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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

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.

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- (R0), intermediate- (0/= R2), 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.

Objective: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. Methods: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. Results: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) (p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p ≤ 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. Conclusion: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.

Objectives A variety of autoimmune conditions occur in association with primary biliary cirrhosis. Among these conditions are sicca syndrome, Raynaud's phenomenon, arthritis, and Hashimoto's thyroiditis. Information is sparse regarding the prevalence and natural history of these conditions when associated with primary biliary cirrhosis and their response to ursodeoxycholic acid treatment. We evaluated the prevalence, natural history, and response to ursodeoxycholic acid therapy of these conditions coassociated with primary biliary cirrhosis. Methods One hundred-eighty patients with primary biliary cirrhosis, enrolled in a prospective randomized controlled trial of ursodeoxycholic acid (13-15 mg/ kg/day), were included. Patients were assessed at study entry and annually. Results At entry, 77/180 patients (43%) had one of the four conditions, and 18/180 patients (10%) had two or more conditions. Sicca syndrome was the most common, occurring in 58/180 patients (32%). After 2 yr, there was no difference between the treatment groups with regard to resolution or spontaneous onset of these autoimmune features. Sicca syndrome was the most common spontaneously developing condition (9% per yr). Sicca syndrome was the most common associated autoimmune condition, present in one-third of our patients. The associated conditions tended to improve over time, with a low rate of spontaneously developing these conditions. Although ursodeoxycholic acid therapy leads to improvement in the underlying liver disease, it did not appear to influence either the development or resolution of these autoimmune features. Conclusions Although ursodeoxycholic acid is beneficial in the treatment of primary biliary cirrhosis, it had no measurable effect on the autoimmune conditions coassociated with the disease.

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.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.Survival free of liver transplantation was significantly improved in the patients treated with UDCA compared with the patients originally assigned to placebo (P0.001; 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 or3.5 mg/dL; P0.0001 and P0.03, respectively) and histological stage IV subgroup (P0.01).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.

We examined the clinical usefulness of measurements of antimitochondrial autoantibodies (AMA) in predicting disease progression in patients with primary biliary cirrhosis (PBC). We determined the relationships between AMA levels measured by indirect immunofluorescence (IF) and those measured by quantitative enzyme immunoassays (EIAs) using recombinant 2-oxo-acid dehydrogenase complex (2-OADC) proteins and the Mayo Risk Score, an established indicator of disease progression in primary biliary cirrhosis (PBC). Results of tests for AMA by either method correlated weakly (r = .24 to .30) with disease progression as indicated by Mayo Risk Scores. The levels of AMA to 2-OADC proteins varied by more than 200-fold between patients but remained relatively constant over time in individual patients. Despite being positively correlated with Mayo Risk Score results, the levels of AMA to 2-OADC proteins were not useful for predicting disease progression in individual patients with PBC. In addition, we found no significant differences in the levels of autoantibodies to 2-OADC proteins among patients with different histological stages of disease. Our results show that measurements of AMA by IF or by quantitative EIA methods with recombinant 2-OADC proteins are not useful parameters for predicting disease progression in patients with PBC.

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.

The detection of antimitochondrial autoantibodies (AMAs) is critical in the diagnosis of primary biliary cirrhosis (PBC). However, conventional laboratory assays to detect AMA are dependent on the time-consuming method of immunofluorescence microscopy, a method often plagued by problems of nonspecificity. AMAs react against mitochondrial autoantigens including the E2 components of the pyruvate dehydrogenase complex (PDC-E2), the branched-chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), and the 2-oxo-glutarate dehydrogenase complex (OGDC-E2). Interestingly, the immunodominant epitopes of PDC-E2, BCOADC-E2, and OGDC-E2 are all conformational lipoate binding sites, but antibodies against them do not cross-react. Although 80% to 90% of sera from patients with PBC react to PDC-E2, approximately 10% patients with PBC react only to BCOADC-E2 and/or OGDC-E2. We have taken advantage of our epitope-mapping studies of the E2 components of PDC, BCOADC, and OGDC, and constructed a "designer" hybrid clone, designated as pML-MIT3, that coexpresses the immunodominant epitopes within the three distinct lipoyl domains. We examined a total of 321 sera, including 186 sera from patients with PBC, to test the immunoreactivity of pMIT3. Of 186 sera from patients with PBC, 152 sera (81.7%) reacted with recombinant fusion protein of PDC-E2, whereas 171 sera (91.9%) showed positive reactivities when probed by immunoblotting against the recombinant fusion protein expressed from the pML-MIT3 clone. Of 34 PBC sera that did not react with recombinant PDC-E2, 18 sera contained BCOADC-E2-specific AMA and 1 serum possessed only OGDC-E2-specific AMA. We also developed an enzyme-linked immunosorbent assay (ELISA), using affinity-purified recombinant fusion protein of pML-MIT3 clone as the antigen source, to quantify specific AMAs in patients with PBC. None of the 135 control sera from patients with primary sclerosing cholangitis (PSC), chronic autoimmune hepatitis (CAH), systemic lupus erythematosus (SLE), or healthy volunteers showed significant reactivity against pML-MIT3 recombinant fusion protein in the ELISA assay. Our results indicate that an ELISA using recombinant, cloned autoantigen of pML-MIT3 is a powerful and very specific method for the detection of AMA.

Five different target mitochondrial autoantigens recognized by sera from patients with primary biliary cirrhosis (PBC) have been identified as subunits of the following 2-oxo acid dehydrogenase complexes: the pyruvate dehydrogenase complex (PDC), the branched chain 2-oxo acid dehydrogenase complex (BCOADC), and the 2-oxoglutarate dehydrogenase complex (OGDC). Unlike the E2 subunits of PDC (PDC-E2) and BCOADC (BCOADC-E2), the E2 subunits of OGDC (OGDC-E2) reactivity of PBC sera and the reactive epitope of OGDC-D2 have not hitherto been studied in detail. In this report, we took advantage of a recombinant fusion protein for OGDC-E2 to address these issues. Eighty of 268 (29.9%) PBC patient sera but none of the 45 controls reacted with recombinant OGDC-E2. The recombinant OGDC-E2 was judged to express the immunodominant epitope, because when sera from patients with PBC were preabsorbed with the recombinant fusion protein, such sera were depleted of reactivity against 48 kD OGDC-E2 when probed on beef heart mitochondria (BHM) but retained reactivity toward PDC-E2 and/or BCOADC-E2. Furthermore, affinity-purified PBC sera against recombinant OGDC-E2 reacted only with native OGDC-E2 and not with any other enzyme components of the 2-oxo acid dehydrogenase complex. Antimitochondrial autoantibodies (AMA) against OGDC-E2 included immunoglobulin (Ig)G2, IgG3 and IgM and the relative titers were as follows: IgG2 > IgG3 > IgM. Finally, using overlapping recombinant polypeptides, it was determined that a minimum of 81 amino acids (residues 67-147) corresponding to the lipoyl domain of OGDC-E2 are necessary for reactivity, suggesting that a conformational autoepitope is recognized by AMA. These data suggest that each of the 2-oxo acid dehydrogenase enzymes has distinct antigenicity despite their similarities in structure and function. The availability of recombinant OGDC-E2 autoantigen will allow the design of additional studies to further our understanding of the role of mitochondrial autoantigens in the pathogenesis of PBC.

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.

Because the osteoporosis occurring in chronic cholestatic liver disease (CCLD) is associated with decreased bone formation and is reversible by liver transplantation, substances retained in plasma during cholestasis may impair osteoblast function. This hypothesis was tested using a new bioassay that measures plasma mitogenic activity (PMA) for normal human osteoblast-like (hOB) cells. In 29 jaundiced patients, mean PMA was 56.4% (P < 0.001) of that in 29 age- and sex-matched normal subjects, and the decrease in PMA was similar in the 14 with CCLD and the 15 with other causes of jaundice. Bile acids and bilirubin are the two major groups of products retained during cholestasis. The common conjugated bile acids and bilirubin were added to normal human plasma in concentrations simulating those found in patients with CCLD. Various bile salts had no effect on PMA whereas unconjugated bilirubin decreased PMA in a dose-dependent fashion (r = -0.98, P < 0.0001) without affecting cell viability. Relatively selective removal of bilirubin from the plasma by photobleaching normalized the decreased PMA in five jaundiced patients but produced no apparent change in five normal subjects. These data support the hypothesis that hyperbilirubinemia or possibly other photolabile substances impair osteoblast proliferative capacity and thus may play a major role in the pathogenesis of the osteoporosis associated with CCLD.

We retrospectively studied 22 patients with hepatopulmonary syndrome (HPS) evaluated at the Mayo Medical Center from 1984 to 1991. All patients had hepatic cirrhosis with clinical evidence of portal hypertension; 13 (59 percent) had severe hypoxemia while breathing room air in the supine position (PaO2 < 60 mm Hg), and 14 of 16 (88 percent) had orthodeoxia breathing room air. On the basis of angiographic observations, we defined type 1 and type 2 patterns of pulmonary vascular abnormalities in HPS. Response to 100 percent oxygen and therapeutic regimens may differ in the angiographic patterns. Substantial deterioration in PaO2 associated with clinically stable hepatic dysfunction was documented in five of seven patients studied with sequential arterial blood gas testing; four subsequently died within 48 months. Overall mortality was 41 percent, occurring a mean of 2.5 years after diagnosis. In 7 of the 22 patients, we prospectively studied the effect of somatostatin analogue given subcutaneously for 4 consecutive days. No significant improvement in PaO2 was documented while breathing room air or 100 percent oxygen (p < 0.05). We conclude that in selected patients with clinically stable hepatic dysfunction and deteriorating oxygenation, the prognosis is poor. Our data in combination with recent surgical reports suggest that liver transplantation may be the treatment of choice in patients with HPS and worsening oxygenation.

Pulmonary function and gas exchange were prospectively studied in 95 patients before and 9 to 15 months following liver transplantation. Pretransplant, the most common PF abnormality was impaired efficiency of gas exchange as measured by Dss. As a group, the mean Dss was 78.0 ± 16.6 percent predicted and was found to be less than $0 percent predicted in 50 patients. As a group, patients with the most severe liver diseases clinically (Child's C classification) had the lowest mean Dss pretransplant. Posttransplant, three findings were of clinical importance: PaCO 2 significantly improved posttransplantation, suggesting a resolution of pretransplant respiratory alkalosis. Expiratory airflow obstruction, measured by a change in the FEV 1 /FVC, was extremely uncommon posttransplant. Mean Dss improved significantly in patients with Child's C severity of liver disease. The most frequent deteriorations in Dss statistically were associated with posttransplant thoracotomy, ARDS, nonspecific pneumonitis, significant pleural effusions and hepatic retransplantation.

Patients with hepatic cirrhosis develop widespread abnormalities in kidney function and vasoactive hormones. These change rapidly after liver transplantation during immunosuppression with cyclosporine. The role of changing eicosanoid excretion and endothelin levels in regulating renal function after transplantation in humans remains uncertain. We studied 32 patients with regard to renal hemodynamics, glomerular filtration, urinary prostacyclin (6-keto-PG-F1-alpha), thromboxane (TBX2), and endothelin before and during the first four weeks after orthotopic liver transplantation. Arterial pressure rose from 106 +/- 2/61 +/- 2 to 146 +/- 4/81 +/- 2 mmHg, (P less than .001), while renal blood flow fell (686 +/- 38 to 453 +/- 24 ml/min/1.73 m2, P less than .05), as did GFR. Pretransplant excretion of 6-keto and TBX2 was above that of normal subjects and fell progressively after transplant, as did plasma renin activity and aldosterone. The 6-keto levels fell below normal after two weeks. The ratio of TBX2/6-keto remained elevated compared with normal subjects throughout the month after transplant (1.54 +/- 0.38 vs. 0.54 +/- 0.07, P less than .01). Endothelin levels rose during the first week (7.4 +/- 1.4 vs. 12.4 +/- 2.7 pg/ml, P less than .05), but fell back to baseline thereafter. These results indicate that high levels of urinary eicosanoids in patients with liver disease fall rapidly after liver transplantation during CsA immunosuppression. Unlike results in many experimental models, these data suggest that renal vasoconstriction in humans may be associated primarily with suppression in renal prostacyclin excretion rather than stimulation of thromboxane.

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.

Intrapulmonary vascular dilatations (IPVD) are extrahepatic complications of acute and chronic liver disorders that can result in severe hypoxemia. Contrast-enhanced (CE) echocardiography provides a noninvasive method to detect right-to-left shunting associated with IPVD. We prospectively studied 40 consecutive liver transplant candidates to determine the relationship between CE echocardiography, arterial blood gases, and standard pulmonary function tests. Two patients had technically unacceptable results of echocardiographic studies. Thirty-eight patients had acceptable results of studies; seven (18.4 percent) of 38 were hypoxemic (PaO 2 2 ≥70 mm Hg. Positive CE echocardiograms suggesting IPVD were found in five (13.2 percent) of 38. Three (9.7 percent) of the 31 patients with PaO 2 ≥70 mm Hg had positive CE echocardiograms. Two (28.6 percent) of the seven hypoxemic patients had positive CE echocardiography. Mean PaO 2 and pulmonary function parameters were not significantly different between those with positive CE echocardiogram compared with those with normal CE echocardiograms. We conclude that for our group of liver transplant candidates, (1) IPVD as suggested by CE echocardiography were not uncommon (13.2 percent), and (2) positive CE echocardiography could be documented in patients who were not hypoxemic (9.7 percent).

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.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 stayor =4 days, hospital length of stayor =15 days, blood usageor =36 U of blood products, infection, rejection, and global resource utilization (an index of cost) greater than the median were considered poor outcomes.Fifty-three patients were studied. Longer ICU stay was associated with lower handgrip strength (P0.01) and lower aromatic amino acid levels (P0.01). Longer total hospital stay and the development of infections were associated with lower branched chain amino acid levels (P0.01 and0.001, respectively). Acute cellular rejection was associated with lower total body fat (P0.001) and higher triglyceride levels (P0.02). Neither death nor higher global resource utilization was associated with any preoperative nutritional parameter.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.

The natural progression of primary biliary cirrhosis (PBC) has been modeled by a number of investigators based on Cox’s proportional hazards analysis1–3. The utility of these models is largely two-fold. On the one hand, these models have been used as a clinical tool in assessing prognosis with or without treatment. For example, the natural history model for PBC has been used in determining prognosis following transplantation, thereby assisting transplant physicians and surgeons in their decisions about patient selection and timing of transplantation4. On the other hand, these models are useful from the standpoint of clinical research. For instance, the prognostic indices of the models may be used as parameters of disease severity in risk stratification in clinical trials evaluating new treatment modalities5.

Prognostic models have been developed for patients with primary biliary cirrhosis and primary sclerosing cholangitis to predict survival without transplantation. In patients undergoing liver transplantation, these models have been used in assessing postoperative mortality and morbidity. Recent data suggest that preoperative recipient physiology, such as impaired functional status or renal insufficiency, is the most important determinant of transplant outcome. Survival, quality of life, morbidities and resource use are the key variables to be considered in the timing of transplantation.

Approximately 5% to 10% of patients with features otherwise consistent with primary biliary cirrhosis (PBC) lack antimitochondrial antibodies (AMA). Most of these patients have other autoantibodies, a syndrome recently named "autoimmune cholangitis." We report our experience in patients with AMA-negative PBC treated with ursodeoxycholic acid (UDCA) and/or liver transplantation (OLT). The study of response to UDCA was performed as follows. While recruiting patients for a previously reported multicenter trial, we identified 8 patients with AMA-negative PBC. The patients were given UDCA and followed up at regular intervals. The characteristics of AMA-negative patients at presentation were similar to those of AMA-positive patients with PBC. The clinical outcomes and sequential liver biochemistries of UDCA treatment were also comparable with those of AMA-positive patients. The study of outcome of OLT was performed as follows. We identified OLT recipients at the Mayo Clinic who had clinical, radiological, and histological features compatible with PBC. Their pretransplant AMA status was determined, and each AMA-negative patient was paired with 2 AMA-positive patients. Of 85 OLT recipients with a diagnosis of PBC, 6 (7.1%) were AMA negative, including 1 who had undergone UDCA therapy. After a median of 36 months of follow-up, graft and patient survival rates and subsequent histological changes (disease recurrence and steroid-resistant or late rejections) were comparable in AMA-negative and -positive PBC patients. In summary, in our experience of 13 AMA-negative PBC patients (including 9 who met the criteria for a diagnosis of autoimmune cholangitis), treatment with UDCA or OLT resulted in similar outcomes to those found in AMA-positive patients. We conclude that AMA status does not affect the response in PBC patients to treatment with UDCA or OLT.

A retrospective study of primary biliary cirrhosis (PBC) was performed to study the Original Mayo Model for predicting survival by a Dutch data-set of patients, presentation of disease progression; assessment of liver transplantation, prediction of post-transplantation survival; and the addition of two laboratory variables to the Original Mayo Model.Survival of 83 patients, 37 of whom underwent transplantation, were studied. Mean follow-up was 6.0 +/- 0.45 SEM years. Risk score at diagnosis, platelet count, and serum sodium were analyzed in a Cox model.The Original Mayo Model estimated survival for low-, medium-, and high-risk groups accurately and it also presented disease progression. Baseline Mayo risk score in a Cox model had a regression coefficient of 1.01, indicating an excellent predictor p0.0001. Platelet count was a predictor of survival (p0.002), whereas serum sodium did not (p = 0.67). A new model combined of the Original Mayo risk score and platelet count predicted survival in high-risk patients somewhat better compared to the Original Mayo Model. With both models, liver transplantation had a significant beneficial effect on survival (p0.001). The scores revealed no significant influence (p = 0.47) for overall post-transplantation survival.The Original Mayo Model remains the model of choice for patients with PBC for prognostication from 3-8 years, is a useful tool in the assessment of liver transplantation but not an indicator of post-transplantation survival. Platelet count showed to have additional prognostic value. A new model combined of platelet count and the Original Mayo risk score did predict survival in high-risk groups slightly better compared to the Original Mayo Model.

The natural history of primary biliary cirrhosis (PBC) is one of slowly progressive cholestasis with liver damage, development of cirrhosis with its concomitant complications, and death unless the patient undergoes liver transplantation. Natural history studies have identified several variables associated with a decreased survival in patients with PBC. The course of the disease can be divided into three time periods: (1) a presymptomatic phase, probably lasting up to 20 years; (2) a symptomatic phase, with anicteric or mild jaundice, lasting up to 5 to 10 years; and (3) a preterminal or accelerated phase with marked jaundice, lasting up to 2 years. Since the course of the disease is one of slow progression leading to liver failure and death unless liver transplantation intervenes, several investigators have developed statistical models to predict survival. The ability to predict survival for individual patients with PBC has been valuable in the management of these patients, particularly in patient selection and timing of liver transplantation. In addition, survival estimates can be utilized in education and counseling patients and their families. These models may also be used to evaluate the efficacy of new treatments by comparing natural history survival with the survival achieved by therapeutic effect. Over the past several decades, the natural history models of PBC have been developed in the absence of effective medical therapy. The efficacy of liver transplantation and survival following liver transplantation has now been quantitatively established. Future efforts should be aimed at determining not only survival of patients with primary biliary cirrhosis in the presence of effective medical therapy but also at assessing the quality of life and cost-effectiveness of medical therapy and liver transplantation in the management of patients with primary PBC.

We studied the outcome of 436 patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) who underwent orthotopic liver transplant (OLT) at three major liver transplant centers. Univariate predictors of outcome included age, Karnofsky score, Child's class, Mayo risk score, United Network for Organ Sharing (UNOS) status, nutritional status, serum albumin, serum bilirubin, international normalized ratio, and the presence of ascites, encephalopathy, renal failure (serum creatinine > 2 mg/dL), and edema refractory to diuretics. Using these predictors, we developed a four variable mathematical prognostic model to help the liver transplant physician predict the following: 1) the amount of intraoperative blood loss; 2) the number of days in the intensive care unit (ICU); and 3) severe complications after surgery. The model uses age, renal failure, Child's class, and United Network for Organ Sharing status. This study is the first to model the outcome of liver transplant in patients with a specific etiology of chronic liver disease (PBC or PSC). The model may be used to help select patients for OLT and to plan the timing of their transplantation.

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.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.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.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.

The results of liver transplantation in patients with PSC are excellent and the quality of life is markedly improved. Indeed, liver transplantation is the therapy of choice for patients with end-stage PSC. However, in an age of cost containment, it appears that there are several advantages to offering transplant to patients with PSC a little bit earlier rather than later in the course of their disease. It appears that we can further improve survival, decrease morbidity, decrease blood usage, and avoid the risk of developing a cholangiocarcinoma, which occurs sporadically but not infrequently in the PSC patient. In addition, avoidance of right upper quadrant surgery, such as biliary or shunt surgery, appears to offer several advantages by decreasing resource utilization and possibly decreasing mortality. Although the UNOS selection guidelines recommend transplantation of the sickest patient, there appears to be accumulating evidence that transplantation in patients earlier in the course of their end-stage liver disease may improve survival, decrease morbidity, and also importantly, decrease the cost associated with this expensive procedure. Ideally, we would recommend consideration for liver transplantation all PSC patients who have (1) a Mayo risk score of4.8 in whom malignancy is ruled out, (2) cirrhosis and complications of portal hypertension such as variceal bleeding, refractory ascites, or portosystemic encephalopathy, or (3) disabling symptoms such as fatigue, pruritus, or recurrent bacterial cholangitis. We believe that biliary surgery to treat dominant strictures should be avoided and that such strictures should be approached either endoscopically or radiographically, which should include brushings, biopsies, and histology to reasonably exclude the diagnosis of cholangiocarcinoma. Finally, we continue to search for risk factors and for early markers of cholangiocarcinoma so these patients can be identified early and this devastating complication can be avoided by early transplantation.

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)

The presence of antimitochondrial antibodies (AMA) is a major criterion for the diagnosis of primary biliary cirrhosis (PBC). Although it is not clear that AMA are involved in the pathogenesis of the disease, the study of these autoantibodies has enabled much information to be accumulated about the specificity of this response. The autoantigens have been identified as components of a functionally related enzyme family, the 2-oxo-acid-dehydrogenase complex. Within this complex, pyruvate dehydrogenase E2 subunit (PDC-E2) has been determined to be the immunodominant autoantigen. Using a panel of mouse monoclonal antibodies and human combinatorial autoantibodies, it has been demonstrated that patients with PBC, but not controls, have an abnormal expression of either PDC-E2 or a cross-reacting molecule in the apical region of biliary epithelium. Others have shown a similar reaction using rabbit sera directed to PDC-E2. Our previous studies have concentrated on AMA-positive patients. In this study, the presence of PDC-E2, class II, immunoglobulin (Ig) A, and B7/BB1 in the bile duct epithelial cells of AMA-positive as well as AMA-negative patients is addressed. Most patients with AMA-negative PBC (seven of nine) react in a fashion similar to AMA-positive patients with intense staining of the apical region of the bile duct epithelial cells of "PDC-E2," increased IgA expression, and little major histocompatibility complex (MHC) class II staining in the early-stage patients. Interestingly, the two AMA-negative patients that did not express PDC-E2 on the apical side of their biliary epithelium had anticentromere antibodies and Sjögren's syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

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.

We reviewed our experience with patients who had biochemical and histological features of primary biliary cirrhosis in the absence of antimitochondrial antibodies (AMA) to better understand this variant of the syndrome.During the period between 1976 to 1992, 597 patients with clinical and histological features of primary biliary cirrhosis were seen at the Mayo Clinic. Thirty-five (5.8%) of these patients were negative for antimitochondrial antibody and had normal cholangiographic studies. The records of these patients were reviewed for this study.No difference was found between the two groups with respect to age, gender, or biochemical features. IgM and gamma-globulin levels were higher in the antimitochondrial antibody-positive than the antimitochondrial antibody-negative patients. What is more important, 96% of the AMA-negative patients who could be tested were positive for antinuclear antibody or anti-smooth-muscle antibodies. These tests were positive in only 56% of the antimitochondrial antibody-positive group (p0.05). The response of five of these patients to ursodeoxycholic acid appeared comparable to the response seen in antimitochondrial antibody-positive patients.Patients with histological features of primary biliary cirrhosis, whether antimitochondrial antibody positive or negative, are quite comparable with respect to clinical and biochemical features. Other autoantibodies, such as antinuclear or anti-smooth-muscle antibodies, are more common in the antimitochondrial antibody-negative group. These two conditions might be part of a spectrum that has been termed "autoimmune cholangitis" and that is characterized by chronic cholestasis, histological features of chronic nonsuppurative destructive cholangitis, and the presence of any of a variety of serum autoantibodies.

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.

Orthotopic liver transplantation (OLT) has been shown to be effective in prolonging life and improving its quality in patients with end-stage liver disease. However, it remains one of the most expensive surgical procedures performed today. In an era when economic efficiency and financial accountability are being emphasized, it is imperative to consider resource utilization in evaluating candidates for OLT. We prospectively followed 106 patients who underwent OLT at the Mayo Clinic for primary biliary cirrhosis and primary sclerosing cholangitis between 1990 and 1994. Hospital and professional charges for the initial hospitalization were obtained on all patients. Univariate and multivariate models were constructed using preoperative clinical variables that had been previously found to be important in predicting clinical outcomes. The preoperative variables considered were age, gender, diagnosis of liver disease, Mayo risk score, Child's score, nutritional status, Karnofsky score, INR, serum levels of albumin, bilirubin, and creatinine, and the presence/absence of ascites, edema, encephalopathy, renal failure (serum creatinine2.0) and gastrointestinal bleeding. Of the 106 patients, 3 were excluded from the analysis because they received multiple transplants during the initial hospitalization. Of the hospital charges we analyzed, the surgical fee for transplantation and donor acquisition expense were fixed in advance and, therefore, excluded. The following preoperative variables were found to be significant in the univariate analysis: Mayo risk score, Child's score, nutritional status, Karnofsky score, INR, serum levels of bilirubin and creatinine, presence of renal failure, and gastrointestinal bleeding. In the multivariate analyses, Karnofsky score of 40 or less was associated with a 48% increase in total charges. Poor nutritional status and renal failure were associated with a 34% and 31% increase, respectively. We identified 3 preoperative variables as significant independent predictors of resource utilization in liver transplantation. In an effort to maximize the economic efficiency with which liver transplantation is performed, we believe these factors should be taken into consideration in determining both the timing of transplantation and the suitability of potential transplant recipients.

The hepatopulmonary syndrome is an uncommon accompaniment of chronic liver disease. The outcome of this disorder after orthotopic liver transplantation is variable. We describe a patient with the hepatopulmonary syndrome who underwent orthotopic liver transplantation for autoimmune hepatitis. Her platypnea and orthodeoxia failed to improve postoperatively. Pulmonary angiography showed large pulmonary arteriovenous shunts that were successfully treated with coil embolotherapy.

Sera from patients with primary biliary cirrhosis inhibit the activity of the mitochondrial pyruvate dehydrogenase complex. We utilized this effect to develop a simple, miniaturized, semiautomated spectrophotometric assay as a diagnostic aid. The sera studied were from 71 patients with primary biliary cirrhosis and 62 other subjects. The assays included enzyme inhibition, immunofluorescence on HEp-2 cells, enzyme-linked immunosorbent assay using recombinant pyruvate dehydrogenase complex-E2 and immunoblotting on bovine heart mitochondria. With the 71 primary biliary cirrhosis sera, on which M2 antibody was detected by immunofluorescence in 64 (90%), antibodies against pyruvate dehydrogenase complex were detected in 53 (83%) by means of enzyme inhibition, in 57 (89%) by means of enzyme-linked immunosorbent assay and in 60 (94%) by means of immunoblotting. Of the 64 sera positive by immunofluorescence, 60 reacted with pyruvate dehydrogenase complex-E2 on immunoblotting, and the miniaturized enzyme inhibition assay was positive in 53 of these. The enzyme inhibition assay and enzyme-linked immunosorbent assay were calibrated to give a specificity of 100%. At this level, the sensitivities for detection of pyruvate dehydrogenase complex antibody were 83% and 87%, respectively. We found no significant changes in levels of reactivity with the enzyme inhibition assay or enzyme-linked immunosorbent assay according to disease stage. Treatment with cyclosporine was accompanied by a significant decrease in levels of antibody to pyruvate dehydrogenase complex-E2 that matched improved indexes of biochemical liver function.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of the present study was to determine the prevalence and natural history of abdominal pain in patients with primary biliary cirrhosis.We studied 178 patients with well-defined primary biliary cirrhosis enrolled in a prospective randomized trial of ursodeoxycholic acid. These patients underwent upper endoscopy and upper abdominal ultrasound prior to entry, at 2 yr, and as indicated. Fourteen patients had additional evaluations including abdominal CT (four), colon x-ray (five), colonoscopy (three), endoscopic retrograde cholangiopancreatography (two), and upper gastrointestinal x-ray (two).Patients with abdominal pain generally presented with right upper quadrant discomfort. Thirty-one patients (17%) had pain at study entry: 33% of these had pain persisting at 1 yr, and 20% of these had pain persisting at 2 yr. The resolution of pain was not clearly affected by ursodeoxycholic acid. Evaluation with ultrasound and upper endoscopy found four patients with asymptomatic cholelithiasis, one with esophageal erosions, four with gastric erosions, one with a gastric ulcer, and two with duodenal erosions. Additional tests were unrevealing in 14 patients. Patients with pain were similar to patients without pain with regard to age, histological stage, gender, and liver biochemistries.We conclude that chronic right upper quadrant pain is not uncommon in patients with primary biliary cirrhosis, that it usually resolves spontaneously, and that upper endoscopy is the most important diagnostic test to use to exclude treatable causes of pain.

The progression of primary biliary cirrhosis was studied in 312 patients who were seen at the Mayo Clinic between January 1974 and May 1984. Follow-up was extended to April 30, 1988, by which time 140 of the patients had died and 29 had undergone orthotopic liver transplantation. These patients generated 1,945 patient visits that enabled us to study the change in the prognostic variables of primary biliary cirrhosis (age, bilirubin value, albumin value, prothrombin time and edema) from the time of referral. Also, using this database and the Cox proportional-hazards regression model, we developed an updated model for primary biliary cirrhosis that can be used to predict short-term survival at any time in the course of the disease. This model uses the values of the prognostic variables measured at the latest patient visit. Comparison of predicted survival from the update model and the natural history model of primary biliary cirrhosis showed that the updated model was superior to the original model for predicting short-term survival. This finding applied to both the Mayo Clinic patients and an independent set of 83 Dutch patients. The Mayo updated model is recommended for improving the accuracy of predictions of survival during the 2 yr after a patient visit.

Cyclosporine induces hypertension and wide-spread vasoconstriction after transplantation in addition to reducing kidney function. We studied hemodynamic, renal, and hormonal effects of monotherapy with nifedipine XL (n = 37) in liver transplant recipients within a year after transplant (median, 4.4 months). Systemic hemodynamics were determined with thoracic electrical bioimpedance. Blood pressure before therapy was 172 +/- 4/108 +/- 2 mm Hg. Sixty-four percent of recipients achieved blood pressures less than 140/90 mm Hg mediated by a fall in systemic vascular resistance index (2427 +/- 245 dyne.s.cm-5.m-2 in responders versus 2905 +/- 281 in nonresponders, P < .01). Despite the fall in systemic vascular resistance, glomerular filtration rates were not changed during nifedipine therapy, as measured by both creatinine and iothalamate clearances. Urinary prostacyclin (6-ketoprostaglandin F1 alpha) was suppressed below normal from 2468 +/- 323 ng/d before transplant to 1103 +/- 99 ng/d (P < .01) after transplant and did not change during nifedipine therapy. Urinary thromboxane B2 and plasma renin activity also fell after transplant and remained low during nifedipine. These data demonstrate that nifedipine can reverse systemic vasoconstriction associated with hypertension after transplantation. Systemic effects were not transmitted to the kidney sufficiently to improve glomerular filtration rate or reverse hormonal changes within the kidney. Hence, vascular and functional regulation of the kidney was dissociated from the systemic circulation during nifedipine administration after transplantation.

Osteoporosis is a frequent extrahepatic complication of primary biliary cirrhosis. Although histologically similar to the osteoporosis commonly seen in postmenopausal females, the pathogenesis and management of bone disease in patients with primary biliary cirrhosis is poorly understood. The experience with a subgroup of patients with primary biliary cirrhosis treated with vitamin D, calcium, and estrogen supplementation was reviewed to determine the effects of medical treatment on hepatic osteodystrophy.The records of 203 women with the diagnosis of primary biliary cirrhosis were reviewed retrospectively for lumbar spine bone mineral density, menopausal status, and supplementation with vitamin D, calcium, and estrogen.The 16 postmenopausal patients treated with estrogen replacement had a statistically significant increase in the lumbar spine bone mineral density at 1 yr (+0.014 +/- 0.049 vs. -0.03 +/- 0.046 g/cm2, p0.038), without a significant change in the serum bilirubin or alkaline phosphatase. In treated patients, vitamin D and calcium supplementation did not lead to significant improvement in lumbar spine bone mineral density.Calcium and vitamin D supplementation, even in the presence of vitamin D deficiency, do not improve lumbar spine bone mineral density in patients with primary biliary cirrhosis. Estrogen replacement in postmenopausal patients, however, does appear to improve lumbar spine bone mineral density without increasing clinical or biochemical cholestasis, a potential complication reported in animal studies. This study should serve as an impetus for a controlled trial of estrogen replacement in postmenopausal patients with primary biliary cirrhosis.

We retrospectively studied 22 patients with hepatopulmonary syndrome (HPS) evaluated at the Mayo Medical Center from 1984 to 1991. All patients had hepatic cirrhosis with clinical evidence of portal hypertension; 13 (59 percent) had severe hypoxemia while breathing room air in the supine position (PaO260 mm Hg), and 14 of 16 (88 percent) had orthodeoxia breathing room air. On the basis of angiographic observations, we defined type 1 and type 2 patterns of pulmonary vascular abnormalities in HPS. Response to 100 percent oxygen and therapeutic regimens may differ in the angiographic patterns. Substantial deterioration in PaO2 associated with clinically stable hepatic dysfunction was documented in five of seven patients studied with sequential arterial blood gas testing; four subsequently died within 48 months. Overall mortality was 41 percent, occurring a mean of 2.5 years after diagnosis. In 7 of the 22 patients, we prospectively studied the effect of somatostatin analogue given subcutaneously for 4 consecutive days. No significant improvement in PaO2 was documented while breathing room air or 100 percent oxygen (p0.05). We conclude that in selected patients with clinically stable hepatic dysfunction and deteriorating oxygenation, the prognosis is poor. Our data in combination with recent surgical reports suggest that liver transplantation may be the treatment of choice in patients with HPS and worsening oxygenation.

The identification and cloning of the mitochondrial autoantigens in primary biliary cirrhosis (PBC) have provided new clues in disease pathogenesis. The two major autoantigens are the E2 subunits of pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase (BCKD). Interestingly, one of these complexes, BCKD-E2, is already well known to clinical medicine based on its association with genetic mutations in maple syrup urine disease (MSUD). Patients with this disease have an inability to metabolize branched-chain amino acids. In the present study, we have taken advantage of the known sequence of BCKD-E2 from normal humans, and addressed the issue of whether there is an altered autoantigen sequence in hepatocytes of individuals with primary biliary cirrhosis. In particular, we examined both the leader sequence and the B-cell immunodominant epitope, the lipoic acid domain. In addition, because patients with PBC have autoantibodies to the BCKD-E2 complex, we have quantitated plasma levels of alpha-ketoacids potentially affected in maple syrup urine disease. These include pyruvic acid (PY), phenylpyruvic acid (PP), alpha-ketoisocaproic acid (KIC) alpha-ketoisovalerate (KIV) and alpha-keto-beta-methylvaleric acid (KMV). The levels of these alpha-ketoacids were compared in patients with primary sclerosing cholangitis and normal volunteers. The sequence of BCKD-E2 obtained from PBC hepatocytes showed homology with normal BCKD. Further studies of autoantigen structure and sequence are clearly indicated, including those involved in mitochondrial transport and localization. Finally, we noted a statistically significant increase in all plasma alpha-ketoacids except alpha-keto-beta-methylvaleric acid in PBC patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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

In summary, we answer the three questions we have previously posed: (a) Can liver transplantation prolong survival? Evolving data from several centers indicate that liver transplantation indeed prolongs survival in patients with PBC and PSC as compared with estimated survival using disease-specific risk scores based on the natural history of PBC and PSC. (b) Can we optimize timing of liver transplantation? Although many factors enter into the timing of liver transplantation, including when the patient is actually referred for liver transplantation and the individual desires of the patient to pursue liver transplantation, evidence is growing that having patients with chronic liver diseases like PBC and PSC undergo transplantation a little earlier in the course of the disease rather than waiting until the patients have experienced life-threatening complications or are on life-support measures can indeed improve early postliver transplant survival. In patients with PBC and PSC, the survival risk score, which reflects disease severity, can serve as an objective measurement to assess and evaluate the effect of liver disease severity on transplant outcome. Indeed, a number of studies have strongly suggested that optimal timing of liver transplantation may indeed be important to improve outcome, decrease morbidity and decrease cost. (c) Does the present allocation system in the United States allow for optimal use of our scarce donor organ resource?(ABSTRACT TRUNCATED AT 250 WORDS)

Before the identification of the major mitochondrial antigens of primary biliary cirrhosis as components of the 2-oxo-acid dehydrogenase enzyme family, mitochondrial autoantigens were believed to be extremely heterogeneous and were divided into nine subtypes termed M1 to M9. This classification was based on the data derived from the relatively nonspecific biochemical and immunological techniques that were available. After the cloning and definition of the major autoantigens, more than 95% of the sera of patients with primary biliary cirrhosis were found to react with components of the 2-oxo-dehydrogenase enzymes; these enzymes correspond to the old M2 classification. Two other "M" species, dubbed M4 and M9, have attracted significant attention because they have been postulated to be prognostic indicators and more recently have been tentatively identified respectively as sulfite oxidase (EC 1.8.3.1) and glycogen phosphorylase (EC 2.4.1.1). Indeed, patients with the "overlap syndrome" are reported to have antibodies to M4 and a poor prognosis, whereas patients with antibodies to M9 have a favorable prognosis. To address the significance and definition of M4 and M9, we performed in-depth studies of sera from 11 patients with the overlap syndrome, 75 patients with primary biliary cirrhosis, 19 chronic active hepatitis patients, 13 patients with primary sclerosing cholangitis, 10 patients with cholangiocarcinoma, 20 patients with systemic lupus erythematosus, 20 patients with alcoholic cirrhosis, 17 patients with scleroderma and 30 normal individuals, using techniques of ELISA, complement fixation, immunoblotting and enzyme inhibition. We report herein that we were unable to show any disease-specific reactivity toward the proposed M4 and M9 antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Atraumatic fractures caused by osteoporosis may be a serious complication of primary biliary cirrhosis. Mean (+/- S.D.) bone mineral density in the lumbar spine in 210 ambulatory women with primary biliary cirrhosis was 1.02 +/- 0.19 gm/cm2, 7% lower than that in 139 age-matched normal women (after adjustment for age and body weight) (p less than 0.001). Bone mineral density in the lumbar spine was inversely related to a risk score index of liver disease severity (r = -0.29, p less than 0.001). The mean rate of bone loss in 105 of these 210 women was 2%/yr +/- 4%/yr, twice as great as in the 139 normal women (p less than 0.02). In 20 women with primary biliary cirrhosis followed up after orthotopic liver transplantation, bone mineral density in the lumbar spine decreased at 3 mo (p less than 0.01), and this decrease may have resulted in atraumatic fractures in 13 of them. Bone mineral density in the lumbar spine then increased (p less than 0.01) so that by 12 mo the median bone mineral density in the lumbar spine was similar to that before transplantation and by 24 mo it was 5% above it. Therefore we conclude that the progressive bone loss observed in primary biliary cirrhosis (which is further accentuated immediately after transplantation) may be halted, and the bone mass may be restored toward normal within 2 to 3 yr after orthotopic liver transplantation.

The incidence and severity of osteopenic bone disease in primary sclerosing cholangitis is poorly defined. Clinical, biochemical and radiographic assessment and bone mineral density measurements of the lumbar spine were carried out in two groups of patients. Group 1 consisted of 30 patients with advanced primary sclerosing cholangitis; group 2 consisted of 18 patients with newly diagnosed primary sclerosing cholangitis. Only one patient had bone pain. All patients were normocalcemic; two had elevated serum parathormone levels. Fourteen patients (47%) from group 1 but no patients from group 2 had low serum 25-hydroxyvitamin D levels. Mean bone mineral density was significantly reduced in group 1 patients (0.97 +/- 0.04 gm/cm2) compared with age-matched and sex-matched controls (1.25 +/- 0.01 gm/cm2, p less than 0.0001), and in 15 patients (50%) bone mineral density was below the fracture threshold (0.98 gm/cm2). The bone mineral density in group 2 was not significantly different from controls, and no patient was below the fracture threshold. In neither group did bone mineral density correlate with serum bilirubin, 25-hydroxyvitamin D, fecal fat excretion, previous drug therapy or the presence of chronic ulcerative colitis. Histomorphometrical examination of bone from four group 1 patients showed increased bone resorption, reduced bone formation, moderate-to-severe osteopenia and no osteomalacia. In conclusion, severe osteopenic bone disease is common in advanced primary sclerosing cholangitis and, like that seen in other cholestatis diseases, is consistent with osteoporosis.

We studied the relationship between selected variables of hepatic and pulmonary function in 47 patients with primary biliary cirrhosis, who were participating in a prospective study to assess sequential pulmonary function at yearly intervals. An additional 20 patients with primary biliary cirrhosis, who were liver transplant candidates awaiting transplantation, were studied. None of the 67 patients ever smoked cigarettes. Severity of primary biliary cirrhosis was characterized by histological stage and the Mayo risk score derived from a Cox regression model that used the following variables: serum bilirubin and serum albumin levels, age, prothrombin time and clinical severity of edema. Pulmonary function assessment included key variables describing expiratory airflow (forced expiratory volume in 1 sec divided by forced vital capacity) and efficiency of gas exchange (steady-state diffusing capacity for carbon monoxide). We found a significant relationship between histological stage of primary biliary cirrhosis and steady-state diffusing capacity (p = 0.02) and between the Mayo risk score for disease severity and steady-state diffusing capacity (p = 0.03). Progressive deterioration of steady-state diffusing capacity was associated with increasing severity of primary biliary cirrhosis. No relationship existed between pulmonary function and the presence of sicca complex or Sjögren's syndrome or the clinical manifestations of portal hypertension (e.g., esophageal varices, ascites and splenomegaly). No significant relationship existed between expiratory airflow and severity of primary biliary cirrhosis. We conclude that in patients with primary biliary cirrhosis who have never smoked, a statistically significant relationship exists between the severity of the liver disease and the efficiency of gas exchange measured by steady-state diffusing capacity.(ABSTRACT TRUNCATED AT 250 WORDS)