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.

The Adrenal Vein Sampling Outcomes Study (AVOS): success rates following adrenalectomy for unilateral primary aldosteronism.

The objective was to determine the clinical and biochemical success rates and assess the nature of follow-up after adrenalectomy in patients with unilateral primary aldosteronism (PA), subtyped by adrenal vein sampling (AVS) in West Australia (WA) using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Clinical and biochemical outcomes were retrospectively evaluated in patients with unilateral PA who underwent adrenalectomy according to AVS between September 2017 and September 2020. Pre- and post-surgical data were collected using a standardised questionnaire, review of clinic letters and examination of private and public pathology results and radiological reports. Follow-up data were available for 47 patients post-adrenalectomy; biochemical outcome data were available for 37 patients, clinical outcome data for 40 patients, with 30 patients having both outcomes available. Final assessment was performed between 0 to 3 months in 23/37 (62.2%) patients with biochemical outcomes, 15/40 (37.5%) with clinical outcomes, and 17/30 (56.7%) with both clinical and biochemical outcomes. Complete biochemical success was achieved in 83.8% (31/37) of patients, with 26.7% (8/30) obtaining both complete clinical and biochemical success. Complete clinical success was achieved in 35.0% (14/40) of patients, with 47.5% (19/40) obtaining partial clinical success. Overall, 93.6% (44/47) of patients derived benefit from adrenalectomy. The outcomes of adrenalectomy for unilateral PA in Western Australian using standardised PASO criteria demonstrate highly comparable clinical and biochemical success rates to international data. However, further standardisation of post-operative follow-up care needs to be implemented to ensure the recommended repeat follow-up assessment criteria are collected.

A variant in the fibronectin (FN1) gene, rs1250229-T, is associated with decreased risk of coronary artery disease in familial hypercholesterolaemia.

BACKGROUND: Increased risk of coronary artery disease (CAD) in familial hypercholesterolaemia (FH) is modified by factors beyond defects in the low-density lipoprotein receptor pathway. The rs1250229-T single nucleotide polymorphism (SNP) in the FN1 gene is associated with CAD in genome-wide association studies and is in linkage disequilibrium with another SNP (rs1250259-T) in FN1 that is associated with decrease fibronectin secretion. OBJECTIVE: We investigated whether rs1250229-T was also associated with prevalent CAD in patients with genetically confirmed FH. METHODS: We collected clinical data from 256 patients with genetically confirmed FH. The FN1 rs1250229 SNP was genotyped on a SEQUENOM platform. The association between rs1250229-T and prevalent CAD was assessed using simple and multiple regression analyses. RESULTS: In patients with FH, the FN1 rs1250229-T (minor) allele was a significant negative predictor of prevalent CAD (odds ratio [OR] 0.353; 95% confidence interval [CI] 0.193 - 0.647; P = 0.001). FN1 rs1250229-T remained a significant predictor of prevalent CAD after adjusting for age, sex, obesity, hypertension, smoking status and lipoprotein(a) concentration (OR 0.200; 95% CI 0.091 - 0.441; P < 0.001). CONCLUSION: The FN1 rs1250229-T allele is inversely associated with CAD in patients with genetically confirmed FH, independently of traditional risk factors. While this finding requires replication, it suggests that the biology of fibronectin may contribute to variation in the risk of CAD in FH.

Detecting patients with Cushing's syndrome: The importance of initial test selection.

BACKGROUND AND OBJECTIVES: The recommended initial tests for suspected Cushing's syndrome are late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC) and the 1 mg overnight dexamethasone suppression test (ONDST). These tests have higher sensitivity and specificity than serum cortisol. The aim of this study was to determine the relative frequency of these requested tests in primary care. METHOD: Initial test selection for investigation of Cushing's syndrome was audited by reviewing pathology request forms for cortisol tests made to a major community-based laboratory in 2019. Those with hypertension or adrenal incidentaloma as the documented indication for testing were included. RESULTS: In 214 of 272 cases (78.7%; 95% confidence interval: 73.2%, 83.3%) initial testing was by measurement of serum cortisol alone. DISCUSSION: The relatively infrequent selection of the higher sensitivity tests (ONDST, UFC and LNSC) for investigation of suspected Cushing's syndrome signifies a risk of delayed or missed diagnosis, with important implications for morbidity and mortality.

Approach to the diagnosis of secondary hypertension in adults.

Presentations that should raise suspicion of secondary hypertension include early-onset, severe or resistant hypertension. A suggestive family history or clinical clues can point to a specific secondary cause. The most common causes and associations are renal disease, primary aldosteronism and obstructive sleep apnoea. Medicines, illicit substances and alcohol may also be responsible. The assessment of patients begins with history taking and examination, to look for clinical clues. Laboratory tests include electrolytes, urea, creatinine and the aldosterone:renin ratio, urinalysis and the urine albumin:creatinine ratio. Abnormal results should prompt further investigation. Initial testing for primary aldosteronism is best done before starting potentially interfering antihypertensive drugs. If the patient is already taking interfering antihypertensive drugs that cannot be stopped, the interpretation of the aldosterone:renin ratio must consider the presence of those drugs. Specialist advice can be sought if needed.

Contemporary perspectives on the genetics and clinical use of lipoprotein(a) in preventive cardiology.

PURPOSE OF REVIEW: The pathogenicity of lipoprotein(a) [Lp(a)] as a risk factor for atherosclerotic cardiovascular disease (ASCVD) is well evidenced and recognized by international consensus-based guidelines. However, the measurement of Lp(a) is not routine clinical practice. Therapeutic agents targeting Lp(a) are now progressing through randomised clinical trials, and it is timely for clinicians to familiarize themselves with this complex and enigmatic lipoprotein particle. RECENT FINDINGS: Recent developments in the understanding of genetic influences on the structure, plasma concentration and atherogenicity of Lp(a) have contextualized its clinical relevance. Mendelian randomization studies have enabled estimation of the contribution of Lp(a) to ASCVD risk. Genotyping individual patients with respect to Lp(a)-raising single nucleotide polymorphisms predicts ASCVD, but has not yet been shown to add value beyond the measurement of Lp(a) plasma concentrations, which should be done by Lp(a) isoform-independent assays capable of reporting in molar concentrations. Contemporary gene-silencing technology underpins small interfering RNA and antisense oligonucleotides, which are emerging as the leading Lp(a)-lowering therapeutic agents. The degree of Lp(a)-lowering required to achieve meaningful reductions in ASCVD risk has been estimated by Mendelian randomization, providing conceptual support. SUMMARY: Measurement of Lp(a) in the clinical setting contributes to the assessment of ASCVD risk, and will become more important with the advent of specific Lp(a)-lowering therapies. Knowledge of an individual patient's genetic predisposition to increased Lp(a) appears to impart little or not additional clinical value beyond Lp(a) particle concentration.

Lipoprotein apheresis and PCSK9 inhibitors for severe familial hypercholesterolaemia: Experience from Australia and New Zealand.

INTRODUCTION: Severe familial hypercholesterolaemia (FH) causes premature disability and death due to atherosclerotic cardiovascular disease and is refractory to standard lipid-lowering therapies. Lipoprotein apheresis (LA) has long been a standard of care for patients with severe FH, but is invasive, expensive and time-consuming for patients and their caregivers. Newer drug therapies, including the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, may reduce the need for LA. MATERIALS AND METHODS: We audited the records of 16 patients (eight homozygous, eight heterozygous) treated with LA in Australia and New Zealand, 14 of whom subsequently commenced PCSK9 inhibitor therapy. LA was performed by cascade filtration in all centres. RESULTS: LDL-cholesterol was acutely lowered by 69 ± 7% in patients with homozygous FH and by 72 ± 9% in those with heterozygous FH, representing time-averaged reductions of 36 ± 12% and 34 ± 5%, respectively. LA was well-tolerated, and patients reported comparable quality of life to population and disease-related norms. After commencement of PCSK9 inhibitors, four of seven patients with homozygous FH had meaningful biochemical responses, with a reduction in the frequency of LA permitted in one patient and complete cessation in another. Four of seven patients with heterozygous FH were able to be managed without LA after commencing PCSK9 inhibitors. CONCLUSION: While PCSK9 inhibitors have reduced the need for LA, some patients with severe FH continue to require LA, and will require it for the foreseeable future. However, emerging therapies, including angiopoetin-like 3 inhibitors, may further reduce the need for LA.

Coronary artery disease and the risk-associated LPA variants, rs3798220 and rs10455872, in patients with suspected familial hypercholesterolaemia.

BACKGROUND: The rs3798220 and rs10455872 single nucleotide polymorphisms (SNPs) in LPA are associated with increased plasma concentrations of lipoprotein(a) [Lp(a)] and coronary artery disease (CAD). METHODS: We investigated the association between rs3798220 and rs10455872 and prevalent CAD in 763 patients with suspected familial hypercholesterolaemia (FH). The rs3798220 and rs10455872 SNPs in LPA were detected using a SEQUENOM platform. RESULTS: Both LPA SNPs were significantly associated with CAD, but only rs3798220 after adjustment for other risk factors (odds ratio [OR] 2.05; 95% confidence interval [CI] 1.02-4.12; p = 0.045), and neither after adjustment for Lp(a) concentrations. Both SNPs were positively and independently associated with increased Lp(a) (rs3798220: OR 1.27; 95% CI 0.96-1.57; p < 0.001. rs10455872: OR 1.41; 95% CI 1.24-1.58; p < 0.001). Plasma concentrations of Lp(a) were independently associated with prevalent CAD (OR 1.28; 95% CI 1.08-1.52, p = 0.005) after adjustment for LPA SNPs and other cardiovascular risk factors. While both the rs3798220 and rs10455872 SNPs were associated with Lp(a) concentrations and prevalent CAD in patients with suspected FH, this was not independent of Lp(a) concentration. CONCLUSIONS: Quantification of Lp(a) is more likely to be useful than assessment of these Lp(a)-associated SNPs to augment CAD risk prediction.

Widening the spectrum of genetic testing in familial hypercholesterolaemia: Will it translate into better patient and population outcomes?

Familial hypercholesterolaemia (FH) is caused by pathogenic variants in LDLR, APOB or PCSK9. Impaired low-density lipoprotein (LDL) receptor function leads to decreased LDL catabolism and premature atherosclerotic cardiovascular disease (ASCVD). Thousands of LDLR variants are known, but assignation of pathogenicity requires accurate phenotyping, family studies and assessment of LDL receptor function. Precise, genetic diagnosis of FH using targeted next generation sequencing allows for optimal treatment, distinguishing FH from pathogenically distinct disorders requiring different treatment. Polygenic hypercholesterolaemia resulting from an accumulation of LDL cholesterol-raising single nucleotide polymorphisms (SNPs) could also be suspected by this approach. Similarly, ASCVD risk could be estimated by broader sequencing of cholesterol and non-cholesterol-related genes. Both of these areas require further research. The clinical management of FH, focusing on the primary or secondary prevention of ASCVD, has been boosted by PCSK9 inhibitor therapy. The efficacy of PCSK9 inhibitors in homozygous FH may be partly predicted by the LDLR variants. While expanded genetic testing in FH is clinically useful in providing an accurate diagnosis and enabling cost-effective testing of relatives, further research is needed to establish its value in improving clinical outcomes.

Pharmacokinetics of flucloxacillin during prolonged intermittent renal replacement therapy in a 76-year-old man.

Prolonged intermittent renal replacement therapy (PIRRT) use has been increasing in critically ill patients with kidney dysfunction. PIRRT can affect the pharmacokinetics of many drugs, although no data is available to guide flucloxacillin dosing in this clinical scenario. Herein, we describe the pharmacokinetics of flucloxacillin, given at 1 g every 4 h during PIRRT, in a 76-year-old, critically ill patient with a methicillin-susceptible Staphylococcus aureus (MSSA) prosthetic joint infection complicated by bacteraemia. Blood samples were taken over 2 days including during a 9-h PIRRT session. A two-compartment model was developed to describe differences in clearance of flucloxacillin during PIRRT and off-PIRRT (9.45 vs. 6.89 L/h). A flucloxacillin dose of 1 g every 4 h during PIRRT therapy appeared to attain adequate exposures for MSSA sepsis in this patient, however higher doses may be required for infection sites with poor drug penetration.

Pharmacokinetics of Benzylpenicillin (Penicillin G) during Prolonged Intermittent Renal Replacement Therapy.

Prolonged intermittent renal replacement therapy (PIRRT) is an increasingly adopted method of renal replacement in critically ill patients. Like continuous renal replacement therapy, PIRRT can alter the pharmacokinetics (PK) of many drugs. In this setting, dosing data for antibiotics like benzylpenicillin are lacking. In order to enable clinicians to prescribe benzylpenicillin safely and effectively, knowledge of the effects of PIRRT on the plasma PK of benzylpenicillin is required. Herein, we describe the PK of benzylpenicillin in 2 critically ill patients on PIRRT for the treatment of penicillin-susceptible Staphylococcus aureus bacteremia complicated by infective endocarditis. Blood samples were taken for each patient taken over dosing periods during PIRRT and off PIRRT. Two-compartment PK models described significant differences in the mean clearance of benzylpenicillin with and without PIRRT (6.61 vs. 3.04 L/h respectively). We would suggest a benzylpenicillin dose of 1,800 mg (3 million units) every 6-h during PIRRT therapy as sufficient to attain PK/pharmacodynamic target.

Clinical guidance on the contemporary use of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies.

There is now significant evidence for the benefits of lowering low-density lipoprotein cholesterol (LDL-c) to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Although statins are the most widely prescribed lipid-lowering therapy that effectively lower LDL-c, especially in combination with ezetimibe, some patients require adjunctive therapy to further lower LDL-c and mitigate attendant risk of ASCVD. The gap can be filled by proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies whose use is currently supported by two recent cardiovascular outcome studies and new treatment guidelines. We provide an overview of extant studies investigating PCSK9 monoclonal antibodies in various patient populations, an update of the guidelines regarding their use and a case-based discussion.

PCSK9 inhibition 2018: riding a new wave of coronary prevention.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates the low-density lipoprotein cholesterol (LDL-c) receptor and thus circulating LDL-c levels. With overwhelming evidence now supporting the reduction in LDL-c to lower the risk of cardiovascular disease, PCSK9 inhibitors represent an important therapeutic target, particularly in high-risk populations. Here, we summarise and update the science of PCSK9, including its discovery and the development of various inhibitors, including the now approved monoclonal antibodies. In addition, we summarise the clinical applications of PCSK9 inhibitors in a range of patient populations, as well as the major randomised controlled trials investigating their use in coronary prevention.

The challenge of improving the diagnostic yield from metanephrine testing in suspected phaeochromocytoma and paraganglioma.

Background Plasma-free metanephrines (PFM) or urinary fractionated metanephrines (UFM) are the preferred biochemical tests for the diagnosis of phaeochromocytoma and paraganglioma (PPGL). Borderline increased results should be followed up to either exclude or confirm diagnosis. Methods We extracted all PFM and UFM results reported by our laboratory over a six-month period from the laboratory information system. We categorized patients with borderline increased results according to whether follow-up testing had been performed as suggested in the initial laboratory report. Questionnaires were then sent to all requesting doctors and medical notes reviewed where available. Results Two hundred and four patients with borderline increased PFM or UFM were identified. Sixty-five (38.5%) of 169 patients with borderline increased PFM had a repeat test out of which 36 were normal and 29 did not normalize. Of 35 patients with borderline increased UFM, 17 (48.6%) had subsequent PFM measurement, out of which 15 were normal. Questionnaires were returned to 106 (52%) patients. Of these, the most frequent indication for testing was hypertension ( n = 50); 15 patients had an incidental adrenal mass and two of these patients were diagnosed with a phaeochromocytoma. Conclusion Only 38% of patients with borderline increased PFM had a repeat PFM measurement. This was not significantly higher when compared with the 28% in a previous audit that we reported in 2010 ( P = 0.10). Forty-nine per cent of patients with a borderline increased UFM had a repeat UFM or PFM measurement. There remains a substantial possibility of missed detection of PPGL.

Improved technical success and radiation safety of adrenal vein sampling using rapid, semi-quantitative point-of-care cortisol measurement.

Objective Primary aldosteronism is a curable cause of hypertension which can be treated surgically or medically depending on the findings of adrenal vein sampling studies. Adrenal vein sampling studies are technically demanding with a high failure rate in many centres. The use of intraprocedural cortisol measurement could improve the success rates of adrenal vein sampling but may be impracticable due to cost and effects on procedural duration. Design Retrospective review of the results of adrenal vein sampling procedures since commencement of point-of-care cortisol measurement using a novel single-use semi-quantitative measuring device for cortisol, the adrenal vein sampling Accuracy Kit. MEASUREMENTS: Success rate and complications of adrenal vein sampling procedures before and after use of the adrenal vein sampling Accuracy Kit. Routine use of the adrenal vein sampling Accuracy Kit device for intraprocedural measurement of cortisol commenced in 2016. Results Technical success rate of adrenal vein sampling increased from 63% of 99 procedures to 90% of 48 procedures ( P = 0.0007) after implementation of the adrenal vein sampling Accuracy Kit. Failure of right adrenal vein cannulation was the main reason for an unsuccessful study. Radiation dose decreased from 34.2 Gy.cm2 (interquartile range, 15.8-85.9) to 15.7 Gy.cm2 (6.9-47.3) ( P = 0.009). No complications were noted, and implementation costs were minimal. Conclusions Point-of-care cortisol measurement during adrenal vein sampling improved cannulation success rates and reduced radiation exposure. The use of the adrenal vein sampling Accuracy Kit is now standard practice at our centre.

PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease.

The identification of the critical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) has rapidly led to the development of PCSK9 inhibition with monoclonal antibodies (mAbs). PCSK9 mAbs are already in limited clinical use and are the subject of major cardiovascular outcomes trials, which, if universally positive, could see much wider clinical application of these agents. Patients with familial hypercholesterolaemia are the most obvious candidates for these drugs, but other patients with elevated cardiovascular risk, statin intolerance or hyperlipoproteinaemia(a) may also benefit. PCSK9 mAbs, administered once or twice monthly, reduce LDL cholesterol levels by 50% to 70%, and appear to be safe and acceptable to patients over at least 2 years of treatment; however, treatment-emergent adverse effects are not always identified in clinical trials, as well-evidenced by statin myopathy. Inclisiran is a promising RNA-based therapy that promotes the degradation of PCSK9 mRNA transcripts and has similar efficacy to mAbs, but with a much longer duration of action. The cost-effectiveness and long-term safety of therapies targeted at inhibiting PCSK9 remain to be demonstrated if they are to be used widely in coronary prevention.

Rare cause of adrenal insufficiency.

A 72-year-old man presented with weight loss, night sweats and haemoptysis and was hypotensive. CT imaging showed rapidly enlarging bilateral adrenal masses, and he was found to have primary adrenal insufficiency. An adrenal gland biopsy revealed the rare diagnosis of primary adrenal lymphoma. This unique case highlights possible rare causes of adrenal masses and adrenal insufficiency, their investigation and management principles.

Isolated brachydactyly type E and idiopathic pancreatitis in a patient presenting to a lipid disorders clinic.

An 18-year-old female tertiary student was referred to a lipid clinic with hypertriglyceridaemia discovered after presentation with acute pancreatitis. The patient's only medication was l-thyroxine for treatment of hypothyroidism. She was overweight, normotensive, with unremarkable facies. However, she had hypermobile hand joints and brachydactyly resulting in loss of left 3-5 and right 4 and 5 knuckle definitions. Radiography revealed shortening of metacarpals 3-5 on the left and 4 and 5 on the right. Her mother had similar skeletal changes, consistent with a dominant mode of inheritance. Abnormally short digits involving the metacarpals, classified as brachydactyly type E, can be isolated or occur as part of a syndrome. Turner syndrome, Albright hereditary osteodystrophy, hypertension with brachydactyly, chromosome 2q37 microdeletion and PTHLH mutations were excluded following clinical, biochemical and genetic testing. No specific treatment was required. Genetic testing for isolated and syndromic forms of brachydactyly facilitates family screening and prepregnancy counselling.