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.

A controlled trial of calcitonin therapy for the prevention of post-liver transplantation atraumatic fractures in patients with primary biliary cirrhosis and primary sclerosing cholangitis.

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 cholangitis 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/cm2 in calcitonin-treated patients (n = 29) and from 0.88 to 0.82 g/cm2 in controls (n = 34); at 12 months, both groups had stabilized to 0.83 g/cm2. 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.

A model to predict survival in patients with end-stage liver disease.

A recent mandate emphasizes severity of liver disease to determine priorities in allocating organs for liver transplantation and necessitates a disease severity index based on generalizable, verifiable, and easily obtained variables. The aim of the study was to examine the generalizability of a model previously created to estimate survival of patients undergoing the transjugular intrahepatic portosystemic shunt (TIPS) procedure in patient groups with a broader range of disease severity and etiology. The Model for End-Stage Liver Disease (MELD) consists of serum bilirubin and creatinine levels, International Normalized Ratio (INR) for prothrombin time, and etiology of liver disease. The model's validity was tested in 4 independent data sets, including (1) patients hospitalized for hepatic decompensation (referred to as "hospitalized" patients), (2) ambulatory patients with noncholestatic cirrhosis, (3) patients with primary biliary cirrhosis (PBC), and (4) unselected patients from the 1980s with cirrhosis (referred to as "historical" patients). In these patients, the model's ability to classify patients according to their risk of death was examined using the concordance (c)-statistic. The MELD scale performed well in predicting death within 3 months with a c-statistic of (1) 0.87 for hospitalized patients, (2) 0.80 for noncholestatic ambulatory patients, (3) 0.87 for PBC patients, and (4) 0.78 for historical cirrhotic patients. Individual complications of portal hypertension had minimal impact on the model's prediction (range of improvement in c-statistic: <.01 for spontaneous bacterial peritonitis and variceal hemorrhage to ascites: 0.01-0.03). The MELD scale is a reliable measure of mortality risk in patients with end-stage liver disease and suitable for use as a disease severity index to determine organ allocation priorities.

Outcome of hospital care of liver disease associated with hepatitis C in the United States.

We describe mortality and resource utilization for inpatient care of hepatitis C (HCV) in comparison to alcohol-induced liver disease (ALD) in the United States and identify factors that affect outcomes. The Healthcare Cost and Utilization Project database, a national inpatient sample was used to identify hospitalization records with diagnoses related to liver disease from HCV and ALD. Outcome of hospitalizations was analyzed in terms of in-hospital deaths and health care resource utilization. For 1995, we estimate that there were 26,700 hospitalizations and 2,600 deaths in acute, nonfederal hospitals in the United States for liver diseases caused by HCV. Total charges for these hospitalizations were $514 million. In comparison, ALD was associated with 101,200 hospitalizations, 13,400 deaths, and $1.8 billion in charges. Simultaneous HCV and alcohol abuse was associated with younger ages at the time of hospitalization and death compared with HCV or ALD alone. In a logistic regression analysis, alcohol abuse (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.5) and human immunodeficiency virus (HIV) infection (OR, 4.5; 95% CI, 4.0-4.9) were associated with an increased risk of death among those with HCV. Liver transplantation and patient death were associated with the largest increase in hospitalization charges. Major complications of cirrhosis, such as variceal bleeding, encephalopathy, and hepatorenal syndrome, and sociodemographic factors, such as race and health insurance, were also significantly associated with the risk of death and hospitalization charges, which were similar in HCV and ALD. This study provides new estimates regarding the public health impact of HCV, for use in health policy decisions and cost-effectiveness analyses of preventive and therapeutic interventions.

Epidemiology and natural history of primary biliary cirrhosis in a US community.

BACKGROUND & AIMS: The epidemiology of primary biliary cirrhosis (PBC) has not been studied systematically in the United States. We report the incidence and prevalence of this condition in the general population. We also examined the validity of the Mayo natural history model for PBC among these unselected patients from the community. METHODS: The Rochester Epidemiology Project entails a computerized index of diagnoses from the health care encounters of residents of Olmsted County, Minnesota. For potential cases identified using this database, the complete (inpatient and outpatient) medical records were reviewed to verify the diagnosis and extract information necessary for the application of the Mayo model. We estimated the incidence and prevalence of PBC in this population and compared the actual survival of patients with PBC in the community with the survival predicted for PBC patients by the Mayo natural history model. RESULTS: The age-adjusted (to 1990 U.S. whites) incidence of PBC per 100,000 person-years for years 1975-1995 was 4.5 (95% confidence interval [CI], 3.1-5.9) for women, 0.7 (95% CI, 0.1-1.3) for men, and 2.7 (95% CI, 1.9-3.5) overall. The age- and sex-adjusted prevalence per 100,000 persons as of 1995 was 65.4 (95% CI, 43.0-87.9) for women, 12.1 (95% CI, 1.1-23.1) for men, and 40.2 (95% CI, 27.2-53.1) overall. The Mayo natural history model accurately predicted the actual survival of these patients. CONCLUSIONS: This first description of the epidemiology of PBC in the United States indicates that its incidence and prevalence in this country are among the highest reported. Outcomes among these unselected patients from a community population further validated the Mayo natural history model of PBC.

Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial.

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.

Impact of nutritional status on outcomes after liver transplantation.

BACKGROUND: Poor preoperative nutritional status has been reported to be associated with adverse outcomes after liver transplantation. Published data are, however, conflicting, with methods of preoperative nutritional assessment and postoperative outcomes varying between studies. METHODS: We prospectively studied the predictive value of preoperative nutritional status for adverse outcomes after liver transplantation. Assessment of preoperative nutritional status included: body cell mass determination, subjective global assessment, anthropometry, handgrip dynamometry, biochemical and amino acid profile, Child's score, and dual-energy x-ray absorptiometry. Death, intensive care unit (ICU) length of stay > or =4 days, hospital length of stay > or =15 days, blood usage > or =36 U of blood products, infection, rejection, and global resource utilization (an index of cost) greater than the median were considered poor outcomes. RESULTS: Fifty-three patients were studied. Longer ICU stay was associated with lower handgrip strength (P<0.01) and lower aromatic amino acid levels (P<0.01). Longer total hospital stay and the development of infections were associated with lower branched chain amino acid levels (P<0.01 and <0.001, respectively). Acute cellular rejection was associated with lower total body fat (P<0.001) and higher triglyceride levels (P<0.02). Neither death nor higher global resource utilization was associated with any preoperative nutritional parameter. CONCLUSIONS: Lower preoperative handgrip strength and branched chain amino acid levels are associated with longer ICU stays and increased likelihood of posttransplant infections. In our program, in which nutritional support was provided to potential recipients exhibiting malnourishment, none of the measured nutritional parameters were associated with mortality or greater global resource utilization.

Reliability and validity of the NIDDK-QA instrument in the assessment of quality of life in ambulatory patients with cholestatic liver disease.

The NIDDK-QA instrument, developed and widely used in liver transplant recipients, assesses quality of life (QOL) in four domains, including liver disease symptoms, physical function, health satisfaction, and overall well-being. We investigated whether the instrument may be used as a disease-specific instrument in ambulatory patients with cholestatic liver disease. The NIDDK-QA instrument was administered in 96 patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) seen at the Mayo Clinic. The SF-36, a well-established generic instrument, was also administered. Standard measures for test-retest reliability, internal consistency, and discriminant and concurrent validity were examined. All patients were ambulatory with mostly normal levels of serum bilirubin and albumin concentrations. The reliability of the NIDDK-QA, as measured by test-retest correlation (Pearson coefficients: 0.82-0.99, P <.01) and by internal consistency (Cronbach's alpha: 0.87-0.94) exceeded conventional acceptability criteria. The correlation between domain scores of the NIDDK-QA and SF-36 was clear and logical in that the physical function domain of NIDDK-QA strongly correlated with the physical component summary score of SF-36 (r = 0.86, P <.01). The overall well-being domain of the NIDDK-QA was closely associated with the mental summary score of SF-36 (r = 0.69, P <.01). Among PBC patients, there was a modest yet significant correlation between the Mayo risk score and overall well-being (r = -0.26, P =.03). In the assessment of QOL in patients with cholestatic liver disease, NIDDK-QA is found reliable and valid. These data, combined with our previous study, demonstrate its applicability in a wide spectrum of disease severity, ranging from early, ambulatory-phase disease to decompensated cirrhosis necessitating liver transplantation.

The timing of liver transplantation in primary biliary cirrhosis.

Primary biliary cirrhosis, the most common chronic cholestatic liver disease in adults, usually progresses to cirrhosis and its complications. Ursodeoxycholic acid therapy delays disease progression, but most patients will ultimately succumb. Liver transplantation is now accepted as the standard treatment for end-stage PBC. Development of major complications of portal hypertension and liver failure, poor quality of life and short survival without transplantation are the major indications for this surgical intervention in patients with primary biliary cirrhosis. Resource use is another key variable to be considered in the timing of liver transplantation. Prognostic models have been developed to predict survival and resource utilization with and without liver transplantation. Prognostic models aid the clinician in the selection and timing of liver transplantation in the patient with primary biliary cirrhosis.

Utility of standard nutritional parameters in detecting body cell mass depletion in patients with end-stage liver disease.

Protein-calorie malnutrition, best measured by body cell mass (BCM) depletion, has been associated with adverse outcomes in patients with end-stage liver disease. We prospectively measured BCM and multiple standard nutritional parameters in patients with end-stage liver disease to determine which, if any, of the traditionally measured nutritional parameters correlate with BCM. A detailed nutritional assessment, including BCM analysis, subjective global assessment, anthropometry, handgrip dynamometry, laboratory tests, and body composition measured by dual-energy X-ray absorptiometry was performed in 69 sequential patients awaiting liver transplantation. The frequency of abnormalities of specific parameters of nutritional status varied between 19% and 99%. Most of the commonly measured parameters of nutritional status correlated poorly with BCM. Patients with depleted BCM (lowest quartile for sex) had midarm circumference (P <.01), arm-muscle circumference (P <.001), handgrip strength (P <.001), blood urea nitrogen (P <.01), and creatinine (P <.01) values less than those for patients with greater BCM (highest 3 quartiles for sex). In multivariate analysis, arm-muscle circumference and handgrip strength were the best predictors of BCM. The combined criteria of handgrip strength less than 30 kg and arm-muscle circumference less than 23 cm have a sensitivity of 94% and a negative predictive value of 97% in identifying patients with depleted BCM. Although abnormalities of nutritional parameters are highly prevalent among patients with end-stage liver disease, most parameters of nutritional status do not correlate with BCM. In patients with end-stage liver disease, arm-muscle circumference and handgrip strength are the most sensitive markers of BCM depletion.

A revised natural history model for primary sclerosing cholangitis.

OBJECTIVE: To describe a natural history model for primary sclerosing cholangitis (PSC) that is based on routine clinical findings and test results and eliminates the need for liver biopsy. PATIENTS AND METHODS: Using the Cox proportional hazards analysis, we created a survival model based on 405 patients with PSC from 5 clinical centers. Independent validation of the model was undertaken by applying it to 124 patients who were not included in the model creation. RESULTS: Based on the multivariate analysis of 405 patients, a risk score was defined by the following formula: R = 0.03 (age [y]) + 0.54 loge (bilirubin [mg/dL]) + 0.54 loge (aspartate aminotransferase [U/L]) + 1.24 (variceal bleeding [0/1]) - 0.84 (albumin [g/dL]). The risk score was used to obtain survival estimates up to 4 years of follow-up. Application of this model to an independent group of 124 patients showed good correlation between estimated and actual survival. CONCLUSIONS: A new model to estimate patient survival in PSC includes more reproducible variables (age, bilirubin, albumin, aspartate aminotransferase, and history of variceal bleeding), has accuracy comparable to previous models, and obviates the need for a liver biopsy.

Adaptation of the Mayo primary biliary cirrhosis natural history model for application in liver transplant candidates.

The Mayo natural history model has been used widely as a tool to estimate prognosis in patients with primary biliary cirrhosis (PBC), particularly liver transplant candidates. We present an abbreviated model in which a tabular method is used to approximate the risk score, which may be incorporated in the minimal listing criteria for liver transplant candidates. Data used in the development and validation of the original Mayo model were derived from 418 patients with well-characterized PBC. To construct an abbreviated risk score in a format similar to that of Child-Turcotte-Pugh score, 1 to 3 cut-off criteria were determined for each variable, namely age (0 point for <38, 1 for 38 to 62 and 2 for >/=63 years), bilirubin (0 point for <1, 1 for 1 to 1.7, 2 for 1.7 to 6.4, and 3 for >6.4 mg/dL), albumin (0 point for >4.1, 1 for 2.8 to 4.1, and 2 for <2.8 g/dL), prothrombin time (1 point for normal and 2 for prolonged) and edema (0 point for absent and 1 for present). The intervals between these criteria were chosen in a way to enable a meaningful classification of patients according to their risk for death. This score is highly correlated with the original risk score (r = 0.93; P <.01). The Kaplan-Meier estimate at 1 year was 90.6% in patients with a score of 6. The abbreviated risk score is a convenient method to quickly estimate the risk score in patients with PBC. An abbreviated score of 6 may be consistent with the current minimal listing criteria in liver transplant candidates.

The economic impact of cytomegalovirus infection after liver transplantation.

BACKGROUND: We studied the economic impact of cytomegalovirus (CMV) disease and its effective reduction with antiviral prophylaxis in liver transplant recipients. METHOD: Analysis of institutional charge data accumulated during a prospective, randomized, controlled trial comparing oral acyclovir 800 mg four times daily for 120 days (ACV) and intravenous ganciclovir 5 mg/kg every 12 h for 14 days followed by ACV for 106 days (GCV) was performed. RESULTS: Liver transplant recipients who developed CMV disease had significantly higher charges (median: $148,300) than those who developed asymptomatic CMV infection ($119,600) or experienced no CMV infection ($114,100) (P<0.01). A multiple linear regression analysis indicated that CMV disease is associated with a 49% increase in charges, independent of other factors influencing increased hospitalization charges. In CMV-seronegative patients who received a CMV-seropositive donor organ, GCV prophylaxis was associated with a significant reduction in charges, as compared to ACV prophylaxis ($113,900 vs. $153,300, respectively; P=0.02). CONCLUSIONS: CMV disease is an independent risk factor for increased resource utilization associated with liver transplantation. The use of an effective prophylactic antiviral regimen provides savings in health care resources, particularly in patients at high risk for developing CMV disease.

Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primary biliary cirrhosis (PBC). However, some patients show an incomplete response to UDCA therapy. Treatment with corticosteroids may be of benefit although at the expense of systemic side effects. Budesonide, a corticosteroid with an extensive first-pass hepatic metabolism appeared promising for the treatment of PBC. The aim of this study was to evaluate the safety and estimate the efficacy of budesonide in patients with PBC, who have shown a suboptimal response to UDCA. Twenty-two patients with PBC, 16 women, median age of 50 who had been on UDCA (13-15 mg/kg/d) for a mean of 46 months (range 6-108 months) and had shown a persistent elevation of alkaline phosphatase activity at least 2 times the upper limit of normal were enrolled. Oral budesonide, 9 mg daily was administered for 1 year and patients continued on the same dosage of UDCA. There was a significant, but transitory improvement in serum levels of total bilirubin (P =.001) and a significant, but marginal improvement in serum alkaline phsophatase (P =.001) with combination therapy. The Mayo risk score increased significantly (P =.02) and there was a significant loss of bone mass (P <.001) of the lumbar spine. Budesonide-induced hyperglycemia and cosmetic adverse effects were noted in 2 patients. In conclusion, oral budesonide appears to add minimal, if any, additional benefit to UDCA, and it is associated with a significant worsening of osteoporosis in patients with PBC.

Timing of liver transplantation.

Under the current environment of liver transplantation, there are several factors to be considered in the timing of liver transplantation. These include expected patient survival with and without liver transplantation, patient's morbidity and quality of life before and after liver transplantation and overall resource utilization. Statistical models have been developed for patients with chronic liver disease, particularly of cholestatic variety. By applying these models in patients being considered for liver transplantation, a window of optimal timing of liver transplantation may be defined in such way that the survival gain is maximized and perioperative mortality minimized. Likewise, a number of pretransplant morbidity indicators such as Child-Pugh score, UNOS status, and renal insufficiency have been found to have a profound influence on post-transplant morbidity, thus resource utilization. An increasing number of investigators have measured and documented a dramatic improvement in the quality of life of patients before and after liver transplantation. As the waiting time and uncertainty of the outcome of liver transplantation increase, consideration of these factors may be useful for physicians evaluating transplant candidates to make best-informed decisions in the selection of candidates and timing for liver transplantation.

Is routine cholangiography useful in men with suspected primary biliary cirrhosis?

The aim of this study was to assess the diagnostic value of cholangiography in men with chronic cholestasis and positive antimitochondrial antibody (AMA) titers who were suspected of having primary biliary cirrhosis (PBC). The authors reviewed retrospectively the records of men who had positive AMA titers over a 16-month period to determine the results of cholangiography. They also reviewed the records of 102 patients with primary sclerosing cholangitis (PSC) from 1989 to 1995 who had undergone cholangiography and testing for AMA. Of 35 men with positive tests for serum AMA, 12 of these patients were referred for cholangiography (11 endoscopic and 1 transhepatic). All completed cholangiograms were normal. A diagnosis of PBC was made in nine patients and atypical autoimmune hepatitis in one. Conversely, only two PSC patients had positive AMA titers (1:20 and 1:80). Both of these patients had coexisting inflammatory bowel disease and cholangiograms diagnostic of PSC. Cholangiography was negative in the male patients with positive AMA titers who were suspected of having PBC. In men with cholestatic liver biochemistries and strongly positive AMA titers, especially in the absence of associated inflammatory bowel disease, routine cholangiography does not add to the diagnostic evaluation.

Effect of pretransplantation ursodeoxycholic acid therapy on the outcome of liver transplantation in patients with primary biliary cirrhosis.

As ursodeoxycholic acid (UDCA) delays the need for transplantation, this could result in patients with more comorbid disease, therefore more likely to have a worse outcome posttransplantation. The aim of this study is to compare posttransplantation outcome in patients who received UDCA versus placebo who subsequently required a liver transplant. Data on all trial patients referred for transplantation were retrospectively collected from three randomized controlled trials of UDCA in patients with primary biliary cirrhosis (PBC). An intent-to-treat analysis was conducted with patients assigned to their original treatment allocation. UDCA and placebo groups were compared at trial entry, transplant referral, just before transplantation, and 1 month and 1 year posttransplantation. From 1987 to 1996, 37 UDCA-treated and 53 placebo patients were referred for transplantation; their age, sex, and serum bilirubin levels were similar at study entry. Immediately before transplantation, these two groups were again similar with respect to age, bilirubin level, Mayo risk score, and serum creatinine level. Posttransplantation survival rates at 1 month were 93.9% in the UDCA group and 88.4% in the placebo group, and 1 year survival rates were 90.3% and 78.4%, respectively (not significant). Posttransplantation, the two groups had similar rates of infection (53.9% v 58%); however, rejection occurred significantly less often in the UDCA group; 42.9% versus 68. 8% in the placebo group (P =.04). The posttransplantation outcome of UDCA-treated patients with PBC is no different from those who were administered placebo. There is no evidence to suggest the beneficial effect of UDCA in delaying the need for transplantation is associated with a worse outcome once liver transplantation becomes necessary.

Hepatic retransplantation in cholestatic liver disease: impact of the interval to retransplantation on survival and resource utilization.

The aim of our study was to quantitatively assess the impact of hepatic retransplantation on patient and graft survival and resource utilization. We studied patients undergoing hepatic retransplantation among 447 transplant recipients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) at 3 transplantation centers. Cox proportional hazards regression analysis was used for survival analysis. Measures of resource utilization included the duration of hospitalization, length of stay in the intensive care unit, and the duration of transplantation surgery. Forty-six (10.3%) patients received 2 or more grafts during the follow-up period (median, 2.8 years). Patients who underwent retransplantation had a 3.8-fold increase in the risk of death compared with those without retransplantation (P <.01). Retransplantation after an interval of greater than 30 days from the primary graft was associated with a 6.7-fold increase in the risk of death (P <.01). The survival following retransplantations performed 30 days or earlier was similar to primary transplantations. Resource utilization was higher in patients who underwent multiple consecutive transplantations, even after adjustment for the number of grafts during the hospitalization. Among cholestatic liver disease patients, poor survival following hepatic retransplantation is attributed to late retransplantations, namely those performed more than 30 days after the initial transplantation. While efforts must be made to improve the outcome following retransplantation, a more critical evaluation may be warranted for late retransplantation candidates.

Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial.

BACKGROUND/AIM: Ursodeoxycholic acid in doses of 13-15 mg x kg(-1) x 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 x kg(-1) x day(-1)), standard-(13-15 mg x kg(-1) x day(-1)), and high- (23-25 mg x kg(-1) x 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 x kg(-1) x day(-1) is safe and well tolerated. The dose of 13-15 mg x kg(-1) x day(-1) appears to be the preferred dose for patients with primary biliary cirrhosis.