Recipients Undergoing Liver Transplantation Research Articles

Association between visceral obesity and tumor recurrence in hepatocellular carcinoma recipients undergoing liver transplantation.

Excessive visceral obesity in recipients of living donor liver transplantation (LDLT) is associated with mortality, and a recent study reported the correlation between visceral adiposity of male LDLT recipients and hepatocellular carcinoma (HCC) recurrence. However, there is no study on the relationship between the donor's visceral adiposity and surgical outcomes in LDLT recipients. We investigated the association of the visceral-to-subcutaneous fat area ratio (VSR) in donors and recipients with HCC recurrence and mortality in LDLT. We analyzed 1386 sets of donors and recipients who underwent LDLT between January 2008 and January 2018. The maximal chi-square method was used to determine the optimal cutoff values for VSR for predicting overall HCC recurrence and mortality. Cox regression analyses were performed to evaluate the association of donor VSR and recipient VSR with overall HCC recurrence and mortality in recipients. The cutoff values of VSR was determined as 0.73 in males and 0.31 in females. High donor VSR was significantly associated with overall HCC recurrence (adjusted hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.06-1.93, p = 0.019) and mortality (HR: 1.35, 95% CI: 1.03-1.76, p = 0.030). High recipient VSR was significantly associated with overall HCC recurrence (HR: 1.40, 95% CI: 1.04-1.88, p = 0.027) and mortality (HR: 1.50, 95% CI: 1.14-1.96, p = 0.003). Both recipient VSR and donor VSR were significant risk factors for HCC recurrence and mortality in LDLT recipients. Preoperative donor VSR and recipient VSR may be strong predictors of the surgical outcomes of LDLT recipients with HCC.

Risk factors of early bacterial infection and analysis of bacterial composition, distribution and drug susceptibility after cadaveric liver transplantation

BackgroundThis study provided a theoretical basis for the clinical diagnosis and treatment of bacterial infection after liver transplantation through analyzing the pathogenic distribution, drug sensitivity and risk factors of bacterial infection after liver transplantation.MethodsWe collected clinical data from 207 recipients undergoing liver transplantation of graft from donation after citizens’ death donors in the Third Xiangya Hospital of Central South University from January 2019 to December 2021 and analyzed the composition and distribution of bacterial pathogens, drug resistance and risk factors of infection.ResultsA total of 90 bacterial infections occurred in 55 recipients within two months after liver transplantation, and the incidence of bacterial infection was 26.6% (55/207). The gram-negative bacteria (46/90, 51.1%) were more prevalent than gram-positive bacteria (44/90, 48.9%). Common sites of infection were the abdominal/biliary tract (26/90, 28.9%), lung (22/90, 22.4%) and urinary tract (22/90, 22.4%). Fourteen cases (6.8%) died after liver transplantation. Klebsiella pneumoniae (17/90, 18.9%) was the most frequent gram-negative bacteria causing infection in liver transplant recipients and 58.7%, 50%, 80.4% and 89.1% of gram-negative bacteria were sensitive to amikacin, minocycline, tigecycline and polymyxin B, respectively. The most common gram-positive bacteria was Enterococcus faecium (30/90, 33.3%) and 97.7%, 100%, 86.4%, 100% and 100% of gram-positive bacteria were sensitive to vancomycin, teicoplanin, daptomycin, tigecycline and linezolid, respectively. Univariate analysis revealed that bacterial infection was associated with female, age (≥ 50 years old), preoperative albumin (≤ 30 g/L), operation duration (≥ 400 min), intraoperative blood loss (≥ 3000 ml) and postoperative ventilator support. Binary Logistic regression analysis showed that female (OR = 3.149, 95% CI: 1.418–6.993, P = 0.005), operation duration (≥ 400 min) (OR = 2.393, 95% CI: 1.202–4.765, P = 0.013) and intraoperative blood loss (≥ 3000 ml) (OR = 2.052, 95% CI: 1.007–4.183, P = 0.048) were independent risk factors for bacterial infection after liver transplantation.ConclusionThe incidence of early bacterial infection after liver transplantation was high, and the infection sites were mainly abdominal/biliary tract, respiratory tract and urinary tract. The most common pathogenic bacterium was gram-negative bacterium. Our study also identified several independent risk factors for bacterial infection after liver transplantation, including female gender, operation duration of 400 min or more, and intraoperative blood loss of 3000 ml or more. By addressing these risk factors, such as implementing strategies to optimize surgical procedures and minimize blood loss, healthcare professionals can work towards reducing the incidence of bacterial infections following liver transplantation.

The long-term outcomes of deceased-donor liver transplantation for primary biliary cirrhosis: a two-center study in China

Background & AimsFactors that influence the outcomes after deceased-donor liver transplantation (DDLT) for primary biliary cirrhosis (PBC) are not well known. We aimed to clarify these effects on the outcomes after DDLT.MethodsWe retrospectively analyzed patients with PBC who underwent DDLT from March 2006 to July 2018 at the organ transplantation center of the First Hospital of Jilin University and the First Central Hospital of Tianjin. Changes in liver function were assessed posttransplantation. Recurrence, survival rate, and complications were recorded at follow-up. The effect of liver transplantation on survival and recurrence was evaluated using univariate and/or multivariate Cox regression analyses.ResultsIn total, 69 patients with PBC undergoing DDLT were included in this study. At 4 weeks posttransplant, all liver function tests were normal. During a median follow-up time of 32 months, 5-year overall survival and recurrence rates were estimated as 95.1% and 21.8%, respectively. A recipient aspartate aminotransferase-to-platelet ratio index (APRI) greater than 2 was negatively associated with survival (P = 0.0018). Multivariate regression analysis demonstrated that age younger than 48 years was an independent risk factor for recurrent PBC in recipients undergoing liver transplantation (hazard ratio 0.028, 95% confidence interval 0.01–0.71, P = 0.03). Posttransplant infections (62%) and biliary tract complications (26%) were the most common complications.ConclusionLiver transplantation is an effective treatment for patients with PBC. Liver function normalizes by 4 weeks posttransplant. Although posttransplant survival rate is high, recurrence is possible. To some extent, survival rate and recurrence rate can be predicted by APRI and age, respectively.

Aging aggravated liver ischemia and reperfusion injury by promoting STING-mediated NLRP3 activation in macrophages.

Although aggravated liver injury has been reported in aged livers post‐ischemia and reperfusion (IR), the underlying mechanism of innate immune activation of aged macrophages is not well understood. Here, we investigated whether and how Stimulator of interferon genes (STING) signaling regulated macrophage proinflammatory activation and liver IR injury. Mice were subjected to hepatic IR in vivo. Macrophages isolated from IR‐stressed livers and bone marrow‐derived macrophages (BMDMs) from young and aged mice were used for in vitro studies. Enhanced nucleotide‐binding domain and leucine‐rich repeat containing protein 3 (NLRP3) activation was found in both livers and macrophages of aged mice post‐IR. NLRP3 knockdown in macrophages inhibited intrahepatic inflammation and liver injury in both young and aged mice. Interestingly, enhanced activation of the STING/ TANK‐binding kinase 1 (TBK1) signaling pathway was observed in aged macrophages post‐IR and mitochondria DNA (mtDNA) stimulation. STING suppression blocked over‐activation of NLRP3 signaling and excessive secretion of proinflammatory cytokines/chemokines in the mtDNA‐stimulated BMDMs from aged mice. More importantly, STING knockdown in macrophages abrogated the detrimental role of aging in aggravating liver IR injury and intrahepatic inflammation. Finally, peripheral blood from the recipients undergoing liver transplantation was collected and analyzed. The results showed that the elderly recipients had much higher levels of TNF‐α, IL‐6, IL‐1β, and IL‐18 post‐transplantation, indicating increased NLRP3 activation in lR‐stressed livers of elderly recipients. In summary, our study demonstrated that the STING‐NLRP3 axis was critical for the proinflammatory response of aged macrophages and would be a novel therapeutic target to reduce IR injury in elderly patients.

Posttransplant Management of Recipients Undergoing Liver Transplantation for Hepatocellular Carcinoma. Working Group Report From the ILTS Transplant Oncology Consensus Conference.

Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus Conference on Liver Transplant Oncology, working group 4 aim was to analyze the data regarding posttransplant management of recipients undergoing LT for HCC. Three areas of research were considered: (1) cancer prediction models and surveillance strategies; (2) tailored IS for cancer recipients; and (3) new adjuvant therapies for HCC recurrence. Following formulation of several questions, a literature search was undertaken with abstract review followed by article retrieval and full-data extraction. The grading of recommendations assessment, development and evaluation (GRADE) system was used for evidence rating incorporating strength of recommendation and quality of evidence.

Malnutrition is Associated with Poor Outcomes after Liver Transplantation

Introduction Malnutrition is prevalent in recipients undergoing liver transplantation. However, the implication of nutritional status on morbidity and mortality remains unclear. This study aims to evaluate the impact of malnutrition on recipient outcomes. Methods A retrospective review of 390 adult recipients who underwent liver transplantation between January 2009 and June 2016 was performed. Recipients with fulminant liver failure or those requiring re-transplantation were excluded. A total of 321 recipients was analysed. Nutritional status was determined by the subjective global assessment (SGA) at wait-listing and at transplantation. Outcome measures comprised the development of infection within the index admission, rejection within 90-days, and biliary anastomotic strictures within 90-days, as well as readmission within 90-days, intensive care unit (ICU) length of stay (LOS), hospital LOS, and overall survival. Results Malnutrition (SGA-B & SGA-C) was identified in 67% of the recipients at wait-listing. Progressive decline in nutritional status was observed at transplantation (wait-list median 4.4-months), where 77% of the recipients were malnourished. Of these, 18% (n=58) were severely malnourished (SGA-C). Severe malnutrition at transplantation was associated with longer ICU LOS (147-hours vs 89-hours, p<0.01), longer hospital LOS (40-days vs 16-days, p<0.01) and increased incidences of infection (55.2% vs 33.8%, p<0.01) when compared to the well-nourished recipients (SGA-A). Other outcome measures were not associated with nutritional status. Conclusion This large study demonstrates the impact of malnutrition on early recipient morbidity. Nutritional interventions prior to transplantation may potentially improve outcomes and reduce the economic burden on our healthcare system.

Prediction of Fluid Responsiveness by a Non-invasive Respiratory Systolic Time Interval Variation Using Heart Sound Signals in Recipients Undergoing Liver Transplantation

BackgroundThe fluid management of cirrhotic patients undergoing liver transplantation (LT) is challenging. Phonocardiography, a graphic recording of heart sounds, provides valuable information concerning heart function and hemodynamic condition. We assessed whether the systolic time interval (STI) and its respiratory variation could predict fluid responsiveness in cirrhotic patients undergoing LT. MethodsThirty LT recipients who needed volume expansion were included. The fluid challenge consisted of 500 mL 5% albumin administered over a period of 10 minutes. STI was measured as the time interval between the maximal amplitude of each heart sound corrected with the corresponding RR interval (cSTI). The respiratory variation in STI (STV) induced by mechanical ventilation was calculated. Responders were defined as those showing a ≥10% increase in stroke volume index after volume expansion. ResultsIn all, 14 of the 30 patients were responders. Significant increases in cSTI were observed after volume expansion in both responders (P < .001) and non-responders (P = .008). Responders showed significant decreases in STV (11.1% ± 4.3% vs 6.1% ± 2.6%, P < .001) after fluid loading, whereas STV in non-responders remained unchanged (6.4% ± 2.6% vs 6.4% ± 4.2%, P = .86). A cut-off value of ≥7.5% STV from baseline could predict fluid responsiveness with an area under the receiver operating characteristic curve of 0.804 (95% confidence interval, 0.618–0.925). ConclusionsIntra-operative STV can predict fluid responsiveness in patients undergoing LT. Beat-to-beat monitoring of STI and STV may be useful as a non-invasive hemodynamic index and for fluid management.

Intrahepatic Cholangiocarcinoma in the Liver Explant After Liver Transplantation: Histological Differentiation and Prognosis.

The aim of this study was to evaluate the outcome of patients with intrahepatic cholangiocarcinoma (ICCA) incidentally found in the explanted liver after liver transplantation. We retrospectively reviewed 1188 recipients undergoing liver transplantation from August 2003 to August 2014; 13 patients were found to have ICCA (1.1%). Recurrence-free survival (RFS) rate was compared between ICCA patients and the matched cohort of 39 patients with hepatocellular carcinoma (HCC). We also investigate the relevance of clinical and pathological parameters in recurrence of ICCA. ICCA patients showed significantly higher recurrence rate with lower 1-year and 3-year RFS rates than HCC patients (recurrence rate, 12.8% vs. 54.8%; 1-year and 3-year RFS rates, 94% and 84% vs. 67% and 42%). Of the 13 ICCA patients, 4 were diagnosed with a well-differentiated ICCA and 9 with a moderately-differentiated ICCA. There was no recurrence among those with a well-differentiated ICCA, whereas 78% recurred in the moderately-differentiated group. The median RFS time for the moderately-differentiated group was 13.0 months, yielding RFS rates of 56% at 1 year and 22% at 3 years. Liver transplantation in patients with a well-differentiated ICCA yielded excellent outcomes as compared to patients with a moderately-differentiated ICCA. This may allow consideration of transplantation in the setting of a well-differentiated ICCA, and obviate the need for adjuvant systemic treatment. Conversely, a moderately-differentiated ICCA carries a poor prognosis with a prohibitively high recurrence rate and poor survival. Liver transplantation should remain a contraindication in this group.

Potential Application of Serum miRNA Signature for Minimization of Immunosuppression and Diagnosis of Rejection Following Liver Transplantation.

We tested the utility of serum miRNA signatures in the minimization of immunosuppression (IS) in adult recipients undergoing liver transplantation. Methods: The ITN030 study recruited 42 patients transplanted for non-HCV liver disease etiologies to undergo minimization of IS. Minimization to complete withdrawal started one year after transplantation and followed an 8-level reduction algorithm with ≥ 8 weeks per level. Randomization eligibility criteria included stable tacrolimus monotherapy and no evidence of rejection on biopsy. 233 serum samples (33 subjects randomized to IS withdrawal and 9 subjects randomized to maintenance) were collected at predetermined intervals: time of randomization, at specific minimization intervals, and when clinically indicated to rule out rejection (ACR) and subjected to miRNA profiling using microRNA PCR panels that includes 752 transcripts (Exiqon). Results:Serum samples with and without biopsy proven rejection were compared in a two-stage study (discovery phase with 14 ACR samples and 37 non-ACR samples; replication phase with 13 ACR samples and 40 non-ACR samples). In the combined dataset, 15 miRNAs remained significantly associated with ACR diagnosis after multiple testing corrections (FDR p-value < 0.05). The 15 miRNAs and time since randomization were used to build a multiple marker panel/signature capable of differentiating ACR from non-ACR in a logistic regression model with forward variable selection. Three miRNAs remained in the final parsimonious model. The logistic regression model consisted of these three miRNAs and provided excellent ability to differentiate ACR from non-ACR with an AUC of 0.898 (95%CI=0.84-0.95), 92.6% sensitivity and 84.2% specificity (p=0.0001). We explored the potential of the serum 3-miRNAs signature to serve as a predictor of ACR during minimization of immunosuppression. Recipients who had no evidence of rejection in their biopsies had no changes in baseline 3-miRNAs. In contrast, recipients with biopsy proven rejection demonstrated elevation in 3-miRNAs that separated them with 95% confidence band from the non-ACR group starting 40 days prior to ACR event. Conclusion:These findings suggest that the 3-miRNAs can be used to guide personalized minimization of IS, predict rejection, and noninvasively diagnose ACR in patients undergoing minimization.

Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation.

It is not clear whether prophylactic antiviral therapy is indicated to improve patient and graft survival in patients undergoing liver transplantation for chronic decompensated hepatitis C virus (HCV) infection. To compare the benefits and harms of different prophylactic antiviral therapies for patients undergoing liver transplantation for chronic HCV infection. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2013), MEDLINE, EMBASE, and Science Citation Index Expanded to February 2013. Only randomised clinical trials irrespective of language, blinding, or publication status and comparing various prophylactic antiviral therapies (alone or in combination) in the prophylactic treatment of patients undergoing liver transplantation for chronic HCV infection. Two authors collected the data independently. We calculated the risk ratio (RR) or mean difference (MD) or hazard ratio (HR) with 95% confidence intervals (CI) using the fixed-effect and the random-effects models based on available case analysis. A total of 501 liver transplant recipients undergoing liver transplantation for chronic HCV infection were randomised in 12 trials to various experimental interventions and control interventions. The proportion of genotype I varied between 49% and 100% in the seven trials that reported the genotype. Only one or two trials were included under each comparison. All the trials were of high risk of bias. Ten trials including 441 liver transplant recipients provided data for this review.There were no significant differences in the 90-day mortality (1 trial; 81 participants; 5/35 (adjusted proportion: 14.2%) in interferon group versus 5/46 (10.9%) in control group; RR 1.31; 95% CI 0.41 to 4.19); mortality at maximal follow-up (2 trials; 105 participants; 7/47 (adjusted proportion: 14.8%) in interferon group versus 10/58 (17.2%) in control group; RR 0.86; 95% CI 0.36 to 2.08); long-term mortality (1 trial; 81 participants; HR 0.45; 95% CI 0.13 to 1.56); mortality at maximal follow-up (1 trial; 54 participants; 1/26 (3.9%) in pegylated interferon group versus 2/28 (7.1%) in control group; RR 0.54; 95% CI 0.05 to 5.59); 90-day mortality (1 trial; 115 participants; 5/55 (9.1%) in pegylated interferon plus ribavirin group versus 3/60 (5.0%) in control group; RR 1.82; 95% 0.46 to 7.25); 90-day mortality (3 trials; 53 participants; 3/37 (adjusted proportion: 4.3%) in HCV antibody group versus 1/16 (6.3%) in placebo group; RR 0.69; 95% CI 0.15 to 3.11); or 90-day mortality (2 trials; 31 participants; 2/14 (adjusted proportion: 16.2%) in HCV antibody high-dose group versus 1/17 (5.9%) in HCV antibody low-dose group; RR 2.75; 95% CI; 0.30 to 25.35). There were no significant differences in the retransplantation at maximal follow-up (2 trials; 105 participants; 2/47 (adjusted proportion: 4.0%) in interferon group versus 2/58 (3.4%) in control group; RR 1.17; 95% CI 0.22 to 6.2); 90-day retransplantation (1 trial; 18 participants; 1/12 (8.3%) in HCV antibody group versus 0/6 (0%) in control group; RR 1.71; 95% CI 0.09 to 32.93); or 90-day retransplantation (1 trial; 12 participants; 1/6 (17.7%) in HCV antibody high-dose group versus 0/6 (0%) in HCV antibody low-dose group; RR 3.00; 95% CI 0.15 to 61.74). There were no significant differences in serious adverse events, graft rejection, worsening of fibrosis, or HCV recurrence between intervention and control groups in any of the comparisons that reported these outcomes. None of the trials reported quality of life, liver decompensation, intensive therapy unit stay, or hospital stay. Life-threatening adverse events were not reported in either group in any of the comparisons. There is currently no evidence to recommend prophylactic antiviral treatment to prevent recurrence of HCV infection either in primary liver transplantation or retransplantation. Further randomised clinical trials with adequate trial methodology and adequate duration of follow-up are necessary.

Racial differences in fibrosis progression after HCV-related liver transplantation.

Black recipients undergoing liver transplantation (LT) for hepatitis C virus (HCV) have decreased patient and graft survival compared with white recipients, a finding that is primarily limited to black recipients of livers from white donors. The cause(s) for these discrepant outcomes are unclear but may be related to HCV disease recurrence. The rates of HCV-related disease recurrence and liver fibrosis progression among black and white liver transplant recipients have not been investigated. In this study, we compared liver fibrosis progression between 105 black and 364 white recipients after HCV-related LT in a multisite cohort study and assessed the impact of donor race. At 6, 12, and 24 months after LT, there was a significantly higher percentage in the black recipient/white donor (B/W) group with severe fibrosis, defined as stage 3 or 4 (F3/F4), compared with all other recipient/donor race combinations. The adjusted odds ratio of developing F3/F4 for the B/W group was 2.54 (1.49-4.69; reference group, white recipient/white donor). Black recipients with black donors demonstrated a similar rate of progression to F3/F4 as white recipients. Patient survival was also decreased in the B/W group compared with other recipient/donor race combinations. African American recipients with white donors have more severe fibrosis progression after HCV-related LT. The mechanisms responsible for accelerating fibrosis progression in this high-risk race-mismatched group need to be investigated.

Phenotypic and Genotypic Differences Between a Child With Vertically Acquired Severe Hepatitis C Liver Disease and His Mother

Phenotypic and Genotypic Differences Between a Child With Vertically Acquired Severe Hepatitis C Liver Disease and His Mother

Effects of Low Central Venous Pressure During Preanhepatic Phase on Blood Loss and Liver and Renal Function in Liver Transplantation

Although the low central venous pressure (LCVP) technique is used to decrease blood loss during liver resection, its efficacy and safety during transplant procedures are still debatable. Our study aimed to assess the effects of this technique and its clinical safety for recipients undergoing liver transplantation. Eighty-six adult patients were randomly divided into a LCVP group and a control group. In the LCVP group, CVP was maintained below 5 mmHg or 40% lower than baseline during the preanhepatic phase by limiting infusion volume, manipulating the patient's posture, and administration of somatostatin and nitroglycerine. Recipients in the control group received standard care. Hemodynamics, blood loss, liver function, and renal function of the two groups were compared perioperatively. A lower CVP was maintained in the LCVP group during the preanhepatic phase, resulting in a significant decrease in blood loss (1922 +/- 1429 vs. 3111 +/- 1833 ml, P < 0.05) and transfusion volume (1200 +/- 800 vs. 2400 +/- 1200 ml, P < 0.05) intraoperatively. Compared with the control group, the LCVP group had a significantly lower mean arterial pressure at 2 h after the start of the operation (74 +/- 11 vs. 84 +/- 14 mmHg, P < 0.05), a lower lactate value at the end of the operation (5.9 +/- 3.0 vs. 7.2 +/- 3.0 mmol/l, P < 0.05), and a better preservation of liver function after the declamping of the portal vein. There were no significant differences in perioperative renal function and postoperative complications between the groups. The LCVP technique during the preanhepatic phase reduced intraoperative blood loss, protected liver function, and had no detrimental effects on renal function in LT.

Model for end-stage liver disease versus the Child-Pugh score in predicting the post-transplant 3-month and 1-year mortality in a cohort of Chinese recipients

This study evaluated the performance of the model for end-stage liver disease (MELD) in predicting post-transplant survival in a cohort of Chinese patients, and compared its predictive ability with that of the Child-Pugh score. The study enrolled 117 adult Chinese patients undergoing liver transplantation for benign end-stage liver diseases from January 1998 to January 2007 to evaluate the baseline characteristics and outcomes. In a median follow-up duration of 90 weeks (range 0.2-373 weeks), 30 patients died. The 3-month and 1-year mortality rates of recipients in group 1 (MELD score <28) were 1.1% and 5.6%, in group 2 (MELD score 28-38) 18.8% and 50.0%, and in group 3 (MELD score >38) 91.7% and 91.7%, respectively. A statistical difference was observed in the mortality rates between the three groups (P < 0.001). At 3 months, the area under the receiver operating characteristic curve of the MELD (0.950) was significantly higher than that of the Child-Pugh score (0.810; P < 0.05). Both the MELD and Child-Pugh score are valid models to predict the short-term or medium-term outcome of Chinese recipients undergoing liver transplantation for benign end-stage liver diseases. The MELD is superior to the Child-Pugh score in predicting the 3-month mortality post-transplantation.

Defective regulation of cholangiocyte Cl −/HCO [overthree] and Na +/H + exchanger activities in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a disorder of unknown origin with autoimmune features. Recently, impaired biliary secretion of bicarbonate has been shown in patients with PBC. Here we have investigated whether bile duct epithelial cells isolated from PBC patients exhibit defects in transepithelial bicarbonate transport by analyzing the activities of 2 ion exchangers, Cl −/HCO[overthree] anion exchanger 2 (AE2) and Na +/H + exchanger (NHE) in isolated cholangiocytes. AE2 and NHE activities were studied in basal conditions and after stimulation with cyclic adenosine monophosphate (cAMP) and extracellular adenosine triphosphate (ATP), respectively. Cholangiocytes were grown from needle liver biopsies from 12 PBC patients, 8 normal controls, and 9 patients with other liver diseases. Also, intrahepatic cholangiocytes were cultured after immunomagnetic isolation from normal liver tissue (n = 6), and from recipients undergoing liver transplantation for end-stage PBC (n = 9) and other forms of liver disease (n = 8). In needle-biopsy cholangiocytes, basal AE2 activity was significantly decreased in PBC as compared with normal livers and disease controls. In addition, we observed that though cAMP increased AE2 activity in cholangiocytes from both normal and non-PBC livers, this effect was absent in PBC cholangiocytes. Similarly, though in cholangiocytes from normal and disease control livers extracellular ATP induced a marked enhancement of NHE activity, cholangiocytes from PBC patients failed to respond to purinergic stimulation. In conclusion, our findings provide functional evidence that PBC cholangiocytes exhibit a widespread failure in the regulation of carriers involved in transepithelial H +/HCO[overthree] transport, thus, providing a molecular basis for the impaired bicarbonate secretion in this cholestatic syndrome. (H EPATOLOGY 2002;35:1513-1521.)