Paul Cook

The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype

Background Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. Methods and Results We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. Conclusions The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.

The Association of Metabolic Syndrome and Urolithiasis

There has been an increasing prevalence of kidney stones over the last 2 decades worldwide. Many studies have indicated a possible association between metabolic syndrome and kidney stone disease, particularly in overweight and obese patients. Many different definitions of metabolic syndrome have been suggested by various organizations, although the definition by the International Diabetes Federation (IDF) is universally considered as the most acceptable definition. The IDF definition revolves around 4 core components: obesity, dyslipidemia, hypertension, and diabetes mellitus. Several hypotheses have been proposed to explain the pathophysiology of urolithiasis resulting from metabolic syndrome, amongst which are the insulin resistance and Randalls plaque hypothesis. Similarly the pathophysiology of calcium and uric acid stone formation has been investigated to determine a connection between the two conditions. Studies have found many factors contributing to urolithiasis in patients suffering from metabolic syndrome, out of which obesity, overweight, and sedentary lifestyles have been identified as major etiological factors. Primary and secondary prevention methods therefore tend to revolve mainly around lifestyle improvements, including dietary and other preventive measures.

Analysis of 17 α-hydroxyprogesterone in bloodspots by liquid chromatography tandem mass spectrometry

Background Monitoring of treatment for patients diagnosed with congenital adrenal hyperplasia (CAH) can be performed by measuring the concentration of 17α-hydroxyprogesterone (17OHP) in bloodspots collected on filter papers. A method is described here for measuring 17OHP by liquid chromatography tandem mass spectrometry (LCMSMS). Methods 17OHP was extracted by liquid–liquid extraction and analysed by LCMSMS. The method was validated for sensitivity, specificity, linearity, recovery, ion suppression, precision and bias. Results The standard curve was linear from 0 to 400 nmol/L. Intra-assay %CVs were <10 and inter-assay %CVs were <15 over the range 10–200 nmol/L. Limit of quantitation was 6 nmol/L. No ion suppression was detected. The only interfering compound detected was deoxycorticosterone, an intermediate steroid with the same molecular weight as 17α-hydroxyprogesterone. The method was more accurate and precise than an existing radioimmunoassay. There was poor correlation between the two assays. Conclusions We have developed a sensitive and specific assay suitable for quantitation of 17OHP in bloodspots. This method performs better than radioimmunoassay and allows smaller samples to be used.

Male hypercalciuric stone formers with low renal calcium reabsorption

Aims Hypercalciuria is a common poorly understood abnormality among stone formers. We aimed to identify hypercalciuric male stone formers with a primary defect in renal calcium reabsorption and to look for associated risk factors. Methods A retrospective cross-sectional database study of 623 male idiopathic calcium stone formers with normal plasma ultrafilterable calcium levels attending the Southampton stone clinic. Filtered calcium was estimated from plasma ultrafilterable calcium (60% of total plasma calcium) and 24 h creatinine clearance. Reabsorbed calcium was the difference between filtered and excreted calcium. Results 276 men had hypercalciuria (urine calcium >7.50 mmol/24 h); 347 had normocalciuria. Hypercalciuric men filtered more calcium than normocalciuric men: median values 247 and 227 mmol/24 h, but the ranges overlapped (175–371 and 153–316 mmol/24 h). However, across the entire filtration range, hypercalciuric men reabsorbed less of the filtered calcium. Among the hypercalciuric men, we noticed differences between those with high and low filtration. We therefore compared data for hypercalciuric men in the highest and lowest filtration quintiles (n=55). Men with high filtration were younger at their first stone episode and had significantly higher plasma ultrafilterable calcium and calcium reabsorption, urinary calcium, oxalate, urate and creatinine excretion and creatinine clearance. 35% with high filtration and 40% with low filtration had recurrent stones; 27% and 20%, respectively, had an affected first-degree relative. Conclusions Hypercalciuric men reabsorbed proportionately less filtered calcium than normocalciuric men. Among hypercalciuric men, the risks for stones were higher in those with a high than a low filtered calcium load and presentation was earlier.

Managing dyslipidaemia for the primary prevention of cardiovascular disease

### What you need to know ### Sources and selection criteria We carried out an electronic search through PubMed and Cochrane database of systematic reviews using the following search terms: “primary prevention,” “dyslipidaemia,” “cardiovascular disease,” “statins,” “statin intolerance,” “ezetimibe,” “PCSK9,” “hypercholesterolaemia diagnosis and treatment.” We also interrogated relevant dyslipidaemia guidelines and personal archives for supporting evidence as discussed and as referenced. Cardiovascular disease (CVD) is the most common underlying cause of death worldwide, accounting for 17.3 million of 54 million total deaths per year. Of these, 8.2 million were caused by ischaemic heart disease and 6.5 million by stroke.1 Mean total cholesterol, calculated low density lipoprotein (LDLc), and triglyceride concentrations have declined over the last 20 years. However, some observational cohort evidence suggests that long term exposure to even modestly elevated cholesterol concentrations is associated with CVD in later life.12 Cholesterol made in the liver and from the diet is transported to peripheral cells by apoB-containing lipoproteins in the blood (fig 1). In a fasting sample, the LDL particles constitute most of the circulating apoB lipoproteins. However, in clinical practice LDL is not measured directly but is calculated (LDLc) (box 1). LDLc has become a metric for treatment success and for diagnosis. Fig 1 Apolipoprotein B, non-HDL lipid transport, and atherosclerosis. Lipoproteins involved in cholesterol are transported from gut and liver to the peripheral tissues, providing fuel, membrane structure, and hormones. Lipoproteins carrying apolipoprotein B (apart from chylomicrons) have the potential to be atherogenic. APOE: apoliprotein e receptor; Chol: cholesterol; FA: fatty acids; IDL: intermediate density lipoprotein; TG: triglyceride; C: chylomicron; CR: chylomicron remnant; LDL: low density …Ryan et al have recently written a useful article on managing dyslipidaemia for the primary prevention of cardiovascular disease1. They consider the evidence regarding the benefits and harms of statin medication and conclude that, “At present we have no way of knowing who will experience the benefits or harms of statin therapy before starting medication”. We would like to highlight to readers a couple of our papers which have addressed this question2. In 2010, we published a large population-based cohort study using the QResearch database (www.qresearch.org) to individualise the risks of statins in men and women in England. We also produced a web calculator www.qintervention.org which allows an individual calculate these risks. In 2018, we published an update to the QDiabetes-2018 algorithm which, for the first time, quantifies the risk of developing diabetes among patients prescribing statins, taking account of their other risk factors3. The web calculator can be found here www.qdiabetes.org/2018. Lastly, we would also like to highlight the publication of QRISK3 https://qrisk.org/three/index.php last year in the BMJ4 which will replace QRISK2 later this year.

PCSK9 inhibition for primary prevention of ischaemic heart disease in heterozygous familial hypercholesterolaemia

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness and safety of PCSK9 inhibitors in the primary prevention of IHD in people with HeFH.

Primary prevention with statins for older adults

Patient preference remains the guiding principle while we wait for better evidence

Dyslipidaemia and cardiovascular risk

### What you need to know A 40 year old man visits his general practitioner for annual antipsychotic monitoring. He is taking risperidone and sertraline for a previous diagnosis of psychotic depression. Recent blood tests showed a total cholesterol of 6.0, low density lipoprotein (calculated) (LDLc) 3.8, high density lipoprotein (HDL) 0.8, non-HDL 5.2, and triglyceride of 3.0 mmol/L; other blood tests were within the reference range. Patients may require consideration of dyslipidaemia and cardiovascular risk for a number of reasons, including pre-existing physical health conditions such as chronic kidney disease; medications such as antipsychotics; family history such as hypercholesterolaemia or ischaemic heart disease; or due to age thresholds, such as cardiovascular disease (CVD) screening in over-40s. This article provides a framework for diagnosing and managing dyslipidaemia, with the aim of reducing patients’ CVD risk. History Ask about Fig 1 Approach to diagnosis and management of hypercholesterolaemia (based on guidance from the National Institute of Health and Care Excellence) The patient advice leaflet, included as a supplementary file with this …

The assessment of iodine status – populations, individuals and limitations

Iodine deficiency is a significant global health concern, and the single greatest cause of preventable cognitive impairment. It is also a growing public health concern in the UK particularly among pregnant women. Biomarkers such as urinary iodine concentration have clear utility in epidemiological studies to investigate population-level iodine status, but determination of iodine status in individuals is much more problematic with current assays. This article reviews the available biomarkers of iodine status and their relative utility at the level of both populations and individuals for the investigation of iodine deficiency and iodine excess.

Bile acid sequestrants for primary prevention of ischaemic heart disease in heterozygous familial hypercholesterolaemia

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness and safety of BAS in the primary prevention of IHD in people with HeFH.