Severe Cholestasis Predicts Recurrent Primary Sclerosing Cholangitis Following Liver Transplantation.

BACKGROUND AIMS: Primary sclerosing cholangitis (PSC) may reoccur following liver transplantation (LT) and the diagnosis established once imaging studies demonstrate the diagnostic cholangiographic appearance. To evaluate whether the development of recurrent PSC (rPSC) is associated with cholestasis soon after LT, we studied whether changes in hepatic biochemistry within the first 12 months were linked with the development of rPSC and graft loss. METHODS: We conducted a retrospective cohort analysis of 158 transplant recipients with PSC in Canada, and 549 PSC transplant recipients from the United Kingdom. We evaluated serum liver tests within 12 months after LT and the subsequent development of a cholangiographic diagnosis of rPSC as a time-dependent covariate using Cox regression. Severe cholestasis was defined as either alkaline phosphatase> 3xupper limit of normal or total bilirubin> 100 µmol/L. RESULTS: Patients who developed rPSC were more likely to have severe cholestasis versus those without at 3 months (20.5% vs 8.2%, p=0.011), at 6 months (17.9% vs. 10.0%, p=0.026) and 12 months (15.4% vs. 7.8%, p=0.051) in the Canadian cohort and at 12 months in the UK cohort (27.9% vs. 12.6%, p<0.0001). By multivariable analysis, development of severe cholestasis in the Canadian cohort at 3 months (HR=2.41, p=0.046) and in the UK cohort at 12 months (HR=3.141, p<0.0001) were both associated with rPSC. Severe cholestasis at 3 months in the Canadian cohort was predictive of graft loss (HR=3.88, p=0.0001). CONCLUSIONS: The development of cholestasis within 3 to 12 months following LT was predictive of rPSC and graft loss.

Customised pre-operative cranioplasty to achieve maximal surgical resection of tumours with osseous involvement-a case series.

PURPOSE: Surgical resection with bony margins would be the treatment of choice for tumours with osseous involvement such as meningiomas and metastasis. By developing and designing pre-operative customised 3D modelled implants, the patient can undergo resection of meningioma and repair of bone defect in the same operation. We present a generalisable method for designing pre-operative cranioplasty in patients to repair the bone defect after the resection of tumours. MATERIALS AND METHODS: We included six patients who presented with a tumour that was associated with overlying bone involvement. They underwent placement of customised cranioplasty in the same setting. A customised implant using a pre-operative imaging was designed with a 2-cm margin to allow for any intra-operative requirements for extending the craniectomy. RESULTS: Six patients were evaluated in this case series. Four patients had meningiomas, 1 patient had metastatic breast cancer on final histology, and 1 patient was found to have an intra-osseous arteriovenous malformation. Craniectomy based on margins provided by a cutting guide was fashioned. After tumour removal and haemostasis, the cranioplasty was then placed. All patients recovered well post-operatively with satisfactory cosmetic results. No wound infection was reported in our series. CONCLUSION: Our series demonstrate the feasibility of utilising pre-designed cranioplasty for meningiomas and other tumours with osseous involvement. Following strict infection protocols, minimal intra-operative handling/modification of the implant, and close follow-up has resulted in good cosmetic outcomes with no implant-related infections.

Incidence and outcome of colorectal cancer in liver transplant recipients: A national, multicentre analysis on 8115 patients.

BACKGROUND & AIMS: De novo malignancies after liver transplantation represent one of the leading causes of death in the long-term. It remains unclear whether liver transplant recipients have an increased risk of colorectal cancer and whether this negatively impacts on survival, particularly in those patients affected by primary sclerosing cholangitis and ulcerative colitis. METHODS: In this national multicentre cohort retrospective study, the incidence of colorectal cancer in 8115 evaluable adult patients undergoing a liver transplantation between 1 January 1990 and 31 December 2010 was compared to the incidence in the general population through standardised incidence ratios. RESULTS: Fifty-two (0.6%) cases of colorectal cancer were identified at a median of 5.6 years postliver transplantation, predominantly grade 2 (76.9%) and stage T3 (50%) at diagnosis. The incidence rate of colorectal cancer in the whole liver transplant population was similar to the general UK population (SIR: 0.92), but significantly higher (SIR: 7.0) in the group of patients affected by primary sclerosing cholangitis/ulcerative colitis. One-, five- and ten-year survival rates from colorectal cancer diagnosis were 71%, 48% and 31%, respectively, and the majority of colorectal cancer patients died of cancer-specific causes. CONCLUSIONS: Liver transplantation alone is not associated with an increased risk of colorectal cancer development. The primary sclerosing cholangitis/ulcerative colitis liver transplant population showed a significantly higher risk of colorectal cancer development than the general population, with a high proportion of advanced stage at diagnosis and a reduced patient survival.

Risk factors for recurrent primary sclerosing cholangitis after liver transplantation.

BACKGROUND & AIMS: The association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) is well recognised. However, the relationship between IBD and recurrent PSC (rPSC) is less well understood. We assessed the prevalence of rPSC and analysed the factors associated with rPSC post-liver transplantation and its influence on graft and patient survival. METHODS: This is a UK multicentre observational cohort study across six of the seven national liver transplant units. All patients undergoing a first liver transplant for PSC between January 1 1990 and December 31 2010 were included. Prospectively collected liver transplant data was obtained from NHSBT and colitis data was retrospectively collected from individual units. RESULTS: There were 679 (8.8%) first transplants for PSC. 347 patients (61.4%) had IBD, of which 306 (88.2%) had ulcerative colitis (UC). 81 (14.3%) patients developed rPSC and 37 (48.7%) of them developed graft failure from rPSC. Presence of UC post-liver transplant (HR=2.40, 95% CI 1.44-4.02) and younger age (HR=0.78, 95% CI 0.66-0.93) were the only factors significantly associated with rPSC. rPSC was associated with over a 4-fold increase in the risk of death (HR=4.71, 95% CI 3.39, 6.56) with 1, 5, and 10-year graft survival rates of 98%, 84%, and 56% respectively compared to 95%, 88%, and 72% in patients who did not develop rPSC. CONCLUSION: The presence of UC post-liver transplant is associated with a significantly increased risk of rPSC. Furthermore, the presence of rPSC increases the rate of graft failure and death, with higher re-transplantation rates.

Reliability of magnetic resonance elastography using multislice two-dimensional spin-echo echo-planar imaging (SE-EPI) and three-dimensional inversion reconstruction for assessing renal stiffness.

BACKGROUND: To evaluate the reliability of MRE using a spin-echo echo-planar imaging (SE-EPI) renal MRE technique in healthy volunteers. METHODS: Institutional review board approved prospective study in which all participants provided written informed consent. Sixteen healthy volunteers comprising seven males and nine females with a median age of 35 years (age range: 23 to 59 years) were included. Coronal 90 Hz and 60 Hz MRE acquisitions were performed twice within a 30-min interval between examinations. Renal MRE reliability was assessed by (i) test-retest repeatability, and (ii) inter-rater agreement between two independent readers. The MRE-measured averaged renal stiffness values were evaluated using: intraclass correlation coefficient (ICC), Bland-Altman and the within-subject coefficient of variation (COV). RESULTS: For test-retest repeatability, Bland-Altman showed a mean stiffness difference between examinations of 0.07 kPa (95% limits of agreement: -1.41, 1.54) at 90 Hz and 0.01 kPa (95% limits of agreement: -0.51, 0.53) at 60 Hz. Coefficient of repeatability was 1.47 kPa and 0.52 kPa at 90 Hz and 60 Hz, respectively. The within-subject COV was 13.6% and 7.7% at 90 Hz and 60 Hz, respectively. ICC values were 0.922 and 0.907 for test-retest repeatability and 0.998 and 0.989 for inter-rater agreement, respectively (P < 0.001). CONCLUSION: SE-EPI renal MRE is a reliable technique.

Magnetic resonance elastography in the detection of hepatorenal syndrome in patients with cirrhosis and ascites.

OBJECTIVE: Hepatorenal syndrome (HRS) is the most lethal cause of renal impairment in cirrhosis. Magnetic resonance elastography (MRE) is a diagnostic test that characterises tissues based on their biomechanical properties. The aim of this study was to assess the feasibility of MRE for detecting HRS in cirrhotic patients. METHODS: A prospective diagnostic investigation was performed. Renal MRE was performed on 21 hospitalised patients with cirrhosis and ascites. Six patients had HRS, one patient had non-HRS renal impairment, and 14 patients had normal renal function. The MRE-measured renal stiffness was compared against the clinical diagnosis as determined by clinical review alongside laboratory and radiologic results. RESULTS: The MRE-measured renal stiffness was significantly lower in patients with HRS (median stiffness of 3.30 kPa at 90 Hz and 2.62 kPa at 60 Hz) compared with patients with normal renal function (median stiffness of 5.08 kPa at 90 Hz and 3.41 kPa at 60 Hz) (P ≤ 0.014). For the detection of HRS, MRE had an area under the receiver operating characteristic curve of 0.94 at 90 Hz and 0.89 at 60 Hz. MRE had excellent inter-rater agreement, as assessed by Bland-Altman and intraclass correlation coefficient (> 0.9). CONCLUSION: MRE shows potential in the detection of HRS. KEY POINTS: • Magnetic resonance elastography (MRE) shows promise in the detection of hepatorenal syndrome. • MRE has the potential to track renal disease in a clinical population. • MRE is a reliable diagnostic test with excellent inter-rater agreement.

Microarray analysis demonstrates up-regulation of the endothelin-1 gene with compensatory down-regulation of the ETA receptor gene in human portal vein.

High blood pressure in the portal vein, portal hypertension (PH), is the final common pathway in liver cirrhosis regardless of aetiology. Complications from PH are the major cause of morbidity and mortality in these patients. Current drug therapy to reduce portal pressure is mainly limited to ß-adrenergic receptor blockade but approximately 40% of patients do not respond. Our aim was to use microarray to measure the expression of ∼20,800 genes in portal vein from patients with PH undergoing transplantation for liver cirrhosis (PH, n=12) versus healthy vessels (control, n=9) to identify potential drug targets to improve therapy. Expression of 9,964 genes above background was detected in portal vein samples. Comparing PH veins versus control (adjusted P-value < 0.05, fold change > 1.5) identified 548 up-regulated genes and 1,996 down-regulated genes. The 2,544 differentially expressed genes were subjected to pathway analysis. We identified 49 significantly enriched pathways. The endothelin pathway was ranked the tenth most significant, the only vasoconstrictive pathway to be identified. ET-1 gene (EDN1) was significantly up-regulated, consistent with elevated levels of ET-1 peptide previously measured in PH and cirrhosis. ETA receptor gene (EDNRA) was significantly down-regulated, consistent with an adaptive response to increased peptide levels in the portal vein but there was no change in the ETB gene (EDNRB). The results provide further support for evaluating the efficacy of ETA receptor antagonists as a potential therapy in addition to ß-blockers in patients with PH and cirrhosis.

Standardizing Cranioplasty Outcomes Following Stroke or Traumatic Brain Injury: Protocol for the Development of a Core Outcome Set.

BACKGROUND: Core outcome sets (COSs) are important and necessary as they help standardize reporting in research studies. Cranioplasty following traumatic brain injury (TBI) or stroke is becoming increasingly common, leading to an ever-growing clinical and research interest, especially regarding the optimal material, cost-effectiveness, and timing of cranioplasty concerning neurological recovery and complications. Consequently, heterogeneous reporting of outcomes from such diverse studies has led to limited meta-analysis ability and an ongoing risk of outcome reporting bias. This study aims to define a standardized COS for reporting in all future TBI and stroke cranioplasty studies. OBJECTIVE: This study has four aims: (1) undertake a systematic review to collate the most current outcome measures used within the cranioplasty literature; (2) undertake a qualitative study to understand better the views of clinicians, patients' relatives, and allied health professionals regarding clinical outcomes following cranioplasty; (3) undertake a Delphi survey as part of the process of gaining consensus for the COS; and (4) finalize consensus through a consensus meeting resulting in the COS. METHODS: An international steering committee has been formed to guide the development of the COS. In addition, recommendations from other clinical initiatives such as COMET (Core Outcomes and Effectiveness Trials) and OMERACT (Outcome Measures in Rheumatology) have been adhered to. Phase 1 is data collection through a systematic review and qualitative study. Phase 2 is the COS development through a Delphi survey and consensus meetings with consensus definitions decided and agreed upon before the Delphi survey begins to avoid bias. RESULTS: Phase 1 started at the end of 2019, following ethical approval in December 2019, and the project completion date is planned for the end of 2022 or beginning of 2023. CONCLUSIONS: This study should result in a consensus on a COS for cranioplasty, following TBI or stroke, to help standardize outcome reporting for future studies, which can be applied to future research and clinical services, help align future studies, build an increased understanding of cranioplasty and its impact on a patient's function and recovery, and help standardize the evidence base. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37442.

Protocol for the development of a multidisciplinary clinical practice guideline for the care of patients with chronic subdural haematoma.

Introduction: A common neurosurgical condition, chronic subdural haematoma (cSDH) typically affects older people with other underlying health conditions. The care of this potentially vulnerable cohort is often, however, fragmented and suboptimal. In other complex conditions, multidisciplinary guidelines have transformed patient experience and outcomes, but no such framework exists for cSDH. This paper outlines a protocol to develop the first comprehensive multidisciplinary guideline from diagnosis to long-term recovery with cSDH. Methods: The project will be guided by a steering group of key stakeholders and professional organisations and will feature patient and public involvement. Multidisciplinary thematic working groups will examine key aspects of care to formulate appropriate, patient-centered research questions, targeted with evidence review using the GRADE framework. The working groups will then formulate draft clinical recommendations to be used in a modified Delphi process to build consensus on guideline contents. Conclusions: We present a protocol for the development of a multidisciplinary guideline to inform the care of patients with a cSDH, developed by cross-disciplinary working groups and arrived at through a consensus-building process, including a modified online Delphi.

Plasma levels of apelin are reduced in patients with liver fibrosis and cirrhosis but are not correlated with circulating levels of bone morphogenetic protein 9 and 10.

BACKGROUND: The peptide apelin is expressed in human healthy livers and is implicated in the development of hepatic fibrosis and cirrhosis. Mutations in the bone morphogenetic protein receptor type II (BMPR-II) result in reduced plasma levels of apelin in patients with heritable pulmonary arterial hypertension. Ligands for BMPR-II include bone morphogenetic protein 9 (BMP9), highly expressed in liver, and BMP10, expressed in heart and to a lesser extent liver. However, it is not known whether reductions in BMP9 and/or BMP10, with associated reduction in BMPR-II signalling, correlate with altered levels of apelin in patients with liver fibrosis and cirrhosis. METHODS: Plasma from patients with liver fibrosis (n = 14), cirrhosis (n = 56), and healthy controls (n = 25) was solid-phase extracted using a method optimised for recovery of apelin, which was measured by ELISA. RESULTS: Plasma apelin was significantly reduced in liver fibrosis (8.3 ± 1.2 pg/ml) and cirrhosis (6.5 ± 0.6 pg/ml) patients compared with controls (15.4 ± 2.0 pg/ml). There was no obvious relationship between apelin and BMP 9 or BMP10 previously measured in these patients. Within the cirrhotic group, there was no significant correlation between apelin levels and disease severity scores, age, sex, or treatment with ß-blockers. CONCLUSIONS: Apelin was significantly reduced in plasma of patients with both early (fibrosis) and late-stage (cirrhosis) liver disease. Fibrosis is more easily reversible and may represent a potential target for new therapeutic interventions. However, it remains unclear whether apelin signalling is detrimental in liver disease or is beneficial and therefore, whether an apelin antagonist or agonist have clinical use.

Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis.

BACKGROUND: BMP9, originating from the liver, and BMP10 are circulating BMPs that preserve vascular endothelial integrity. We assessed BMP9, BMP10 and soluble endoglin (sEng) levels and their relationships to liver disease severity and associated pulmonary vascular syndromes in a cohort of well-characterised liver disease patients. METHODS: Plasma samples from patients with liver disease (n = 83) and non-disease controls (n = 21) were assayed for BMP9, BMP10 and sEng. Levels were also assessed in a separate cohort of controls (n = 27) and PoPH patients (n = 8). Expression of mRNA and immunohistochemical staining was undertaken in liver biopsy specimens. Plasma BMP activity was assessed using an endothelial cell bioassay. FINDINGS: Plasma BMP9 and BMP10 levels were normal in patients with compensated cirrhosis or fibrosis without cirrhosis, but markedly reduced in patients with decompensated cirrhosis, including those with hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PoPH). Liver biopsy specimens revealed reduced mRNA expression and immunostaining for these ligands. Patient plasma samples with reduced BMP9 and BMP10 levels exhibited low BMP activity that was restored with exogenous BMP9. Endoglin mRNA expression was increased in cirrhotic livers and elevated circulating sEng levels in PoPH and HPS patients suggested increased endothelial sEng shedding in these syndromes. INTERPRETATION: Plasma BMP9 and BMP10 levels are reduced in decompensated cirrhosis, leading to reduced circulating BMP activity on the vascular endothelium. The pulmonary complications of cirrhosis, PoPH and HPS, are associated with markedly reduced BMP9 and BMP10 and increased sEng levels, suggesting that supplementation with exogenous ligands might be a therapeutic approach for PoPH and HPS.