The epidemiology of primary sclerosing cholangitis (PSC) in the United States is unknown. We report the incidence, clinical spectrum, and outcomes of PSC in Olmsted County, Minnesota.
Using the ...Rochester Epidemiology Project, a medical records linkage system in Olmsted County, Minnesota, we identified county residents with PSC, and the diagnosis was confirmed according to clinical, biochemical, radiographic, and histologic criteria.
Twenty-two patients met diagnostic criteria for PSC in 1976–2000. The age-adjusted (to 2000 U.S. whites) incidence of PSC in men was 1.25 per 100,000 person-years (95% CI, 0.70 to 2.06) compared with 0.54 per 100,000 person-years (95% CI, 0.22 to 1.12) in women. The prevalence of PSC in 2000 was 20.9 per 100,000 men (95% CI, 9.5 to 32.4) and only 6.3 per 100,000 women (95% CI, 0.1 to 12.5). Seventy-three percent of cases had inflammatory bowel disease, the majority with ulcerative colitis. Survival among PSC patients was significantly less than expected for the Minnesota white population of similar age and gender (
P < 0.001).
These data represent the first population-based estimates of the incidence and prevalence of PSC in the United States. The incidence and prevalence of PSC were approximately one third of those previously described for primary biliary cirrhosis in the same population. Our data suggest that the prevalence of PSC in the United States, with its attendant medical burdens, is significantly greater than previously estimated.
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disorder that can progress to cirrhosis, shortening life expectancy. PBC patients are often asymptomatic, present with biochemical ...cholestasis, and test positive (≥90%) for antimitochondrial antibodies (AMAs) in serum. Although AMA positivity without biochemical cholestasis may indicate increased risk of future PBC development, the contribution of these antibodies to pathogenesis remains enigmatic. Environmental risks and genetic determinants are likely implicated in PBC etiology. Given the familial aggregation of PBC, we hypothesized that AMAs also aggregate among relatives of PBC probands. We investigated the prevalence of AMAs in first‐degree relatives (FDRs) of PBC probands to examine whether AMAs aggregate in such pedigrees. Using a PBC family registry, we prospectively screened for AMAs in the serum of 306 FDRs in 145 pedigrees, 350 PBC probands, and 196 controls who were age‐matched, sex‐matched, race‐matched, and residence‐matched to probands. The prevalence of AMA in FDRs and controls was 13.1% and 1%, respectively. Greater prevalence of AMA was found in female FDRs of PBC probands sisters (20.7%), mothers (15.1%), and daughters (9.8%) than in male FDRs brothers (7.8%), fathers (3.7%), and sons (0%). Conclusions: AMAs aggregate among FDRs of PBC probands. Our data have clinical implications for FDRs of PBC probands because AMA positivity may suggest susceptibility to PBC. Thus, the identification and follow‐up of these relatives may lead to earlier disease diagnosis and treatment. Furthermore, if AMA development is heritable, this trait will provide a basis to dissect the genetic predisposition to PBC. (HEPATOLOGY 2007.)
Important innovations, such as hepatitis B immune globulin (HBIG) and lamivudine, have been introduced to the care of patients undergoing liver transplantation (OLT) for viral hepatitis B (HBV) (over ...the last 15 years). We analyzed survival of OLT recipients with HBV in the United States to examine the effect of these innovations. A retrospective analysis was conducted based on data collected prospectively by the United Network for Organ Sharing in all adult (older than 18) patients undergoing primary OLT in the United States between 1987 and 2002. OLT recipients with HBV were identified by the principal diagnosis of acute or chronic HBV or positive results on HBV markers. Patients were divided into Era 1 (1987‐1991), Era 2 (1992‐1996), and Era 3 (1997‐2002). Era 1 consisted of 6,708 patients (675 with HBV), Era 2 consisted of 13,995 patients (1,005 with HBV), and Era 3 consisted of 20,730 patients (1,723 with HBV). More recent patients were older and had less advanced liver disease and shorter ischemic time. The survival of patients with HBV was significantly better for Era 2 than for Era 1 (P < .01) and for Era 3 than for Era 2 (P < .01). There was no difference in survival between patients with HBV and all other diagnoses for Era 3 (P = .14). In the multivariable analysis, the effect of these eras persisted when other variables such as recipient and donor age, warm ischemic time, pre‐OLT disease severity, and hepatocellular carcinoma (HCC) were taken into account. Unlike previous reports, fulminant disease and Asian race had no effect on patient survival. In conclusion, these data underscore the effectiveness of therapeutic innovations that have occurred in the past two decades and indicate timely and widespread adoption of these measures by transplant centers nationwide. (Liver Transpl 2004;10:968–974.)
The usual method of estimating survival probabilities, namely the Kaplan-Meier method, is suboptimal in the analysis of deaths on the transplant waiting list. Death, transplantation, and withdrawal ...from list must all be considered. In this analysis, we applied the competing risk analysis method, which allows evaluating these end points individually and simultaneously, to compare the risk of waiting list death across era, blood types, liver disease diagnosis, and severity (Model for End-stage Liver Disease; MELD). Of 861 patients registered on the waiting list at Mayo Clinic Rochester between 1990 and 1999, 657 (76%) patients underwent transplantation, 82 (10%) died while waiting, 41 (5%) withdrew from the list, and 81 (9%) patients were still waiting as of February 2002. The risk of death at 3 years was 10% by the competing risk analysis. During the study period, the median time to transplantation increased from 45 to 517 days. In univariate analyses, there was no significant difference in the risk of death by era of listing (P = .25) or blood type (P = .31), whereas the risk of death was significantly higher in patients with alcohol-induced liver disease and those with higher MELD score (P < .01). A multivariable analysis showed that after adjusting for MELD, blood type, and diagnosis, patients listed in the latter era had higher mortality. In conclusion, the competing risk analysis method is useful in estimating the risk of death among patients awaiting liver transplantation.
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.
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.
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.
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.
Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease frequently leading to development of cirrhosis and its complications. Ursodeoxycholic acid (UDCA) is a beneficial medical ...therapy for patients with PBC. Improvement in some histological features, but not in histological stage, has been reported after 2 years of UDCA therapy. Thus, longer follow‐up may be necessary to determine whether UDCA has a favorable effect on histological stage of disease and progression to cirrhosis. Our aim was to determine the long‐term effects of UDCA therapy on histological stage and progression to cirrhosis in patients with PBC. Sixteen unselected patients with noncirrhotic PBC who had been on long‐term UDCA therapy (13‐15 mg/kg/d) for 6.6 ± 0.4 years (range, 5‐9 years) were identified and their histological finding during treatment compared with that of 51 noncirrhotic patients with PBC who had received ineffective therapy (d‐penicillamine DPCA or placebo) for 5.6 ± 0.07 years (range, 5‐8 years). Histological stage was determined using the Ludwig classification. The rate of progression to cirrhosis (stage 4) was significantly less in the UDCA group than in the control group (13% vs. 49%P= .009). Although the overall rate of progression of histological stage was less in the UDCA group than in the control group (50% vs. 71%), this difference was not significant (P= .1). A marked improvement in liver biochemistries and Mayo risk score was noted in all patients during UDCA therapy; however, this improvement was not significantly different between patients who progressed and those who did not. In conclusion, long‐term UDCA therapy appeared to delay the development of cirrhosis in PBC.
We examined whether consideration of repeated model for end‐stage liver disease (MELD) measurements for patients listed for liver transplantation improves predictive value beyond current MELD alone. ...Clinical data were extracted for all adult primary liver transplantation candidates from our institution who were listed with the United Network for Organ Sharing (UNOS) between 1990 and 1999. Serum creatinine, bilirubin, and international normalized ratio (INR) were obtained from an institutional laboratory database. Cox models were constructed using current MELD, change in MELD (Delta), and number of MELD scores to predict survival on the waiting list. Eight hundred and sixty‐one patients met inclusion criteria, 639 underwent transplantation, and 80 died while waiting. A one‐unit increment in current MELD imparted significant hazard ratios ranging from 1.12 to 1.19 in all models. Delta MELD was predictive of mortality univariately, but less predictive when current MELD was included, and not predictive when considered with both current and number of MELD scores. Overall, current MELD is the single most important determinant of mortality risk on the waiting list. Delta MELD is predictive of death only within 4 d of the event; however, part of this correlates with the dying process itself, thus limiting Delta MELD's utility in survival prediction models.
Background and Aims The pathogenesis of primary biliary cirrhosis (PBC) is unknown. The role of cytokines such as tumor necrosis factor‐α (TNF‐α) and transforming growth factor‐β (ΤGF‐β), and the ...effect of ursodeoxycholic acid (UDCA) in modifying the cytokine environment in patients with PBC has remained largely unstudied. Our aims were to determine: (i) the relationship between serum levels of TNF‐α and TGF‐β and the severity of PBC; and (ii) the effects of UDCA therapy on TNF‐α and TGF‐β levels in patients with PBC.
Methods We studied 90 patients who had been treated with UDCA (53 patients) or placebo (37 patients) for 2 years as part of a randomized, double‐blind, controlled trial. Patients were divided into histological stage I/II or stage III/IV disease. Serum TNF‐α and TGF‐β levels were quantified by enzyme‐linked immunoabsorbent assay.
Results Baseline levels of TNF‐α were significantly greater in patients with stage III/IV compared to stage I/II disease. After 2 years of treatment with UDCA, patients showed a significantly greater decrease in TNF‐α levels and progression risk score compared to placebo‐treated patients. TNF‐α and TGF‐β levels were significantly reduced compared to baseline levels in the UDCA‐treated group after 2 years, while there was no significant change in the levels of placebo‐treated patients.
Conclusions Serum TNF‐α and TGF‐β levels may reflect severity of disease in patients with PBC. The beneficial effects of UDCA therapy may be explained by lowering serum levels of these two cytokines.
Liver transplantation (LT) is an established therapy for patients with end‐stage primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). In this report, we describe the health status ...and quality of life (QOL) in patients with these cholestatic liver diseases before and after LT. A QOL questionnaire was completed by 157 adult patients with PBC or PSC before and 1 year after liver transplantation at the Mayo Clinic or Baylor University Medical Center. This questionnaire measured four aspects of QOL, including symptoms; physical, social, and emotional functioning; health perceptions; and overall QOL. Changes in these QOL parameters before and after LT were described, and regression analysis was used to assess the relationships between clinical and QOL factors. There were no differences in QOL parameters between patients with PBC and PSC. QOL following transplantation was substantially better than before transplantation. This was observed in all four aspects of QOL. The degree of improvement as measured by effect size (difference in mean scores divided by the pretransplantation standard deviation) was 0.53 for symptoms (P<.01), 1.16 for function (P < .01), 2.37 for health satisfaction (P < .01), and 1.16 for overall QOL (P< .01). Patients' overall QOL before transplantation was significantly related to subjective and objective health status indicators and clinical factors such as ascites and renal dysfunction. QOL at 1‐year follow‐up, however, could not be adequately predicted by the pretransplantation subjective health status and clinical factors. Patients with end‐stage cholestatic disease undergoing LT experience substantial improvement in all aspects of QOL addressed in this study. The patients' QOL 1 year after LT could not be predicted by pretransplantation variables used in this study
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.
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