Long-term outcomes of liver transplantation for homozygous familial hypercholesterolaemia in Australia and New Zealand.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (FH) causes severe cardiovascular disease from childhood. Conventional drug therapy is usually ineffective; lipoprotein apheresis (LA) is often required. Liver transplantation (LT) can correct the metabolic defect but is considered a treatment of last resort. Newer drugs including lomitapide and evinacumab might reduce the need for apheresis and LT. We sought to determine the long-term outcomes following LT in Australia and New Zealand. METHODS: We analysed demographic, biochemical and clinical data from all patients in Australia and New Zealand who have received LT for homozygous FH, identified from the Australia and New Zealand Liver and Intestinal Transplant Registry. RESULTS: Nine patients (five female; one deceased; seven aged between 3 and 6 years at the time of LT and two aged 22 and 26 years) were identified. Mean follow-up was 14.1 years (range 4-27). Baseline LDL-cholesterol off all treatment was 23 ± 4.1 mmol/L. Mean LDL-cholesterol on medical therapy (including maximal statin therapy in all patients, ezetimibe in three and LA in five) was 11 ± 5.7 mmol/L (p < 0.001). After LT, mean LDL-cholesterol was 2.6 ± 0.9 mmol/L (p = 0.004) with three patients remaining on statin therapy and none on LA. One patient died from acute myocardial infarction (AMI) three years after LT. Two patients required aortic valve replacement, more than 10 years after LT. The remaining six patients were asymptomatic after eight to 21 years of follow-up. No significant adverse events associated with immunosuppression were reported. CONCLUSIONS: LT for homozygous FH was highly effective in achieving substantial long-term reduction in LDL-cholesterol concentrations in all nine patients. LT remains an option for severe cases of homozygous FH where drug therapy combined with apheresis is ineffective or unfeasible.

Impact of cardiac dysfunction on morbidity and mortality in liver transplant candidates.

The prognostic role of cardiac dysfunction in cirrhotic patients is increasingly recognized. We studied its impact on morbidity and mortality before and after liver transplantation (LT) including development of post-transplant cardiovascular disease (CVD). In this retrospective study, cirrhotic patients who underwent LT assessment from January 2010 to December 2020 were reviewed. Demographics, cardiac investigations and clinical courses were analyzed to identify the prevalence of cardiac dysfunction and its role in LT outcomes. Survival analysis was performed using Cox proportional hazard regression modelling, with LT as a time-varying covariate and as an interaction variable with cardiac dysfunction. Three hundred and eight patients (70% male) were studied. The median (interquartile range) age at LT assessment was 56 (12) years. Cardiac dysfunction was found in 178 (58%) patients (diastolic, 169; systolic, 26; both, 17) and was significantly associated with hepatorenal syndrome/acute kidney injury and peri- and post-transplant morbidity (adjusted odds ratio [aOR] 1.94, 95% CI 1.06-3.52, P < .001; aOR 2.01, 95% CI 1.06-3.82, P = .033; aOR 1.9, 95% CI 1.01-3.65, P = .023, respectively). Cardiac dysfunction was not associated with mortality before (adjusted hazard ratio [aHR] 1.01, 95% CI .99-1.01) or after LT (aHR .74, 95% CI .4-1.05. Post-transplant CVD (61% cardiac failure) occurred in 36 patients, and there was no significant association with cardiac dysfunction (P = .11). Cardiac dysfunction was common in LT candidates and was significantly associated with morbidity before and after LT. Studies on the role of advanced echocardiographic parameters to improve diagnosis of cardiac dysfunction and optimize LT outcomes are needed.

Association of physiological reserve measures with adverse outcomes following liver transplantation.

BACKGROUND AND AIM: The comparative utility of physiological reserve measures in predicting important clinical outcomes following liver transplantation (LT) requires further study. The aim of this work was therefore to compare the utility of physiological reserve measures in predicting early adverse clinical outcomes post-LT. METHODS: A single-center, retrospective cohort study of LT patients consecutively recruited between 1 January 2015, and 31 August 2020. Outcomes measured were sepsis and death within 12 months of LT, hospital length of stay (LOS), and intensive care LOS. Physiological reserve measures were handgrip strength, mid-arm muscle circumference, and cardiopulmonary exercise testing (CPET) measures. Analysis was performed using univariate and multivariate logistic regression for sepsis and death, and univariate and multivariate Cox regression for hospital and intensive care LOS. RESULTS: Data were obtained for 109 subjects. Patients were predominantly (64%) male with a median (interquartile range [IQR]) age of 57 (49-63) and median (IQR) Model for End-Stage Liver Disease score of 16 (11-21). In multivariate analysis, the odds of sepsis were lower in patients in the highest versus lowest tertile (odds ratio = 0.004; 95% confidence interval [CI] 0.00-0.13; P = 0.002). Hospital LOS was linearly associated with handgrip strength (hazard ratio [HR] = 1.03; 95% CI 1.00-1.06; P = 0.03) in multivariate analysis. Intensive care LOS was associated with peak VO2 (HR 1.83; 95% CI 1.06-3.16; P = 0.03) and VE/VCO2 slope (HR 0.71; 95% CI 0.58-0.88; P = 0.002) in multivariate analysis. CONCLUSION: Handgrip strength and CPET both identify candidates at high risk of adverse outcomes after LT.

The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome.

This study investigated the effect of recipient and donor genetic variability on dose-adjusted steady-state tacrolimus concentrations (Css ) and clinical outcomes 3 and 6 months after liver transplant. Twenty-nine recipients and matched donor blood samples were genotyped for 27 single nucleotide polymorphisms including CYP3A5*3 (rs776746), ABCB1 haplotype and immune genes. Associations between genetic variability and clinical parameters and Css and the occurrence of rejection and nephrotoxicity were analysed by multivariate and multinomial logistic regression modelling and Jonckheere-Terpstra tests examined the impact of combined donor/recipient CYP3A5 expression on Css . At 3 months post-transplant modelling revealed an association between tacrolimus Css and recipient CASP1 rs580523 genotype (P = 0.005), accounting for 52% Css variance. Jonckheere-Terpstra tests revealed that as combined donor/recipient CYP3A5 expression increased, Css decreased (P = 0.010 [3 months], 0.018 [6 months]). As this is the first report of CASP1 genetic variability influencing tacrolimus Css , further validation in larger cohorts is required.

High rates of indeterminate interferon-gamma release assays for the diagnosis of latent tuberculosis infection in liver transplantation candidates.

BACKGROUND AND AIMS: Screening for latent tuberculosis infection (LTBI) is recommended prior to solid organ transplantation. Interferon-gamma release assays (IGRAs) are the most widely used test for LTBI screening; however, assessment of IGRA performance in patients with end-stage liver disease is limited. The purpose of this study was to evaluate the prevalence and predictors of indeterminate (INDT) IGRA results in liver transplantation candidates. METHODS: Between March 2011 and May 2018, we retrospectively analyzed 155 patients undergoing liver transplantation assessment, who underwent IGRA testing (Quantiferon-TB Gold, QFT-G) to exclude LTBI. Characteristics of patients, including age, gender, etiology of liver disease, MELD score, and absolute lymphocyte counts, were compared by QFT-G result (determinate vs INDT). RESULTS: Of the 155 patients screened, the rate of positive, negative, and INDT results were 5.2%, 69.8%, and 25%, respectively. The only variable independently associated with an indeterminate test on multivariate analysis was MELD score (odds ratio = 1.07, 95% CI = 1.01-1.14 per unit increase; P = 0.014). In 95% of INDT tests, both TB antigen tube and the positive control tube were negative and repeat testing gave the same indeterminate result, suggestive of anergy rather than laboratory error. CONCLUSIONS: Our study suggests a high rate of INDT IGRA results during screening of liver transplant candidates for LTBI, associated with severity of liver disease and anergy. Because of the high rate of INDT QFT-G testing in this setting, individualized risk assessment is required including a thorough assessment of clinical risk factors and knowledge of local TB prevalence.

Effect of Nonsurgical Periodontal Therapy on the Glycaemic Control of Nondiabetic Periodontitis Patients: A Clinical Biochemical Study.

PURPOSE: To compare the HbA1c levels in nondiabetic subjects with periodontitis and periodontally healthy controls and to evaluate the effect of nonsurgical periodontal therapy on the glycaemic control in nondiabetic subjects with periodontitis. MATERIALS AND METHODS: A total of 220 nondiabetic subjects between 35 and 60 years old were selected and divided into two groups: group A (case group), comprised of subjects with chronic periodontitis, and group B (control group), comprised of subjects with healthy periodontium. Periodontal clinical parameters (plaque index, modified sulcular bleeding index, probing depth and clinical attachment level) were used to assign the subjects into the respective groups. The HbA1c level was estimated for both groups using a commercially available kit. Subjects in group A underwent nonsurgical periodontal therapy in two to four sessions along with oral hygiene instructions. The periodontal parameters and HbA1c levels were again evaluated in the test group three months following periodontal therapy. RESULTS: The HbA1c levels were higher in the case group (A) than the control group (B). Three months following periodontal therapy in group A, there was improvement in periodontal parameters. The HbA1c levels decreased significantly from baseline to 3 months. CONCLUSION: The results of this study found chronic periodontitis to be associated with a significant increase in glycosylated haemoglobin levels in nondiabetic periodontitis subjects. Furthermore, with improvement of periodontal status, the glycaemic levels return to near normal values.

Clinical effects of subgingivally delivered spirulina gel in chronic periodontitis cases: a placebo controlled clinical trial.

AIMS AND OBJECTIVES: The aim of this study was to assess the clinical effects of Spirulina in-situ gel as an adjunct to Scaling And Root Planning (SRP) in the treatment of chronic periodontitis subjects. MATERIAL AND METHODS: 64 sites were selected with probing pocket depth of ≥5mm and they were divided into 2 groups; 33 sites were treated with SRP along with spirulina gel (Group A) and 31 sites were treated with SRP alone (Group B). Clinical parameters were recorded at baseline before SRP and at 120(th) day after the treatment therapy. The parameters included Probing Pocket Depth (PPD) and Clinical Attachment Level (CAL). RESULTS: Both the groups showed significant improvement in the parameters. However, Group A (SRP along with spirulina) showed statistically significant decrease in mean probing pocket depth and gain in the clinical attachment level after 120 days as compared to Group B SRP alone. CONCLUSION: Locally delivered spirulina gel, along with scaling and root planning, has been shown to cause a beneficial impact. The efficacy of the product as a local drug delivery system in the non-surgical treatment of periodontitis without any side effects has been proved. Spirulina appears to be promising. It exerts strong anti-inflammatory effects which are closely connected with its antioxidative activity. This study can have a significant impact on the treatment procedures of periodontitis, with the use of blue green algae in the future.

Liver transplantation: a small-volume unit experience.

BACKGROUND: Results of liver transplantation have improved significantly over the last three decades. Hospital volume has been cited as an important outcome factor. The South Australian (SA) programme commenced in 1992 as the fourth centre in Australia. METHODS: Patient and graft survival curves were computed from the Australian and New Zealand (ANZ) Liver Transplant Registry. SA results were compared with the rest of ANZ. All recipients of a cadaveric liver from the start of the SA programme in 1992 until the 100th case in 2005 were included and compared with recipients from ANZ in the same period. RESULTS: In SA, 100 recipients received 104 grafts (average 8.0/year). In the same period 1438 recipients received 1530 grafts in ANZ (mean 23.4/year per unit). The median follow up was 6.2 years. Patient and graft survival curves were similar (P = 0.51, log-rank test.) Survival rates at 1, 5 and 10 years were 0.93, 0.83, 0.61 and 0.88, 0.80, 0.72 for SA and ANZ, respectively (P = NS). There was trend towards a higher mortality rate of recurrent hepatitis C in SA patients when compared with the rest of ANZ (4.0 vs 1.3% respectively, P = 0.06). Recipient variables, such as age and primary liver disease did not differ between SA and ANZ. For the SA patients the biliary anastomotic stricture rate was 20%, primary non-function rate was 2%, hepatic artery thrombosis 1% and portal vein thrombosis 1%. CONCLUSION: Good results are possible in a small-volume unit for cadaveric adult liver transplant.