Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis.

UNLABELLED: 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 (>or=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.

Deaths on the liver transplant waiting list: an analysis of competing risks.

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.

Employment and health insurance in long-term liver transplant recipients.

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.

Predicting survival among patients listed for liver transplantation: an assessment of serial MELD measurements.

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.

Outcome of liver transplantation for hepatitis B in the United States.

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.

Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Results of long-term ursodiol treatment for patients with primary biliary cirrhosis.

OBJECTIVE: When ursodeoxycholic acid (UDCA) is used for the treatment of primary biliary cirrhosis, it has been associated with biochemical improvement, histological stability, reduced risk of esophageal varices, and increased survival free of transplantation. There is limited information available about the long-term outcome of these patients with primary biliary cirrhosis on UDCA treatment. To address this, we reviewed the long-term results from patients enrolled in our original randomized study with up to 12 yr of follow-up. METHODS: From April 1988 to March 1992, a total of 180 patients were enrolled into a randomized, controlled trial evaluating UDCA (n = 89) versus placebo (n = 91). When the randomized portion of the study concluded in May 1992, patients were switched to active medication and followed for up to an additional 8 yr. RESULTS: Twenty-eight patients originally assigned to UDCA and 42 patients originally assigned to placebo have died or undergone transplantation. The patients who died or were transplanted were more histologically advanced at entry (p < 0.001). Seventy-six of the remaining 110 patients return for regular follow-up; mailed questionnaires were returned by an additional 25 patients, and nine patients have been lost to follow-up. Twenty-two of the 76 patients we follow have normal liver tests (ALP, bilirubin, and AST). Patients with normal liver tests had significantly lower levels of ALP and AST at baseline (p < 0.05), but did not differ in histological stage or total bilirubin from those with persistently abnormal tests. CONCLUSIONS: UDCA appears to be of most benefit when instituted in early stage disease. Although a substantial percentage of patients will achieve biochemical normalization on UDCA alone, there is a continued need for therapeutic options for others who have less complete biochemical responses.

Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis.

BACKGROUND AND AIMS: The pathogenesis of primary biliary cirrhosis (PBC) is unknown. The role of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), 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-alpha and TGF-beta and the severity of PBC; and (ii) the effects of UDCA therapy on TNF-alpha and TGF-beta 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-alpha and TGF-beta levels were quantified by enzyme-linked immunoabsorbent assay. RESULTS: Baseline levels of TNF-alpha 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-alpha levels and progression risk score compared to placebo-treated patients. TNF-alpha and TGF-beta 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-alpha and TGF-beta 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.