: Background/Aims: Ursodeoxycholic acid (UDCA) is an effective therapy for most patients with primary biliary cirrhosis (PBC). During the management of these treated patients, a number of clinically ...important issues arose including which patients might be candidates for combined therapy, which patients require endoscopy for variceal bleeding, and how survival can be predicted during treatment. Our aims were: 1) to identify factors associated with a suboptimal response to UDCA in patients with PBC; 2) to define a simple, non‐invasive method to predict those PBC patients most apt to have esophageal varices; and 3) to determine the reliability of the Mayo survival model in predicting the course of UDCA treated patients. Methods: We analyzed the prospectively collected data of 180 patients, who we continue to follow, with PBC who participated in a randomized, placebo‐controlled trial of UDCA. Results: After six months of UDCA therapy, patients with serum alkaline phosphatase levels less than twice normal (p<0.04), and/or a Mayo risk score<4.5 (p<0.04) were more likely to respond favorably to treatment over a two year period. The Mayo risk score was the single risk factor independently predictive of development of varices (p<0.01); 93% of patients who developed varices had a Mayo risk score4. The Mayo survival model, recalculated after 6 months on UDCA therapy accurately predicted patient survival. Conclusions: Suboptimal responders to UDCA can be identified by assessment of serum alkaline phosphatase levels, and/or Mayo risk score. A Mayo risk score above 4 helps in selecting patients for endoscopic surveillance for varices and the Mayo survival model accurately predicts the clinical course in patients with PBC receiving UDCA.
Background/Aims
: Accelerated bone loss occurs early after liver transplantation (OLT) and, in cholestatic patients with pre-existing osteopenia, causes spontaneous fracturing. This study aimed to ...investigate the efficacy of calcitonin, a powerful inhibitor of bone resorption, in preventing or reducing the accelerated rate of bone loss and fracturing which occurs in patients with primary biliary cirrhosis and primary sclerosing cholarigitis early after OLT.
Methods
: Sixty-three patients undergoing OLT for primary biliary cirrhosis (
n
=26) and primary sclerosing cholarigitis (
n
=37) were randomized to receive: (a), 100 IU/day of salmon calcitonin subcutaneously for the first 6 months posttransplant; or (b), no therapy. At pretransplant, and at 4 and 12 months after OLT, patients were investigated clinically, biochemically, by bone mineral density of the lumbar spine, and by radiographs of the thoracolumbar spine, chest and site of any bone pain.
Results
: The bone mineral density of the lumbar spine fell equally at 4 months in both groups, from 0.85 to 0.81 g/cm
2
in calcitonin-treated patients (
n
=29) and from 0.88 to 0.82 g/cm
2
in controls (
n
=34); at 12 months, both groups had stabilized to 0.83 g/cm
2
. Fracturing was the same in both groups.
Conclusions
: Calcitonin therapy for the first 6 months after OLT is unable to prevent or reduce accelerated bone loss or spontaneous fractures which occur in the first posttransplant year.
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. (Gastroenterology 1996 May;110(5):1515-8)
This study was conducted to examine factors affecting health insurance and employment status in long‐term liver transplant (OLT) recipients. All adult primary OLT recipients surviving at least 1 year ...were surveyed using existing questionnaires. Out of 217 eligible recipients, 186 (86%) responded. The median age of respondents was 55 years with a median survival after OLT of 3.4 years. The majority (98%) of respondents had health insurance coverage. Thirty‐four (18%) reported having lost and/or having been denied health insurance since OLT, and 63 (34%) switched health insurance since OLT. Of the 179 that reported employment status, 98 (55%) were employed, including homemakers and students, while 39 (22%) were retired and 42 (24%) unemployed. The majority (76%) of those unemployed cited poor health as the reason for unemployment, followed by 5 (12%) who feared loss of disability or Medicaid benefits. Fourteen reported to have been denied or terminated from employment because of their transplant. In the regression analysis, employment prior to transplantation (odds ratio (OR) = 5.1), age less than 57 (OR = 5.1), physical function score >52.4 (OR = 3.6) and general health score >33.3 (OR = 7.6) were significantly associated with employment. These data may help identify high‐risk pre‐OLT patients for intervention measures such as work rehabilitation.
The Child‐Pugh classification is a simple, convenient prognostic measure in patients with liver cirrhosis. We investigated the relative role of the Child‐Pugh classification and the Mayo model in the ...assessment of survival in patients with primary sclerosing cholangitis (PSC). Of the 173 patients described in the original Mayo PSC natural history model, 147 patients had sufficient information in the medical record to allow computation of the Child‐Pugh score. We used our most recent modification of the Mayo model to compute the risk score, based on patient's age, serum levels of bilirubin, albumin, and aspartate aminotransferase and history of variceal bleeding. Using the risk score (R), patients were divided into the low‐ (R < 0), intermediate‐ (0 ≤ R < 2), and high‐risk (R ≥ 2) groups. Kaplan‐Meier estimates and proportional hazards analysis were used to evaluate the two prognostic models. Although there was a statistically significant correlation between the Child‐Pugh and Mayo risk scores, two‐thirds of the patients had a Child‐Pugh score of 5 or 6 and a relatively wide range of risk scores (−1.1‐4.3). The probability of survival for 7 years in patients in the low‐, intermediate‐, and high‐risk groups was 92%, 74%, and 40% for Child‐Pugh class A (n = 96) and 100%, 62%, and 28% for Child‐Pugh class B patients (n = 44), respectively. There were only a small number (n = 7) of Child‐Pugh class C patients. In our age‐adjusted multivariate analysis, each unit increase in the Mayo risk score was associated with a 2.5‐fold increase in the risk of death (95% confidence interval: 1.8‐3.4, P < .01), whereas Child‐Pugh classification had no significant impact on survival (Child‐Pugh B vs. A: risk ratio = 1.1 95% confidence interval: 0.6‐2.0; Child‐Pugh C versus A: risk ratio = 0.6 95% confidence interval: 0.2‐1.8). In contrast to the Child‐Pugh classification, which was developed for advanced liver cirrhosis, the Mayo model provides valid survival information, particularly in patients early in the course of PSC.
To address the effect of ursodeoxycholic acid therapy on development of esophageal varices in patients with primary biliary cirrhosis.
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.
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.
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.
Background/Aim: Ursodeoxycholic acid in doses of 13–15 mg·kg
−1·day
−1, is a safe and cost-effective treatment for patients with primary biliary cirrhosis. However, very limited information exists ...regarding the most appropriate dose of ursodeoxycholic acid. The aim of the study was to compare three dosages of ursodeoxycholic acid with respect to changes in liver biochemistries, Mayo risk score, biliary enrichment with ursodeoxycholic acid and side effects over at least a 1-year period.
Methods: A total of 155 patients were randomized to receive low- (5–7 mg·kg
−1·day
−1), standard-(13–15 mg·kg
−1·day
−1), and high- (23–25 mg·kg
−1·day
−1) doses of ursodeoxycholic acid.
Results: The improvements in alkaline phosphatase (
p=0.0001), aspartate aminotransferase (
p=0.0001), Mayo risk score (
p=0.002), and ursodeoxycholic acid enrichment (
p=0.0001) were significantly greater in the standard- and high-dose groups compared to the low-dose group, but not between the standard- and high-dose groups. Changes in serum bilirubin were similar between the three groups (
p=0.07). No significant effects on symptoms were noted with any dose. No patients discontinued ursodeoxycholic acid because of side effects or toxicity.
Conclusions: Ursodeoxycholic acid in doses of 5–25 mg·kg
−1·day
−1 is safe and well tolerated. The dose of 13–15 mg·kg
−1·day
−1 appears to be the preferred dose for patients with primary biliary cirrhosis.
Patients with nonalcoholic steatohepatitis (NASH) may develop progressive liver dysfunction necessitating liver transplantation (OLT). We report the incidence of recurrent disease and outcome in ...patients undergoing OLT for NASH. Patients transplanted for NASH were identified according to pretransplant and explant liver histology. Patients with significant alcohol consumption were excluded. Medical records were reviewed to extract pre- and posttransplant data, including sequential body weight, biochemistry, and graft histology. Of 622 liver explants, eight patients had features consistent with NASH. All patients were female with a median age of 58. Seven patients were diagnosed with NASH preoperatively, including three who had undergone jejunoileal bypass. One patient was diagnosed as cryptogenic cirrhosis. At a median of 15 months following OLT, all of the eight patients were alive with no graft failure. Six patients developed persistent fatty infiltration in their graft, three of whom had accompanying hepatocellular degeneration, consistent with a diagnosis of recurrent NASH. In two patients, transition from mild steatosis to steatohepatitis and early fibrosis was observed over one to two years. The patients who did not develop recurrent steatosis had significant weight loss following transplantation, although the length of follow-up was relatively short. Patients undergoing OLT for NASH may develop recurrent steatosis shortly after transplantation, with possible progression to steatohepatitis and fibrosis. Although longer follow-up is necessary to determine the eventual prognosis related to the recurrent fat and fibrosis in the graft, patients with endstage liver disease due to NASH should be considered good candidates for OLT.
Background/Aim: Osteoporosis is a common complication of primary biliary cirrhosis but there is no accepted therapy for the osteoporosis. In this randomized controlled trial, we compared the effects ...of etidronate to placebo on the treatment of osteoporosis associated with primary biliary cirrhosis.
Methods: Sixty-seven patients with primary biliary cirrhosis and osteopenia, defined by bone mineral density criteria (T-score <−2.0) were enrolled. Measurements of the lumbar spine and proximal femur, as well as x-rays of the lumbar spine, were obtained. Patients received cyclical etidronate 400 mg/day for 14 days every 3 months for at least 1 year. Supplemental calcium was administered on the days patients did not receive etidronate.
Results: Of the 67 patients entered, 60 completed at least 1 year of therapy. There was no significant difference in changes in bone density at either the lumbar spine or femur in patients receiving etidronate when compared to placebo. Fractures occurred in eight patients, four receiving etidronate. Etidronate therapy was associated with a significant reduction in markers of bone turnover compared to placebo. These changes did not correlate with changes in bone density.
Conclusions: Cyclical etidronate administered with supplemental calcium did not significantly improve bone density in patients with primary biliary cirrhosis.
Patients with primary biliary cirrhosis (PBC) may be at increased risk for malignancies. Several studies have addressed the risk of specific malignancies; however, there is little information about ...overall incidences of malignancies in these patients. We hypothesize that these patients may be at an increased risk for cancer. We performed a retrospective chart review evaluating patients with the diagnosis of PBC and malignancies. We reviewed records of patients with PBC presenting to the Mayo Clinic between 1976 and 1985. The diagnosis of PBC was made using evidence of cholestasis, positive antimitochondrial antibody titers and liver biopsy findings consistent with PBC. The incidence of malignancies were then compared with published data by the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute. Of the 1,692 patients with PBC in the Mayo Clinic data base, 114 patients were identified with primary cancer. The number of malignancies was higher than would be anticipated by chance alone; with 93 observed versus 62.4 expected events (P < .001). Hepatobiliary malignancies had a relative risk of 46 (P < .0001) for women and 55 (P < .0001) in men. There was a dramatic increased risk for development of hepatobiliary malignancies. PBC patients might benefit from more aggressive surveillance for hepatobiliary malignancies during their lifetime
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