not recorded in any case. CONCLUSIONS: Although UDCA at a dose of 28-32 mg/kg/day is well tolerated, this dosage does not seem to benefit most patients with PBC responding incompletely to a dose of 13-15 mg/kg/day. The results of this pilot study would seem to discourage further controlled trials of high-dose UDCA in suboptimal responders to the standard dose of UDCA.

Adult↗
PubMed2001

Primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic cholestatic disease characterized by periductal inflammation of intrahepatic and extrahepatic bile ducts with obliterative fibrosis and duct loss. Significant loss of bile ducts leads to interference with bile flow and ultimately results in cirrhosis of the biliary type. Aside from viral hepatitis and alcoholic liver disease, primary sclerosing cholangitis is one of the most common indications for liver transplantation. Although there is no known beneficial therapy for these patients, research aimed toward better understanding the pathogenetic mechanisms and clinical trials with promising new agents are ongoing.

Cholagogues and Choleretics↗