The predictive value of the sFlt-1/PlGF ratio in suspected preeclampsia in a New Zealand population: A prospective cohort study.

BACKGROUND: Internationally, placental growth factor (PlGF)-based tests are used as prognostic markers in suspected preeclampsia. However, Ministry of Health guidelines do not currently endorse PlGF-based tests in New Zealand (NZ). AIMS: To investigate the predictive value of soluble fms-like tyrosine kinase 1 (sFlt-1)/PlGF ratio in suspected preeclampsia in a NZ population. MATERIALS AND METHODS: A prospective cohort study of singleton pregnancies at 20+0 -36+6 weeks gestation with suspected preeclampsia as defined by Society of Obstetric Medicine Australia and NZ (SOMANZ) criteria. PRIMARY OBJECTIVE: to evaluate a sFlt-1/PlGF ratio >38 at ≤35+0 weeks gestation to predict birth ≤14 days. SECONDARY OBJECTIVES: to assess a sFlt-1/PlGF ratio cut-off of 38 at ≤37+0 weeks gestation, to rule out preeclampsia ≤1 week, rule in preeclampsia ≤4 weeks, and to predict perinatal outcome. Clinicians were blinded to sFlt-1/PlGF ratio results. RESULTS: Included were 222 participants, 19.4% Maori and 10.4% Pasifika. A sFlt-1/PlGF >38 predicted birth ≤14 days, positive predictive value (PPV) 51.4% (95% CI, 39.6-63.0) and negative predictive value (NPV) 95.9% (95% CI, 91.4-98.1), median (interquartile range) days to birth 14 (2-27) vs 49 (33-70), P < 0.000. A sFlt-1/PlGF cut-off of 38 ruled out preeclampsia ≤1 week (NPV 96.2% (95% CI, 92.3-98.2)) and ruled in preeclampsia ≤4 weeks (PPV 75.0% (95% CI, 65.0-82.9)). A sFlt-1/PlGF >38 was associated with greater perinatal morbidity. CONCLUSIONS: The predictive value of the sFlt-1/PlGF ratio in NZ is comparable to that reported in international trials. Used in clinical practice the sFlt-1/PlGF ratio may aid risk stratification in suspected preeclampsia, directing limited resources to those pregnancies at highest risk.

Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.

Pathogenic heterozygous variants in HMBS encoding the enzyme hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase, cause acute intermittent porphyria (AIP). Biallelic variants in HMBS have been reported in a small number of children with severe progressive neurological disease and in three adult siblings with a more slowly, progressive neurological disease and distinct leukoencephalopathy. We report three further adult individuals who share a distinct pattern of white matter abnormality on brain MRI in association with biallelic variants in HMBS, two individuals with homozygous variants, and one with compound-heterozygous variants. We present their clinical and radiological features and compare these with the three adult siblings previously described with leukoencephalopathy and biallelic HMBS variants. All six affected individuals presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. This recognizable pattern of MRI abnormalities is seen in all six adults described here. Biallelic variants in HMBS cause a phenotype that is distinct from AIP. It is not known whether AIP treatments benefit individuals with HMBS-related leukoencephalopathy. One individual reported here had improved neurological function for 12 months following liver transplantation followed by decline and progression of disease.

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.

Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2.

We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.

Evaluation of the NZ guidelines for screening for persistent postpartum hyperglycaemia following gestational diabetes.

BACKGROUND: Recent New Zealand guidelines recommend annual glycated haemoglobin (HbA1c) measurements from three months postpartum, replacing the glucose tolerance test (GTT) at six weeks, to screen for persistent hyperglycaemia following gestational diabetes. Data suggest that this screening approach may miss cases of type 2 diabetes, but are they detected at subsequent screening and will screening rates improve? AIMS: Our aim was to evaluate the effectiveness of HbA1c monitoring in improving screening rates following gestational diabetes and in detecting postpartum hyperglycaemia. MATERIALS AND METHODS: During 2015 in Christchurch, all women with gestational diabetes were offered HbA1c and GTT measurements at three months postpartum and subsequent annual HbA1c measurements were recommended. Data from electronic hospital records were collected for a minimum 18 months postpartum. RESULTS: Of the cohort of 333 women, 218 (65%) completed both HbA1c and GTT at three months postpartum, 74 (22%) HbA1c only, 16 (5%) GTT only, 25 (8%) no screening; 184 (55%) had subsequent HbA1c tests. Diabetes was detected by GTT in five (2%) women and by HbA1c in only one out of five (20%); the disagreement between tests resolved in three out of four (75%) women with subsequent testing. Prediabetes was detected by GTT in 30 (14%) women; however, HbA1c only detected five out of 30 (17%) and subsequent HbA1c testing identified a further two out of 30 with prediabetes. CONCLUSIONS: HbA1c measurement at three months postpartum had a good uptake. However, most cases of diabetes were identified by subsequent HbA1c testing, the uptake of which was suboptimal. The importance of annual HbA1c monitoring following gestational diabetes needs greater emphasis.

Is There a Role for HbA1c in Pregnancy?

Outside pregnancy, HbA1c analysis is used for monitoring, screening for and diagnosing diabetes and prediabetes. During pregnancy, the role for HbA1c analysis is not yet established. Physiological changes lower HbA1c levels, and pregnancy-specific reference ranges may need to be recognised. Other factors that influence HbA1c are also important to consider, particularly since emerging data suggest that, in early pregnancy, HbA1c elevations close to the reference range may both identify women with underlying hyperglycaemia and be associated with adverse pregnancy outcomes. In later pregnancy, HbA1c analysis is less useful than an oral glucose tolerance test (OGTT) at detecting gestational diabetes. Postpartum, HbA1c analysis detects fewer women with abnormal glucose tolerance than an OGTT, but the ease of testing may improve follow-up rates and combining HbA1c analysis with fasting plasma glucose or waist circumference may improve detection rates. This article discusses the relevance of HbA1c testing at different stages of pregnancy.

Effectiveness of EDACS Versus ADAPT Accelerated Diagnostic Pathways for Chest Pain: A Pragmatic Randomized Controlled Trial Embedded Within Practice.

STUDY OBJECTIVE: A 2-hour accelerated diagnostic pathway based on the Thrombolysis in Myocardial Infarction score, ECG, and troponin measures (ADAPT-ADP) increased early discharge of patients with suspected acute myocardial infarction presenting to the emergency department compared with standard care (from 11% to 19.3%). Observational studies suggest that an accelerated diagnostic pathway using the Emergency Department Assessment of Chest Pain Score (EDACS-ADP) may further increase this proportion. This trial tests for the existence and size of any beneficial effect of using the EDACS-ADP in routine clinical care. METHODS: This was a pragmatic randomized controlled trial of adults with suspected acute myocardial infarction, comparing the ADAPT-ADP and the EDACS-ADP. The primary outcome was the proportion of patients discharged to outpatient care within 6 hours of attendance, without subsequent major adverse cardiac event within 30 days. RESULTS: Five hundred fifty-eight patients were recruited, 279 in each arm. Sixty-six patients (11.8%) had a major adverse cardiac event within 30 days (ADAPT-ADP 29; EDACS-ADP 37); 11.1% more patients (95% confidence interval 2.8% to 19.4%) were identified as low risk in EDACS-ADP (41.6%) than in ADAPT-ADP (30.5%). No low-risk patients had a major adverse cardiac event within 30 days (0.0% [0.0% to 1.9%]). There was no difference in the primary outcome of proportion discharged within 6 hours (EDACS-ADP 32.3%; ADAPT-ADP 34.4%; difference -2.1% [-10.3% to 6.0%], P=.65). CONCLUSION: There was no difference in the proportion of patients discharged early despite more patients being classified as low risk by the EDACS-ADP than the ADAPT-ADP. Both accelerated diagnostic pathways are effective strategies for chest pain assessment and resulted in an increased rate of early discharges compared with previously reported rates.

Association of Clinical Characteristics With Familial Hypercholesterolaemia Variants in a Lipid Clinic Setting: A Case-Control Study.

Objective: Familial hypercholesterolaemia (FH) variant positive subjects have over double the cardiovascular risk of low-density-lipoprotein-cholesterol (LDL-C) matched controls. It is desirable to optimise FH variant detection. Methods: We identified 213 subjects with FH gene panel reports (LDLR, APOB, PCSK9, and APOE) based on total cholesterol >310 mg/dL; excluding triglycerides >400 mg/dL, cascade screening, and patients without pre-treatment LDL-C recorded. Demographic, clinical and lipid parameters were recorded. Results: A 31/213 (14.6%) patients had pathogenic or likely pathogenic FH variants. 10/213 (4.7%) had variants of uncertain significance. Compared with patients without FH variants, patients with FH variants were younger (median age, 39 years vs. 48 years), had more tendon xanthomata (25.0% vs. 11.4%), greater proportion of first degree relatives with total cholesterol >95th percentile (40.6% vs. 16.5%), higher LDL-C (median, 271 mg/dL vs. 236 mg/dL), and lower triglycerides (median, 115 mg/dL vs. 159 mg/dL). The Besseling et al. model (c-statistic 0.798) improved FH variant discrimination over Friedewald LDL-C (c-statistic 0.724), however, Dutch Lipid Clinic Network Score (DLCNS) did not (c-statistic 0.665). Sampson LDL-C (c-statistic 0.734) had similar discrimination to Friedewald. Conclusion: Although tendon xanthomata and first degree relatives with high total cholesterol >95th percentile were associated with FH variants, DLCNS or Simon Broome criteria did not improve FH detection over LDL-C. Sampson LDL-C did not significantly improve discrimination over Friedewald. Although lower triglycerides and younger age of presentation are positively associated with presence of FH variants, this information is not commonly used in FH detection algorithms apart from Besseling et al.

Artefactually low creatinine by Beckman Coulter enzymatic method due to immunoglobulin M paraprotein interference.

An 81-year-old man was admitted to hospital with symptomatic coronavirus disease (COVID-19) infection. He had a background of progressive chronic inflammatory demyelinating polyneuropathy associated with Waldenstrom's macroglobulinaemia. His plasma creatinine on four separate samples was inconceivably low (all ≤13 µmol/L), as measured by a Beckman Coulter enzymatic assay) after being 72 µmol/L 3 months earlier. On further investigation, his serum immunoglobulin M (IgM) was 15.4 g/L and his plasma creatinine measured by Roche enzymatic and Roche Jaffe methods was 62 µmol/L and 64 µmol/L, respectively. This was consistent with results post dilution studies and polyethylene glycol (PEG) precipitation on the Beckman Coulter assay. There was no evidence of similar interference when reviewing creatinine results from 10 other patients with IgM paraproteinaemia who had been tested in our laboratory. Clinicians and laboratorians are reminded that enzymatic creatinine is not free from interferences. IgM paraprotein negative interference of enzymatic creatinine is rare and specific to a patient's IgM and assay combination, but should be considered in patients with an unexplained low enzymatic creatinine result. Useful investigations to identify an interference include dilution studies, PEG precipitation and measuring creatinine on an alternative method such as Jaffe, mass spectrometry or an enzymatic method from a different platform.

Reference intervals for deconjugated urine metanephrines by Bhattacharya analysis.

BACKGROUND: Urine metanephrines are used to screen for phaeochromocytoma or paraganglioma (PPGL). Current reference intervals (RI) derived in healthy individuals are not age or sex-stratified, and lower than in hypertensive patients, leading to high false positive rates. This study aims to determine age and sex-stratified RI from a contingent screening population. METHODS: Patients with 24-h deconjugated urine metanephrines from 3/6/2010 to 27/8/2022 were included (2936 males, 5285 females), initially by liquid chromatography-electrochemical detection (LC-ECD) then liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bhattacharya analysis was used after log transformation to determine age and sex-stratified RI for metanephrine excretion, normetanephrine excretion, metanephrine/creatinine and normetanephrine/creatinine ratios. RESULTS: Normetanephrine excretion increases with age (RI: males: 18-<30 years: <3.4 µmol/24 h, 30-<40 years: <3.7 µmol/24 h, 40+ years: <5.3 µmol/24 h; females: 18-<30 years: <2.7 µmol/24 h, 30-<40 years: <3.1 µmol/24 h, 40+ years: <3.7 µmol/24 h), while metanephrine excretion was consistent across adulthood (RI: males: 18+ years: <1.8 µmol/24 h; females: 18+ years: <1.2 µmol/24 h). However, normetanephrine/creatinine and metanephrine/creatinine increase steadily with age after early adulthood, likely due to a decrease in muscle mass, with females having higher normetanephrine/creatinine and metanephrine/creatinine ratios. CONCLUSIONS: Age and sex-stratified RI were derived for metanephrine excretion, normetanephrine excretion, metanephrine/creatinine and normetanephrine/creatinine ratios. This is expected to reduce false positives while flagging most PPGL.

Verification of point-of-care analysers for C-reactive protein, lipid studies and glycated haemoglobin.

Due to increased convenience and faster test results, interest in point-of-care testing (PoCT) has grown significantly. Though PoCT may improve the speed and convenience of testing, the devices need to be fit for their intended purpose. Our aim was to verify the performance of Roche cobas b 101 and Abbott Afinion 2 for C-reactive protein (CRP), lipid studies and glycated haemoglobin (HbA1c), and Siemens Atellica DCA for HbA1c. For all PoCT analysers and measurands, accuracy was assessed by method comparison with central laboratory analysers. Passing-Bablok linear regression was performed, and Bland-Altman plots were generated. The proportion of samples within the Royal College of Pathologists of Australasia Quality Assurance Programs Analytical Performance Specifications (RCPAQAP APS) was assessed. Within-run and between-day imprecision was assessed and compared with manufacturer claims and biological variation or clinical guidelines for desirable imprecision. For CRP, both evaluated PoCT analysers had all samples within the RCPAQAP APS and had optimal imprecision according to biological variation. For lipid studies, the Roche cobas b 101 had most samples within the RCPAQAP APS, with two of 22 cholesterol, one of 22 high-density-lipoprotein-cholesterol (HDL-C) and zero of 22 triglyceride comparisons outside the RCPAQAP APS. The Abbott Afinion 2 had a positive bias with all three measured parameters, although the effect was more limited in the calculated parameters cholesterol:HDL-C ratio, non-HDL-C and low-density-lipoprotein-cholesterol (LDL-C). For HbA1c, all analysers had acceptable imprecision for monitoring with coefficient of variation (CV) <3% and minimal bias at the treatment target (HbA1c 53 mmol/mol or 7.0%). However, significant biases were apparent at higher or lower HbA1c for all analysers. All evaluated analysers were fit for purpose for CRP and for serial monitoring of HbA1c, although bias in some analysers was present at extremes of HbA1c. For lipid studies, the Roche cobas b 101 had fewer results outside the RCPAQAP allowable limits, and better precision. The Abbott Afinion 2 had a positive bias on both the cholesterol and HDL-C, but there is limited clinical impact when calculating cholesterol:HDL-C, LDL-C and non-HDL-C.

High penetrance, recurrent attacks and thrombus formation in a family with hereditary coproporphyria.

Hereditary coproporphyria (HCP) is the rarest of the autosomal dominant acute porphyrias with an estimated incidence of 0.02 per 10 million per year. HCP has been considered to be mild in presentation compared with the more common acute intermittent porphyria although there is limited information comparing the subtypes. Penetrance in the acute porphyrias is low with 90% of patients with a mutation never exhibiting symptoms. We present seven members from a family with HCP with a novel mutation in whom penetrance and severity are high. In addition, they appear to have a high rate of veno-thromboembolism. Penetrance is confirmed at 57% but is suspected to be 71%. The first patient experienced life-threatening complications, four of the seven have had recurrent attacks and the development of opioid dependence has complicated management. The case series documents the impact of a new mRNA interference molecule givosiran as well as a plan for embryo selection which is not commonly used in porphyria. The use of ketamine for the treatment of acute attacks is also documented for the first time in the porphyria literature. The use of international registries would aid the characterisation and management of this very rare disease.

Hb Westport [ß121 (GH4) Glu>Asp; HBB:c.366A>C]: A novel ß-globin variant interfering with HbA1c measurement.

OBJECTIVES: To describe a novel ß-globin variant that interferes with HbA1c analysis by cation exchange HPLC. DESIGN AND METHODS: Diabetes screening by HbA1c measurement was assessed using cation exchange HPLC and an immunoassay point-of-care analyzer. Routine hemoglobinopathy screening was performed including CBC, HbF and HbA2 measurement by cation exchange HPLC and capillary electrophoresis (CE). Further variant characterization was undertaken by ESI TOF mass spectrometry and DNA sequencing. RESULTS: Discordant HbA1c results were obtained for our subject, with elevated HbA1c of 52 mmol/mol measured by cation exchange HPLC and a normal level of 34 mmol/mol by immunoassay. Abnormal HbA1c peak shape prompted hemoglobinopathy screening to investigate potential variant interference. Cation exchange HPLC (using ß-thalassemia program) and CE results were apparently normal, with HbF and HbA2 detected within reference intervals. ESI TOF mass spectrometry revealed the presence of a variant ß-globin chain. A novel missense variant was confirmed at codon 121 of the ß-globin gene [ß121 (GH4) Glu>Asp; HBB: c.366A>C], which we have named Hb Westport. CONCLUSIONS: Hb Westport is a novel ß-globin variant that interferes with HbA1c measurement by Bio-Rad D-100 cation exchange HPLC, giving a falsely elevated result. This was clinically significant for our subject because the erroneously elevated HbA1c value was above the diabetes diagnostic threshold. Alternative methods for diabetes assessment should be considered in subjects with Hb Westport.

The performance of high sensitivity troponin for the diagnosis of acute myocardial infarction is underestimated.

BACKGROUND: Many papers evaluating high sensitivity troponin assays make the diagnosis of myocardial infarction based on conventional troponin assays in clinical use at the time of recruitment. Such analyses often do not show superiority of high sensitivity assays compared with contemporary assays meeting precision guidelines. METHODS: Three hundred and twenty-two patients presenting to the emergency department between November 2006 and April 2007 for evaluation for acute coronary syndrome had serial (0 h and >6 h) bloods taken to compare troponin assays (Roche hsTnT, Abbott TnI, Roche TnT and Vitros TnI). The diagnosis of myocardial infarction was made using each troponin assay separately with which that same assay was analysed for diagnostic performance. RESULTS: The rate of myocardial infarction would be 38.9% using serial hsTnT, 31.3% using serial Abbott TnI, 27.1% using serial TnT and 26.4% using serial Vitros TnI. The baseline sensitivities (0 h) are 89.9% (85.2-93.3) for hsTnT, 77.9% (71.0-87.5) for Abbott TnI, 73.0% (65.6-78.7) for TnT and 86.8% (74.6-94.4%) for Vitros TnI. The specificities (peak 0 h and >6 h samples) are 93.1% (91.2-93.1) for hsTnT, 88.3% (86.5-88.3) for Abbott TnI, 92.2% (90.5-92.2) for TnT and 90.6% (70.1-90.6) for Vitros TnI. CONCLUSIONS: hsTnT has superior sensitivity for myocardial infarction than even assays at or near guideline precision requirements (Abbott and Vitros TnI). The specificity of hsTnT assay is not as poor as previous analyses suggest.

Intermittent severe, symptomatic hyponatraemia due to the nephrogenic syndrome of inappropriate antidiuresis.

A 20-year-old fit male soldier presented on two separate occasions 16 months apart with severe, symptomatic hyponatraemia and a clinical and biochemical picture consistent with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In the intervening period, repeated plasma sodium values were in the reference range. Intensive investigation failed to reveal a cause for SIADH that was initially considered idiopathic. The description of a family comprising several adults with intermittent or water load induced-hyponatraemia associated with an activating mutation in the arginine vasopressin (AVP) receptor type 2 (AVPR2) raised the question of whether our patient could have a similar 'nephrogenic syndrome of inappropriate antidiuresis'. Mutational screening of AVPR2 in our patient revealed a single missense mutation (R137C) in the second intracellular loop, which has been associated with constitutive activation of the AVPR2. In conclusion, adults with intermittent, severe hyponatraemia may have a constitutively activating mutation in the AVPR2 with resultant nephrogenic syndrome of inappropriate antidiuresis. Patients with idiopathic SIADH, particularly those with unmeasurable circulating AVP concentrations, should be considered for mutational screening of AVPR2.