ABCB4 Mutations in Adults Cause a Spectrum Cholestatic Disorder Histologically Distinct from Other Biliary Disease.

BACKGROUND: Mutations in the ABCB4 gene are associated with failure of bile acid emulsification leading to cholestatic liver disease. Presentations range from progressive familial intrahepatic cholestasis type 3 (PFIC3) in childhood, to milder forms seen in adulthood. AIMS: We sought to characterize adult disease with particular reference to histology which has been hitherto poorly defined. METHODS: Four unrelated adults (three female, mean age 39 years) and three sisters presenting with cholestatic liver disease in adulthood, associated with variants in the ABCB4 gene, were identified. Clinical review and detailed blinded histopathological analysis were performed. RESULTS: Two novel pathogenic ABCB4 variants were identified: c.620 T > G, p.(Ile207Arg) and c.2301dupT, p.(Thr768TyrfsTer26). Sub-phenotypes observed included low-phospholipid-associated cholelithiasis syndrome (LPAC), intrahepatic cholestasis of pregnancy (ICP), drug-induced cholestasis, idiopathic adulthood ductopenia, and adult PFIC3. Of note, 5/7 had presented with gallstone complications (4 meeting LPAC definition) and 4/6 females had a history of ICP. Considerable overlap was observed phenotypically and liver transplantation was required in 3/7 of patients. Histologically, cases generally demonstrated ductopenia of the smaller tracts, mild non-ductocentric portal inflammation, bilirubinostasis, significant copper-associated protein deposition, and varying degrees of fibrosis. CONCLUSIONS: Adults with ABCB4 mutations may harbor a spectrum of cholestatic disease phenotypes and can progress to liver transplantation. We observed a distinct histological pattern which differs from classical biliary disease and describe two novel pathogenic ABCB4 variants. ABCB4 sequencing should be considered in patients with relevant cholestatic phenotypes and/or suggestive histology; accurate diagnosis can guide potential interventions to delay progression and inform family screening.

Observations on the ex situ perfusion of livers for transplantation.

Normothermic ex situ liver perfusion might allow viability assessment of livers before transplantation. Perfusion characteristics were studied in 47 liver perfusions, of which 22 resulted in transplants. Hepatocellular damage was reflected in the perfusate transaminase concentrations, which correlated with posttransplant peak transaminase levels. Lactate clearance occurred within 3 hours in 46 of 47 perfusions, and glucose rose initially during perfusion in 44. Three livers required higher levels of bicarbonate support to maintain physiological pH, including one developing primary nonfunction. Bile production did not correlate with viability or cholangiopathy, but bile pH, measured in 16 of the 22 transplanted livers, identified three livers that developed cholangiopathy (peak pH < 7.4) from those that did not (pH > 7.5). In the 11 research livers where it could be studied, bile pH > 7.5 discriminated between the 6 livers exhibiting >50% circumferential stromal necrosis of septal bile ducts and 4 without necrosis; one liver with 25-50% necrosis had a maximum pH 7.46. Liver viability during normothermic perfusion can be assessed using a combination of transaminase release, glucose metabolism, lactate clearance, and maintenance of acid-base balance. Evaluation of bile pH may offer a valuable insight into bile duct integrity and risk of posttransplant ischemic cholangiopathy.

Liver transplantation in adults with liver disease due to common variable immunodeficiency leads to early recurrent disease and poor outcome.

Common variable immunodeficiency (CVID) is the most common form of primary immunodeficiency characterized by antibody deficiency, recurrent bacterial infections, and autoimmunity. Advanced chronic liver disease occurs in a subset of patients with CVID and manifests with various histological features, such as nodular regenerative hyperplasia, inflammation, fibrosis, and cholangiopathy. We present a case series characterizing the outcomes in adult patients transplanted for primary CVID-related liver disease. We discuss the unique transplantation challenges faced in this primary immunodeficiency group including susceptibility to infections and early disease recurrence. There is a statistically significant decrease in 3-year and 5-year survival after liver transplantation in those with CVID-related liver disease (55% at 3 and 5 years) compared with all-comers (89% at 3 years, 81% at 5 years), prompting a need for discussion of suitability of transplantation in this group of patients as well as methods for reducing posttransplantation risk such as scrupulous search for infectious agents and reduction of immunosuppression. Liver Transplantation 24 171-181 2018 AASLD.

Normothermic Perfusion in the Assessment and Preservation of Declined Livers Before Transplantation: Hyperoxia and Vasoplegia-Important Lessons From the First 12 Cases.

BACKGROUND: A program of normothermic ex situ liver perfusion (NESLiP) was developed to facilitate better assessment and use of marginal livers, while minimizing cold ischemia. METHODS: Declined marginal livers and those offered for research were evaluated. Normothermic ex situ liver perfusion was performed using an erythrocyte-based perfusate. Viability was assessed with reference to biochemical changes in the perfusate. RESULTS: Twelve livers (9 donation after circulatory death [DCD] and 3 from brain-dead donors), median Donor Risk Index 2.15, were subjected to NESLiP for a median 284 minutes (range, 122-530 minutes) after an initial cold storage period of 427 minutes (range, 222-877 minutes). The first 6 livers were perfused at high perfusate oxygen tensions, and the subsequent 6 at near-physiologic oxygen tensions. After transplantation, 5 of the first 6 recipients developed postreperfusion syndrome and 4 had sustained vasoplegia; 1 recipient experienced primary nonfunction in conjunction with a difficult explant. The subsequent 6 liver transplants, with livers perfused at lower oxygen tensions, reperfused uneventfully. Three DCD liver recipients developed cholangiopathy, and this was associated with an inability to produce an alkali bile during NESLiP. CONCLUSIONS: Normothermic ex situ liver perfusion enabled assessment and transplantation of 12 livers that may otherwise not have been used. Avoidance of hyperoxia during perfusion may prevent postreperfusion syndrome and vasoplegia, and monitoring biliary pH, rather than absolute bile production, may be important in determining the likelihood of posttransplant cholangiopathy. Normothermic ex situ liver perfusion has the potential to increase liver utilization, but more work is required to define factors predicting good outcomes.

Time spent in hospital after liver transplantation: Effects of primary liver disease and comorbidity.

AIM: To explore the effect of primary liver disease and comorbidities on transplant length of stay (TLOS) and LOS in later admissions in the first two years after liver transplantation (LLOS). METHODS: A linked United Kingdom Liver Transplant Audit - Hospital Episode Statistics database of patients who received a first adult liver transplant between 1997 and 2010 in England was analysed. Patients who died within the first two years were excluded from the primary analysis, but a sensitivity analysis was also performed including all patients. Multivariable linear regression was used to evaluate the impact of primary liver disease and comorbidities on TLOS and LLOS. RESULTS: In 3772 patients, the mean (95%CI) TLOS was 24.8 (24.2 to 25.5) d, and the mean LLOS was 24.2 (22.9 to 25.5) d. Compared to patients with cancer, we found that the largest difference in TLOS was seen for acute hepatic failure group (6.1 d; 2.8 to 9.4) and the largest increase in LLOS was seen for other liver disease group (14.8 d; 8.1 to 21.5). Patients with cardiovascular disease had 8.5 d (5.7 to 11.3) longer TLOS and 6.0 d (0.2 to 11.9) longer LLOS, compare to those without. Patients with congestive cardiac failure had 7.6 d longer TLOS than those without. Other comorbidities did not significantly increase TLOS nor LLOS. CONCLUSION: The time patients spent in hospital varied according to their primary liver disease and some comorbidities. Time spent in hospital of patients with cancer was relatively short compared to most other indications. Cardiovascular disease and congestive cardiac failure were the comorbidities with a strong impact on increased LOS.

A retrospective study assessing fully covered metal stents as first-line management for malignant biliary strictures.

OBJECTIVES: Fully covered self-expanding metal stents (FCSEMS) constitute the first type of metal stent that can easily be removed endoscopically and/or intraoperatively, which may be advantageous in the management of distal malignant biliary strictures (DMBS). To assess the efficacy of FCSEMS as first-line treatment for DMBS, we compared patency, survival and complication rates between FCSEMS, uncovered self-expanding metal stents (USEMS) and plastic stents (PS). METHODS: This was a multicentre retrospective study of 315 consecutive patients with DMBS, who underwent endoscopic retrograde cholangiopancreatography and stenting (FCSEMS, USEMS or PS) at two hospitals between 1 January 2007 and 31 December 2013. Stent patency and patient survival were compared using the Kaplan-Meier method; complication rates were compared using Fisher's exact test; and Cox regression analysis was used to screen for confounding factors. RESULTS: FCSEMS were associated with prolonged stent patency (median=145 days) compared with USEMS (median=110 days, P<0.003) and PS (median=34 days, P<0.001). Biliary sepsis rates were lower for FCSEMS compared with PS (4.7 vs. 17.8%, P=0.02), whereas pancreatitis rates were higher for FCSEMS compared with USEMS (7.8 vs. 1.0%, P=0.04), but not PS (2.6%, P=NS). CONCLUSION: The use of FCSEMS as first-line management for DMBS is associated with longer patency and reduced complication rates compared with the use of PS. However, the higher rate of pancreatitis compared with USEMS requires further evaluation in a large randomized controlled trial.

Time-varying impact of comorbidities on mortality after liver transplantation: a national cohort study using linked clinical and administrative data.

OBJECTIVE: We assessed the impact of comorbidity on mortality in three periods after liver transplantation (first 90 days, 90 days-5 years and 5-10 years). DESIGN: Prospective cohort study using records from the UK Liver Transplant Audit (UKLTA) linked to Hospital Episode Statistics (HES), an administrative database of hospital admissions in the English National Health Service (NHS). Comorbidities relevant for liver transplantation were identified from the 10th revision of the International Classification of Diseases (ICD-10) codes in HES records of admissions in the year preceding their operation. Multivariable Cox regression was used to estimate HRs for three different time periods after liver transplantation. SETTING: All liver transplant centres in the NHS hospitals in England. PARTICIPANTS: Adults who received a first elective liver transplant between April 1997 and March 2010 in the linked UKLTA-HES database. OUTCOMES: Patient mortality in three different time periods after transplantation. RESULTS: Among 3837 recipients, 45.1% had comorbidities. Recipients with cardiovascular disease had statistically significantly higher mortality in all three periods after transplantation (first 90 days: HR=2.0; 95% CI 1.4 to 2.9, 90 days-5 years: 1.6; 1.2 to 2.2, beyond 5 years: 2.8; 1.7 to 4.4). Prior congestive cardiac failure (3.2; 2.1 to 4.9) significantly increased mortality only in the first 90 days. History of non-hepatic malignancy appeared to increase risk over all periods, but significantly only in the first 90 days (1.9; 1.0 to 3.6). A diagnosis of connective tissue disease, dementia, diabetes, chronic pulmonary and renal disease did not have a significant impact on mortality in any period. CONCLUSIONS: The impact of comorbidities present at the time of transplantation changes with time after transplantation. Renal disease, pulmonary disease and diabetes had no impact on mortality in contrast to previous reports.

Linkage of a national clinical liver transplant database with administrative hospital data: methods and validation.

INTRODUCTION: The UK Liver Transplant Audit (UKLTA) database contains clinical information on all liver transplants carried out in the UK. To expand its potential for research and service evaluation, we linked it to the Hospital Episode Statistics (HES), an administrative database of all admissions to English National Health Service (NHS) hospitals. MATERIALS AND METHODS: In the UKLTA database, we identified the linkable records of first liver transplantation between April 1997 and March 2010. We linked UKLTA records to HES records on the basis of NHS number, gender, date of birth, and postcode, as well as procedure codes for liver transplantation and dates of transplant. In linked records, agreement of primary liver disease diagnoses according to both databases was expressed as a proportion of the linked records and using kappa statistic. RESULTS: There were 5,815 linkable records in the UKLTA database, of which 4,959 records were successfully linked with HES (85.3%). Among these, 4,922 records (99.3%) had at least one diagnosis coded in HES relevant to an indication for liver transplantation. The overall agreement of primary liver disease diagnoses between UKLTA data and HES was 77.8% (95% CI 76.6%-79.0%) with a kappa of 0.75 (0.74-0.76). Diagnostic agreement can be further improved by using broader groupings of clinically related diagnoses. CONCLUSION: Linkage of clinical data and administrative hospital data provides a rich resource for the study of liver transplantation.

Outcomes of transplantation of livers from donation after circulatory death donors in the UK: a cohort study.

OBJECTIVES: Outcomes of liver transplantations from donation after circulatory death (DCD) donors may be inferior to those achieved with donation after brain death (DBD) donors. The impact of using DCD donors is likely to depend on specific national practices. We compared risk-adjusted graft loss and recipient mortality after transplantation of DCD and DBD livers in the UK. DESIGN: Prospective cohort study. Multivariable Cox regression and propensity score matching were used to estimate risk-adjusted HR. SETTING: 7 liver transplant centres in the National Health Service (NHS) hospitals in England and Scotland. PARTICIPANTS: Adults who received a first elective liver transplant between January 2005 and December 2010 who were identified in the UK Liver Transplant Audit. INTERVENTIONS: Transplantation of DCD and DBD livers. OUTCOMES: Graft loss and recipient mortality. RESULTS: In total, 2572 liver transplants were identified with 352 (14%) from DCD donors. 3-year graft loss (95% CI) was higher with DCD livers (27.3%, 21.8% to 33.9%) than with DBD livers (18.2%, 16.4% to 20.2%). After adjustment with regression, HR for graft loss was 2.3 (1.7 to 3.0). Similarly, 3-year mortality was higher with DCD livers (19.4%, 14.5% to 25.6%) than with DBD livers (14.1%, 12.5% to 16.0%) with an adjusted HR of 2.0 (1.4 to 2.8). Propensity score matching gave similar results. Centre-specific adjusted HRs for graft loss and recipient mortality seemed to differ among transplant centres, although statistical evidence is weak (p value for interaction 0.08 and 0.24, respectively). CONCLUSIONS: Graft loss and recipient mortality were about twice as high with DCD livers as with DBD livers in the UK. Outcomes after DCD liver transplantation may vary between centres. These results should inform policies for the use of DCD livers.

A comparison of MR elastography and 31P MR spectroscopy with histological staging of liver fibrosis.

OBJECTIVES: Conventional imaging techniques are insensitive to liver fibrosis. This study assesses the diagnostic accuracy of MR elastography (MRE) stiffness values and the ratio of phosphomonoesters (PME)/phosphodiesters (PDE) measured using (31)P spectroscopy against histological fibrosis staging. METHODS: The local research ethics committee approved this prospective, blinded study. A total of 77 consecutive patients (55 male, aged 49 ± 11.5 years) with a clinical suspicion of liver fibrosis underwent an MR examination with a liver biopsy later the same day. Patients underwent MRE and (31)P spectroscopy on a 1.5 T whole body system. The liver biopsies were staged using an Ishak score for chronic hepatitis or a modified NAS fibrosis score for fatty liver disease. RESULTS: MRE increased with and was positively associated with fibrosis stage (Spearman's rank = 0.622, P < 0.001). PME/PDE was not associated with fibrosis stage (Spearman's rank = -0.041, p = 0.741). Area under receiver operating curves for MRE stiffness values were high (range 0.75-0.97). The diagnostic utility of PME/PDE was no better than chance (range 0.44-0.58). CONCLUSIONS: MRE-estimated liver stiffness increases with fibrosis stage and is able to dichotomise fibrosis stage groupings. We did not find a relationship between (31)P MR spectroscopy and fibrosis stage. KEY POINTS: Magnetic resonance elastography (MRE) and MR spectroscopy can both assess the liver. MRE is superior to ( 31 ) P MR spectroscopy in staging hepatic fibrosis. MRE is able to dichotomise liver fibrosis stage groupings. Gradient-echo MRE may be problematic in genetic haemochromatosis.

The impact of serum potassium concentration on mortality after liver transplantation: a cohort multicenter study.

BACKGROUND: Potassium plays a key role in human metabolism in both health and disease. The impact of recipient serum potassium concentration [K] on mortality after liver transplantation has not been described previously. METHODS: We assessed the effect of recipient [K] on the survival of adult first single-organ liver transplant recipients in the United Kingdom and Ireland between March 1, 1994, and February 28, 2007 (n=5942), adjusting for recipient, donor, and graft characteristics. RESULTS: The overall risk-adjusted mortality significantly varied by [K], being higher among hyperkalemic ([K]>5.0 mmol/L) recipients (n=424, hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.01-1.88) and those with [K] of 4.5-5.0 mmol/L (n=1154, HR 1.47, 95% CI 1.13-1.91), compared with hypokalemic ([K]<3.5 mmol/L) recipients (n=360). However, the excess mortality was confined to the first posttransplant year among hyperkalemic recipients (HR 1.61, 95% CI 1.10-2.35) with no significant difference thereafter (HR 1.03, 95% CI 0.62-1.73). This was also true for recipients with [K] of 4.5 to 5.0 mmol/L (< or =1 year: HR 1.70, 95% CI 1.22-2.38; >1 year: HR 1.09, 95% CI 0.71-1.66). In contrast, those with [K] of 3.5 to 3.9 mmol/L (n=1518) and [K] of 4.0-4.4 mmol/L (n=2091) had similar risk-adjusted mortality at the above time points. When [K] was used as a continuous variable in the multivariable analysis, a mmol increase in [K] was associated with an increased adjusted risk of mortality of 27% (95% CI 12%-44%) at 1 year and 19% (95% CI 7%-31%) at 5 years. CONCLUSION: Recipient [K] is an independent predictor of death after liver transplantation. This finding could be of clinical utility in the management, risk stratification, selection, and prioritization of appropriate candidates for transplantation among patients with end-stage liver disease.

Candidate selection and organ allocation in liver transplantation.

Optimal candidate selection and organ allocation should offer liver transplantation to those who are sufficiently sick to justify the procedure but not too sick to benefit from it, in an order determined by patients' projected survival benefit, matching organs of sufficiently good quality to the appropriate recipients. Significant steps have been made in recent years toward devising selection and allocation criteria based on more objective and evidence-based definitions of candidate disease severity, transplant futility, organ quality, and appropriate donor-recipient matching. However, much work remains to be done in the future.

Quality of life up to 30 years following liver transplantation.

Liver transplantation provides a return to a satisfactory quality of life (QOL) for the majority of patients in the short to medium term (first 5 years), but there is very little information on the QOL in the longer term and the factors influencing it. We therefore undertook a single-center cross-sectional analysis to determine QOL in patients 10 or more years after liver transplantation. All liver transplant recipients who were followed up at the Cambridge Transplant Unit for 10 or more years (transplanted between 1968 and 1994) and resident in the United Kingdom were asked to complete by post the Short Form 36 version 2 and the Ferrans and Powers questionnaires to evaluate their QOL. Univariate and multivariate analysis were performed to assess the relationship between a range of clinical parameters and QOL. One hundred two patients were invited to participate, and 61 (59.8%) responded. Overall, the patients reported a satisfactory QOL. On the Ferrans and Powers questionnaire, the patients had a mean Quality of Life Index score of 24.5. Factors associated with reduced physical functioning were age > 50 years at transplantation, female gender, and recurrence of the primary liver disease. On the Short Form 36 version 2 questionnaire, recipients had reduced physical functioning but normal mental health parameters in comparison with the normal population. Age > 60 years at the time of survey, female gender, and posttransplant complications were associated with reduced physical functioning. In conclusion, patients 10 or more years after liver transplantation generally have a good QOL, although physical functioning is reduced. Addressing issues such as recurrent disease and posttransplant problems such as osteoporosis may help to improve long-term QOL.

A randomized controlled trial of late conversion from calcineurin inhibitor (CNI)-based to sirolimus-based immunosuppression in liver transplant recipients with impaired renal function.

Renal impairment is common in patients after liver transplantation and is attributable in large part to the use of calcineurin inhibitor (CNI)-based immunosuppression. We sought to determine whether conversion to sirolimus-based immunosuppression was associated with improved renal function. In a single-center, randomized, controlled trial, 30 patients at least 6 months post liver transplantation were randomized to remain on CNI-based immunosuppression or to switch to sirolimus-based immunosuppression. The primary outcome measure was change in measured glomerular filtration rate (GFR) between baseline and 12 months. Of 30 patients randomized, 3 were withdrawn at randomization, leaving 14 patients on CNI and 13 on sirolimus. There was a significant improvement in delta GFR following conversion to sirolimus at 3 months (7.7 mL/minute/1.73 m2; 95% confidence interval, 3.5-11.9) and 1 yr (6.1 mL/minute/1.73 m2; 95% confidence interval, 0.9-11.4). The difference in absolute GFR between the 2 study groups was significant at 3 months (P=0.02), but not at 12 months (P=0.07). The principal adverse events following conversion were the development of skin rash (9 of 13 patients, 69%) and mouth ulcers (5 of 13 patients, 38%). Two patients developed acute rejection at 2 and 3 months following conversion, 1 in association with low sirolimus levels and 1 having stopped the drug inadvertently. In conclusion, overall, this study suggests that conversion to sirolimus immunosuppression is associated with a modest improvement in renal function. Side effects were common, but tolerable in most patients and controlled with dose reduction.

The impact of serum sodium concentration on mortality after liver transplantation: a cohort multicenter study.

Modification of the current allocation system for donor livers in the United States to incorporate recipient serum sodium concentration ([Na]) has recently been proposed. However, the impact of this parameter on posttransplantation mortality has not been previously examined in a large risk-adjusted analysis. We assessed the effect of recipient [Na] on the survival of all adults with chronic liver disease who received a first single organ liver transplant in the UK and Ireland during the period March 1, 1994 to March 31, 2005 (n=5,152) at 3 years, during the first 90 days, and beyond the first 90 days, adjusting for a wide range of recipient, donor, and graft characteristics. Compared to those with normal [Na] (135-145 meq/L; n=3,066), severely hyponatremic recipients ([Na]<130 meq/L, n=541), had a higher risk-adjusted mortality at 3 years (hazard ratio [HR] 1.28; 95% confidence interval [CI], 1.04-1.59; P<0.02). The excess mortality was, however, confined to the first 90 days (HR 1.55; 95% CI, 1.18-2.04; P<0.002) with no significant difference thereafter. This was also true for hypernatremic recipients ([Na]>45 meq/L, n=81), who had an even greater risk-adjusted mortality compared to normonatremic recipients (overall: HR 1.85; 95% CI, 1.25-2.73; P<0.002; 90 days: HR 1.12; 95% CI, 0.55-2.29; P=0.8), whereas mildly hyponatremic recipients ([Na] 130-134 meq/L, n=1,127) had similar risk-adjusted mortality to those with normal [Na] at the same time points. In conclusion, recipient [Na] is an independent predictor of death following liver transplantation. Attempts to correct the [Na] toward the normal reference range are an important aspect of pretransplantation management.

Is there disparity between risk and incidence of cardiovascular disease after liver transplant?

BACKGROUND: Hypertension and hypercholesterolemia are recognized complications of liver transplantation, but whether they contribute to the development of cardiovascular disease is uncertain. We aimed first to determine the prevalence of risk factors for coronary heart disease (CHD) after liver transplantation and second to study the effect of liver transplantation on the predicted 10-year risk of developing CHD and the incidence of cardiovascular events in comparison with a matched local population. METHODS: Data on blood pressure, serum lipids, weight, diabetes mellitus, smoking, and incidence of myocardial infarction (MI) and stroke were obtained retrospectively from the case notes of 181 consecutive adult liver transplant recipients (median follow-up 54 months). The Framingham coronary risk equations were used to calculate the 10-year probability of developing CHD. RESULTS: The prevalences of hypertension and hypercholesterolemia after transplantation were 77% and 62%, respectively. The predicted 10-year risk of CHD increased from 6.9% before transplantation to 11.5% at 1 year after transplantation, whereas that of a matched local population was 7%. Compared with a matched nontransplant population, the incidence ratios for MI and stroke were 0.55 (95% confidence interval, 0.01-3.06 ) and 1.45 (95% confidence interval, 0.18-5.22), respectively. No patients died from MI or stroke. CONCLUSIONS: Liver transplant recipients have a high prevalence of risk factors for cardiovascular disease, exceeding that of the general population, and have a higher predicted risk of developing CHD. Despite this, there were no deaths from CHD or stroke during the study period.

Liver transplantation.

Liver transplantation has evolved from an experimental procedure to an acceptable therapy for end-stage liver disease. The major challenges now faced are donor organ shortage, long-term complications related to immunosuppressive therapy, and the prevention and treatment of disease recurrence.

Transjugular intrahepatic portosystemic stent-shunt and liver transplantation--how safe is the bridge?

Many of the current indications for use of transjugular intrahepatic stent-shunts are also indications for consideration of orthotopic liver transplantation. Tripathi et al. report a similar operative mortality and early graft function in a series of cases transplanted with a TIPSS compared to apparently matched controls, although a higher frequency of post-operative renal dysfunction.