A prospective natural history study of coronary atherosclerosis following liver transplantation.

BACKGROUND & AIMS: Cardiovascular disease remains a leading cause of mortality following liver transplantation (LT). Whether it may be partially attributable to accelerated development of subclinical coronary artery disease is unclear. We sought to assess the longitudinal effect of LT on coronary plaque burden. METHODS: A prospective observational study was conducted in 30 asymptomatic patients who underwent computed tomographic coronary angiography (CTCA) pre- and a median 4-years following LT. Serial changes were quantified using coronary artery calcium score (CACS) and semi-quantitative CTCA scores, in a blinded fashion. High-risk plaque (HRP) characteristics were also assessed. Plaque progression was defined using prognostically significant cut-offs. RESULTS: In the study population (age 59.8 ± 8 years, 80% male), 93 of 459 coronary segments had plaque at baseline. On follow-up CTCA, 68 (+73.1%) new lesions appeared in segments without plaque initially. Nineteen (63.3%) patients demonstrated a clinically significant rise in plaque burden on CACS and semi-quantitative indices on CTCA (all p<0.001). CAD-RADS score rose to ≥4 (≥70% stenosis) in 9 (30%) patients, necessitating ischemia-guided revascularization in 3 (10%) patients. While the absence of coronary calcification or plaque pre-LT was protective, presence of HRP and development of post-transplant metabolic syndrome were both strong independent predictors of atherosclerosis progression. CONCLUSIONS: Our findings suggest that LT is associated with early progression of coronary atherosclerosis. Accelerated progression was noted particularly in those with HRP and post-transplant metabolic syndrome. Understanding the mechanisms of this novel observation and the potential role of preventive cardiovascular therapies in this population merit further study.

Immune function biomarker QuantiFERON-monitor is associated with infection risk in cirrhotic patients.

AIM: To investigate whether a novel immune function biomarker QuantiFERON-Monitor (QFM) can identify cirrhotic patients at greatest risk of infection. METHODS: Adult cirrhotic patients on the liver transplant waiting list were recruited for this observational cohort study from a tertiary liver transplant referral unit. The immune function biomarker, QFM was performed using the same method as the widely available Quantiferon-gold assay, and measures output in interferon gamma in IU/mL after dual stimulation of the innate and adaptive immune systems. Ninety-one cirrhotic patients were recruited, with 47 (52%) transplanted on the day of their QFM. The remaining 44 (48%) were monitored for infections until transplant, death, or census date of 1st February 2014. RESULTS: Cirrhotic patients express a median QFM significantly lower than healthy controls (94.5 IU/mL vs 423 IU/mL), demonstrating that they are severely immunosuppressed. Several factors including model for end stage liver disease, presence of hepatocellular carcinoma, bilirubin, international normalized ratio and haemoglobin were associated with QFM on univariate analysis. Disease aetiology did not appear to impact QFM. On multivariate analysis, only Child-Pugh score and urea were significantly associated with a patient's immune function as objectively measured by QFM. In the 44 patients who were not transplanted immediately after their blood test and could be monitored for subsequent infection risk, 13 (29.5%) experienced a pre-transplant infection a median 20 d (range 2-182) post-test. QFM < 214 IU/mL was associated with HR = 4.1 (P = 0.01) for infection. A very low QFM < 30 IU/mL was significantly associated (P = 0.003) with death in three patients who died while awaiting transplantation (HR = 56.6). CONCLUSION: QFM is lower in cirrhotics, allowing objective determinations of an individual's unique level of immune dysfunction. Low QFM was associated with increased susceptibility to infection.

Mechanisms of hepatitis B virus escape after immunoglobulin therapy.

Passive immunoprophylaxis with hepatitis B immunoglobulin is used to reduce the risk of infection of grafts after liver transplantation and also to protect newborn children of hepatitis B virus-infected mothers. The use of hepatitis B immunoglobulin is associated with the emergence of variant viruses or escape mutants that have specific amino acid substitutions in immunodominant epitopes. Under these circumstances, high serum titres of the virus may be observed in the context of apparently protective levels of antibody to hepatitis B surface antigen. The potential impact of hepatitis B surface antigen variation on vaccination strategies remains a contentious issue. As the burden of hepatitis B virus is dramatically reduced by major vaccination programmes, a greater proportion of carriers will demonstrate hepatitis B surface antigen variation from wild-type. The degree of protection afforded by current vaccines from subsequent infection by variants of the virus is unknown. Concern is raised over the potential impact of hepatitis B surface antigen variation on hepatitis B virus polymerase inhibitor susceptibility, and the reduced sensitivity of current antigen assays for detection of hepatitis B surface antigen variants.