Severe hyponatraemia in hospital patients is associated with prolonged admissions and significantly increased mortality compared with normonatraemic patients. A particular group at high risk of death are those whose Na levels fall after admission. They may represent a 'sicker' group, and deserve increased monitoring and surveillance.

Objective-Analysis of long-term (30 years) clinical history and response to treatment of 13 patients with the D374Y mutation of PCSK9 (PCSK9 patients) from 4 unrelated white British families compared with 36 white British patients with heterozygous familial hypercholesterolemia attributable to 3 specific mutations in the low-density lipoprotein (LDL) receptor gene (LDLR) known to cause severe phenotype. Methods and Results-The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8Ϯ14.7 versus 30.2Ϯ15.7 years; Pϭ0.003), had higher pretreatment serum cholesterol levels (13.6Ϯ2.9 versus 9.6Ϯ1.6 mmol/L; Pϭ0.004) that remained higher during treatment with simvastatin (10.1Ϯ3.0 versus 6.5Ϯ0.9 mmol/L; Pϭ0.006), atorvastatin (9.6Ϯ2.9 versus 6.4Ϯ1.0 mmol/L; Pϭ0.006), or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0Ϯ1.6 versus 5.4Ϯ1.0 mmol/L; Pϭ0.001), and were affected Ͼ10 years earlier by premature coronary artery disease (35.2Ϯ4.8 versus 46.8Ϯ8.9 years; Pϭ0.002). LDL from PCSK9 patients competed significantly less well for binding to fibroblast LDL receptors than LDL from either controls or LDLR patients. Conclusions-These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications. Key Words: coronary disease Ⅲ atherosclerosis Ⅲ familial hypercholesterolemia Ⅲ statins Ⅲ ezetimibe F amilial hypercholesterolemia (FH) is a common autosomal dominant disorder caused by mutations in the lowdensity lipoprotein (LDL) receptor gene (LDLR) leading to defective catabolism of plasma LDL by the liver and characterized by elevated levels of LDL cholesterol, tendon xanthomas, and excessive deposition of cholesterol in the arterial wall, causing premature atherosclerosis. 1 An almost identical clinical syndrome to FH, called familial defective apolipoprotein B (apoB), can occur as a result of a dominantly inherited mutation of the ApoB gene, which encodes the ligand for the LDL receptor, causing impaired catabolism of LDL. 2 Recently, heterozygous missense variants in a gene named PCSK9 (protein convertase subtilisin/kexin9) have been described to cosegregate with hypercholesterolemia in families of European origin. [3][4][5][6] PCSK9 encodes a putative protease, which is a member of the subtilisin-like protein convertase family. 7,8 Its physiological role has not yet been elucidated, but there is substantial evidence that it is involved in cholesterol homeostasis. 9 -12 PCSK9 is responsive to sterols and is a putative sterol regulatory element-binding protein (SREBP) target in mice. 11,12 Adenovirus-mediated overexpression of wild-type PCSK9 in mice led to severe hypercholesterolemia by decreasing the amount of LDL receptor protein in the liver without reducing LDL receptor mRNA levels. 13 However, similar overexpression of 2 naturally occurring PCSK9 mis...

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Aims: To evaluate the assessment and management of severe hyponatraemia in a large teaching hospital. Methods: Inpatients with serum sodium ,125 mmol/l were identified prospectively from a laboratory database over a six month period. Notes were examined and data extracted. Case notes were carefully reviewed retrospectively by a consultant endocrinologist with regard to accuracy of the diagnosis and the appropriateness of investigations and management. Results: 104 patients with a serum sodium ,125 mmol/l were identified. Mean (SD) age was 69 (14), 52% were female, mean hospital stay was 16 (12) days, and overall mortality 27%. Adequate investigations were rarely performed. Only 28 (26%) had plasma osmolality measured, 29 (27%) urine osmolality, 11 (10%) urinary sodium, 8 (8%) plasma cortisol, and 2 (2%) a short Synacthen test. Comparing the ''ward'' and ''specialist review'' diagnoses, there were significant discrepancies for ''no cause found'' (49% v 27%, p,0.001), alcohol (6% v 11% p,0.01), and syndrome of inappropriate antidiuresis (20% v 32%, p = 0.001). Treatment was often illogical with significant management errors in 33%. These included fluid restriction and intravenous saline given together (4%) and fluid restriction in diuretic induced hyponatraemia (6%). Mortality was higher in the group with management errors (41% v 20% p = 0.002). Conclusion: Severe hyponatraemia is a serious condition, but its investigation and evaluation is often inadequate. Some treatment patterns seem to be arbitrary and illogical, and are associated with higher mortality.H yponatraemia is the most common electrolyte disturbance encountered in clinical practice, with a prevalence up to 15% in a general hospital population.1 2 It is associated with considerable morbidity and mortality, but with differing views on optimal management.3 The evaluation of hyponatraemia can be challenging. Clinical judgment and laboratory investigations are important to help elucidate a diagnosis. Two recent studies have looked specifically at the investigation and management of hyponatraemia in a hospital setting.4 5 Both studies examined populations with severe hyponatraemia (plasma sodium (120 mmol/l) and concluded that investigations were often inadequate. Both reports however, involved small numbers of patients (47 and 42 patients respectively). In a separate report, Hochman et al looked at a population with less severe hyponatraemia (plasma sodium (130 mmol/l) and commented on aetiology, treatment, and prognosis. They found a high mortality rate (30%) and concluded that this was secondary to the underlying medical condition, rather than the degree of hyponatraemia or the subsequent treatment. 6 None of these studies addressed the accuracy of the diagnoses reached, or whether management was clinically appropriate. Also, the question of whether inappropriate management of hyponatraemia is correlated with adverse outcome, has not been reported.We have therefore studied a large cohort of patients to assess the accuracy of diagnosis and appropriatene...