Early primary biliary cirrhosis: just delayed or different?
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Autoantibodies↗
Biomedical subjects
K D Lindor
Publications and source records attributed to K D Lindor.
Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis.
BACKGROUND & AIMS: Long-term ursodeoxycholic acid (UDCA) therapy slows the progression of primary biliary cirrhosis. This study examined the effect of UDCA therapy on survival free of liver transplantation in a large group of patients. METHODS: Data from three clinical trials were combined in which patients with primary biliary cirrhosis were randomly assigned to receive UDCA (n = 273) or placebo (n = 275). After 2 years, patients from French and Canadian studies received UDCA for up to 2 years. Patients from the American study remained on their assigned treatment for up to 4 years. RESULTS: Survival free of liver transplantation was significantly improved in the patients treated with UDCA compared with the patients originally assigned to placebo (P < 0.001; relative risk, 1.9; 95% confidence interval, 1.3-2.8). Subgroup analyses showed that survival free of liver transplantation was significantly improved in medium- and high-risk groups (serum bilirubin level, 1.4 to 3.5 or > 3.5 mg/dL; P < 0.0001 and P < 0.03, respectively) and histological stage IV subgroup (P < 0.01). CONCLUSIONS: Long-term UDCA therapy improves survival free of liver transplantation in patients with moderate or severe disease. An effect in patients with mild disease is probably not found because they do not progress to end-stage disease in 4 years.
Adult↗
Review: nonalcoholic steatohepatitis.
Nonalcoholic steatohepatitis (NASH) is a reasonably well-defined clinicopathological entity; it has been reported more commonly in women than in men or children of both sexes and it appears to be most closely associated with obesity, diabetes mellitus and related abnormalities, such as hyperlipidaemia and hyperglycaemia. However, the association with female gender, obesity and diabetes may not be as close as suggested by the literature and an underlying condition cannot be discerned in all cases. The natural history of the disease is poorly understood; the associated biopsy features span a wide spectrum, reaching from uncomplicated, clinically non-progressive fatty liver (not NASH in a strict sense) to a slowly progressive fatty liver with inflammation and fibrosis, to steatohepatitis with submassive hepatic necrosis, which has a subfulminant course and is often fatal. Non-progressive fatty liver appears to be very common but is of little clinical importance. The slowly progressive form of the disease represents NASH as encountered by most clinicians and pathologists. It is a common liver disease in current practice; patients may present with cirrhosis and even HCC arising from steatohepatitic cirrhosis. Subfulminant NASH has become exceedingly rare because many clinicians are now aware of the hazards of sudden weight loss, particularly in morbidly obese patients. Treatment options for NASH are still limited. The promotion of gradual weight loss in obese patients is the most widely recommended therapy but, unfortunately, this is very difficult to achieve. Avoidance of precipitous weight loss and careful control of diabetes mellitus are important and undisputed parts of patient management. Administration of UDCA as a treatment of NASH is still under study; it may be effective in some patients. The treatment of established steatohepatitic cirrhosis does not differ substantially from that of other types of cirrhosis and includes orthotopic liver transplantation.
Diabetes Complications↗
Ursodeoxycholic acid delays the onset of esophageal varices in primary biliary cirrhosis.
OBJECTIVE: To address the effect of ursodeoxycholic acid therapy on development of esophageal varices in patients with primary biliary cirrhosis. MATERIAL AND METHODS: We compared, as part of a prospective treatment trial, the risk of varices developing in patients with primary biliary cirrhosis who received ursodeoxycholic acid (13 to 15 mg/kg daily) versus those who received placebo for up to 4 years. Upper endoscopy was performed every 2 years or as indicated clinically. At the end of the 4-year period, all patients in the placebo group were offered ursodeoxycholic acid therapy. During follow-up, the risk of developing endoscopically confirmed varices was assessed. RESULTS: The 180 patients who entered the ursodeoxycholic acid trial were assessed for the presence or absence of varices by esophagogastroduodenoscopy; 139 patients had no varices, and 41 patients demonstrated varices on initial examination. At 4 years, the risk of newly developing endoscopically confirmed varices was 16% for the ursodeoxycholic acid-treated patients and 58% for the placebo-treated patients (P < 0.001). Thus, the use of ursodeoxycholic acid was associated with a significantly lower risk of developing varices in patients with primary biliary cirrhosis. CONCLUSION: In addition to biochemical improvement, delay in death, and prolongation of time to orthotopic liver transplantation, ursodeoxycholic acid has now been demonstrated to decrease the risk of esophageal varices developing in patients with primary biliary cirrhosis.
Aged↗
Time course of histological progression in primary biliary cirrhosis.
Histological staging is used for stratification and assessment of treatment efficacy in therapeutic trials for primary biliary cirrhosis (PBC). Knowledge of the rate of progression of the histological changes would be helpful in the design (duration) and conduct of clinical trials. The histological stages were recorded for liver biopsies performed annually on 222 patients during a randomized, placebo-controlled clinical trial in which therapy with D-penicillamine (DPCA) was shown to be ineffective. These data were analyzed using a Markov model to describe the time course of histological progression in PBC. At study entry, 15 patients were stage I, 56 were stage II, 96 were stage III, and 55 were stage IV. Histological progression was observed after 1 year in 41%, 43%, and 35% of the patients, and after 2 years in 62%, 62%, and 50% of the patients who were stage I, stage II, and stage III at entry, respectively. After 4 years biopsies showed cirrhosis in 31% and 50% of the patients in stage I and stage II at entry, respectively. A minority (20%) of the precirrhotic patients showed histological stability; sustained histological regression was rarely observed (2%). Our data suggest that a majority of patients with PBC will progress histologically within 2 years. The distribution of histological stages over time may be helpful in determining the number of patients and length of time necessary to appreciate a treatment effect on histological progression in clinical trials for PBC.
Biopsy↗
Primary biliary cirrhosis clinical research single-topic conference.
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3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
The role of ultrasonography and automatic-needle biopsy in outpatient percutaneous liver biopsy.
The risk of complications from percutaneous liver biopsy is low, but discomfort is common and complications require hospitalization in approximately 4% of patients. The optimal method of performing these biopsies is unknown. The goal of our study was to determine whether the use of ultrasonography in the biopsy room immediately prior to or during the procedure would lessen the risk of complications and to compare the safety and efficacy in obtaining tissue by use of a Trucut needle versus an automatic biopsy needle. Between 1992 and 1994, 836 patients were entered into a randomized study (489 in Rochester, MN; 347 in Barcelona, Spain). Patients were randomized immediately prior to liver biopsy into four groups: Trucut needle, or automatic biopsy needle, and with or without ultrasonography. Fisher's Exact Test and a logistic regression model were also used to assess the effect of needle and ultrasonography on the odds for complications. The four biopsy groups were well-matched at entry with respect to age, sex, underlying liver disease, hemoglobin, prothrombin time, and platelet count. The use of ultrasound was associated with a decreased rate of hospitalization for pain, hypotension, or bleeding (2 vs. 9, P < .05). No difference in safety was found between the two types of needles. The number of passes needed to obtain specimens was similar for all four groups. The average length of the specimen was slightly greater with ultrasonographic-guided biopsies (1.7 mm vs. 1.6 mm, P < .05) and with biopsies obtained using the automatic biopsy needle when compared with the Trucut needle (1.7 mm vs. 1.5 mm, P < .05), but this did not seem to be clinically important. The addition of ultrasonography reduces complications in patients undergoing percutaneous liver biopsy. The type of needle appears to offer little difference in safety or yield of diagnostic tissue. The use of ultrasonography for guidance of percutaneous liver biopsy will lead to a lower rate of complications. The value of this benefit must be weighed against the added cost of ultrasonographic guidance.
Adolescent↗
Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.
Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase activities with hepatic steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Our aim was to conduct a pilot study to evaluate the safety and estimate the efficacy of ursodeoxycholic acid (UDCA) and clofibrate in the treatment of NASH. Forty patients were diagnosed with NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound. Twenty-four patients received 13 to 15 mg/kg/d of UDCA for 12 months. Sixteen patients with hypertriglyceridemia were placed on clofibrate, 2 g/day for 12 months. Twenty-five women and 15 men entered the study. Six of 40 patients (15%) withdrew because of side effects. Four additional patients were withdrawn because of noncompliance; one of them later required liver transplantation. In the UDCA group, the decreases in mean serum levels of alkaline phosphatase, alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) as well as histological grade of steatosis were significant. Among the patients treated with clofibrate, no change from baseline was found in mean ALT, aspartate transaminase (AST), GGT, bilirubin, triglycerides, and cholesterol, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase activities decreased significantly from baseline. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this 1-year pilot study. However, treatment of NASH with UDCA for 12 months resulted in significant improvement in alkaline phosphatase, ALT, GGT, and hepatic steatosis. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial.
Alanine Transaminase↗
Diagnosis and therapy of cholestatic liver disease.
The majority of cholestatic liver diseases can be diagnosed with a carefully performed history taking, physical examination, and appropriate imaging studies. In a minority of cases, however, liver biopsy may be necessary to establish the diagnosis. In addition to the treatment of the specific liver disease, therapy should address the management of complications unique to cholestasis and progressive liver failure.
Adult↗
Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis.
BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) has been shown to be a safe and effective treatment for patients with primary biliary cirrhosis; however, its effect on patient survival is less certain. To study this issue, the survival of patients receiving long-term UDCA treatment was compared with that of a control group, adjusting for their risk scores based on the Mayo model. METHODS: One hundred eighty patients were randomized to receive either 13-15 mg.kg-1.day-1 UDCA (n = 89) of placebo (n = 91). After the study closure, the patients originally receiving placebo were switched to active drug, and prospective follow-up was continued for 3 years. Patients were censored at the time of transplantation, voluntary withdrawal, of crossover of the placebo group (efficacy analysis). The survival of the two groups was adjusted for risk scores at the time of entry to the study. A secondary analysis was an intent-to-treat analysis, whereby patients were followed up regardless of their voluntary withdrawal or crossover. RESULTS: At the time of analysis, the patients receiving placebo had a significantly increased risk of death and/or requiring transplantation (relative risk, 2.6; P = 0.04) compared with the UDCA-treated patients CONCLUSIONS: UDCA should be considered as a safe, effective, and life-extending treatment for patients with primary biliary cirrhosis.
Adult↗
Ursodeoxycholic acid and methotrexate for primary sclerosing cholangitis: a pilot study.
OBJECTIVE: Ursodeoxycholic acid (UDCA) and methotrexate (MTX) are both undergoing evaluation for the treatment of patients with primary sclerosing cholangitis (PSC). In this pilot study, we sought to study the safety and estimate of efficacy of a combination of these two drugs administered over a 2-yr period in patients with PSC. METHODS: Nineteen patients with well defined PSC were entered prospectively into a pilot study with anticipation of 2-yr follow-up. The patients received UDCA (13-15 mg/kg/day)in divided doses in conjunction with MTX (0.25 mg/kg/wk). The results of treatment were compared with a concurrently studied, but not randomized, group of 10 patients receiving UDCA alone. At entry, the two groups were comparable with respect to age, sex, liver biochemistries, and histological stage when available. RESULTS: During this period, five patients treated with the combination of UDCA and MTX were severed from the study (three referred for transplantation, one death from small bowel cancer, and one with pre-existing, high ileostomy output who withdrew voluntarily). MTX was discontinued by the investigators in an additional five patients (hair loss in three, pulmonary problems in two). There was no change in fatigue or itching compared with baseline in the group receiving the UDCA/MTX combination. Changes in biochemistries from baseline values were not different in the group receiving UDCA and MTX compared with the group receiving UDCA alone. Furthermore, after MTX was withdrawn and UDCA was continued, there was no clear evidence of further biochemical change. The use of MTX in combination with UDCA was associated with toxicity without any further improvement in liver biochemistries compared with the use of UDCA alone. CONCLUSION: This pilot study found no evidence to support the use of MTX in combination with UDCA for patients with PSC.
Adult↗
Effects of ursodeoxycholic acid on hepatic inflammation and histological stage in patients with primary biliary cirrhosis.
OBJECTIVES: Ursodeoxycholic acid (UDCA) has been reported to be of benefit in the treatment of primary biliary cirrhosis; however, the effects of UDCA on the histological features of primary biliary cirrhosis are uncertain. The goal of this study was to determine the histological effects of 2 yr of treatment with UDCA compared to placebo in a prospective randomized trial of primary biliary cirrhosis. We also sought to correlate the changes in inflammation and histological stage with changes in serum bilirubin, Mayo Risk Score, and the percentage of UDCA in bile in these patients. METHODS: Sixty-one patients (32 receiving UDCA, 29 receiving placebo) who had initial and 2-yr biopsies were studied. Biopsy specimens were evaluated by a single pathologist under coded identification. The degree of inflammation and histological stage were graded on a scale of 0 to 4. RESULTS: There was no significant difference in the degree of inflammation with UDCA treatment when compared to the placebo group at 2 yr. There was a significant but weak indirect association between degree of enrichment of UDCA and changes in inflammation (r = -0.34, p = .02). There was no detectable change in stage in either the UDCA-treated or placebo group when comparing pre- and posttreatment specimens. There were no associations with changes in serum bilirubin or Mayo Risk Score and degree of inflammation. CONCLUSIONS: No significant changes in the degree of inflammation or histological stage were apparent after 2 yr of treatment with UDCA or in the placebo group. A tendency toward improvement in inflammation was noted with greater degrees of biliary UDCA enrichment. Longer term studies will be necessary to determine whether UDCA has a beneficial effect on histological stage.
Bilirubin↗
Colchicine and ursodeoxycholic acid for primary biliary cirrhosis: emerging results.
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Colchicine↗
The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study.
Ursodeoxycholic acid (UDCA) and methotrexate (MTX) have both been proposed as treatments for patients with primary biliary cirrhosis (PBC). It has been suggested that a combination of the two drugs may offer advantages over either used separately. In this pilot study, we sought to evaluate the safety and efficacy of this combination for patients with PBC. Thirty-two patients with antimitochondrial antibody positive PBC were prospectively entered into a pilot study and received UDCA, 13 to 15 mg/kg/d, in conjunction with MTX, 0.25 mg/kg/wk, for a period of 2 years. The results of this treatment were compared with those obtained from 180 patients with PBC studied in a placebo-controlled trial of UDCA alone conducted during the same period. Patients in the pilot study and randomized study were comparable with regard to age, gender, and liver biochemistries. The UDCA/MTX-treated patients were of earlier histologic stage and had a lower mean Mayo risk score. During this period, seven patients in the UDCA/MTX group were withdrawn, four for pulmonary toxicity (two who required hospitalization), and one each with mouth ulcer, extreme fatigue, and hair loss. The use of UDCA/MTX was not associated with improvement in symptoms. In the patients receiving UDCA/MTX, biochemical changes were comparable to those of patients receiving UDCA alone but superior to those in the placebo group (P < .05). Histological changes were comparable in all groups at 2 years. Cessation of MTX while UDCA was continued led to no deterioration in liver biochemistries.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Two cases from the spectrum of nonalcoholic steatohepatitis.
Nonalcoholic steatohepatitis is a poorly understood disease that mimics alcoholic liver disease histologically. Its natural history is not well defined, although gradual progression to cirrhosis has been described. Most patients with this condition have been obese, with or without associated diabetes or hyperlipidemia. No known effective treatment exists for nonalcoholic steatohepatitis, although weight loss may have a beneficial effect. We report two cases of nonalcoholic steatohepatitis. One patient with well-established nonalcoholic steatohepatitis had cirrhosis with a complete loss of fat on subsequent liver biopsy despite a gain in weight, simulating cryptogenic cirrhosis. In another patient, the condition improved after use of ursodeoxycholic acid; this agent may be a potential therapeutic agent for the treatment of nonalcoholic steatohepatitis. We believe these two cases represent the spectrum of this condition: on the one end is a progressive liver disease that in some instances may be a cause of cryptogenic cirrhosis; at the other end, a potentially treatable liver condition.
Adult↗
Serum lipid and fat-soluble vitamin levels in primary sclerosing cholangitis.
We reviewed the initial lipid and fat-soluble vitamin levels in 56 patients with primary sclerosing cholangitis (PSC) enrolled in a randomized, placebo-controlled trial evaluating ursodeoxycholic acid. We also evaluated lipid and vitamin levels in a group of 87 patients with advanced PSC being evaluated for liver transplantation. Of the patients entering the therapeutic trial, 41% had total serum cholesterol levels greater than the 95th percentile, whereas only 20% had high-density lipoprotein cholesterol levels above normal, and only one (2%) had an elevated triglyceride level. Total cholesterol levels were correlated with serum bilirubin levels and were lower in early versus later histologic stages (206 +/- 61 vs. 248 +/- 79, p = 0.04). Of the 87 pretransplant patients, 29% had elevated serum cholesterol levels and 17% had elevated serum triglyceride levels. Total serum cholesterol levels correlated inversely with total serum bilirubin levels in this group. In patients in the therapeutic trial, vitamin A deficiency was seen in 40%, vitamin D deficiency in 14%, and vitamin E deficiency in 2% of those tested. More prominent deficiencies of fat-soluble vitamins occurred in the pretransplant group of patients, with 82% deficient in vitamin A, 57% deficient in vitamin D, and 43% deficient in vitamin E. We conclude that hypercholesterolemia and fat-soluble vitamin deficiencies are frequent in patients with PSC and are more common with more severe disease. Patients with PSC, especially with advanced liver disease, should be screened for fat-soluble vitamin deficiencies and supplemented accordingly.
Bilirubin↗
Characterisation of patients with a complete biochemical response to ursodeoxycholic acid.
Ursodeoxycholic acid (UDCA) leads to biochemical and clinical improvement in many patients with primary biliary cirrhosis (PBC); although, the response is variable. This study compared UDCA treated patients with complete normalisation of biochemical functions to those without such improvement. Of the 65 patients receiving UDCA, 12 (19%) showed normalisation of liver biochemical functions at two years. The remaining 53 patients showed a less complete response. Mean (SD) alkaline phosphatase and total serum bilirubin values were significantly lower at entry in the patients whose liver biochemistry tests normalised (912 (732) U/l v 1417 (1021) U/l, p = 0.003, and 0.7 (12.1 (5.2) mumol/l v 38.9 (48.5) mumol/l, p = 0.0002, respectively), and percentage of UDCA in biliary bile acid was higher (56.3 (9.5)% v 38.3 (21.1)%, p = 0.03). Patients with biochemically and histologically less severe disease, and greater enrichment of biliary bile with UDCA, are more likely to respond favourably to the drug. The main objective of continued study will be to find out if normal liver biochemical functions can retard disease progression. The association of greater UDCA enrichment with complete biochemical responses suggests that higher doses of UDCA should be evaluated.
Adult↗
Bone disease in primary biliary cirrhosis: does ursodeoxycholic acid make a difference?
Ursodeoxycholic acid (UDCA) has been proposed as beneficial therapy for patients with primary biliary cirrhosis (PBC). The effects of UDCA on metabolic bone disease, a major source of morbidity in patients with PBC, are essentially unknown. Preliminary information suggests that UDCA may improve biochemical indices of bone disease, although information about the effects of UDCA on bone density is lacking. In this study, we describe the effects of UDCA on lumbar spine bone mineral densities over a 3-year period during which patients were enrolled in a randomized, double-blind, therapeutic trial of UDCA for the treatment of PBC. Lumbar spine dual-photon densitometry was measured at entry and annually. Eighty-eight patients, 50 in the UDCA group and 38 in the placebo group, had serial measurements available for up to 3 years. There was no statistical difference between the two treatment groups at entry with respect to histological stage, total bilirubin, age, use of calcium supplement, vitamin D levels, or estrogen. After 3 years of treatment, there was no significant difference in the lumbar spine bone densitometry measurements between the UDCA-treated and placebo groups. We conclude that, after 3 years of treatment, UDCA is not associated with statistically significant differences in the rate of bone loss from the lumbar spine in patients when compared with placebo despite beneficial effects of treatment on the underlying liver disease. Further efforts to define effective treatments for the bone disease need to be pursued.
Adult↗