Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.

BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.

Validation of a prediction score model to distinguish acute coronary syndromes from other conditions causing raised cardiac troponin T levels.

OBJECTIVE: Serum cardiac troponins can be elevated in acute coronary syndromes (ACS) and other non-ACS conditions. We investigated the usefulness of a prediction score model comprising clinical variables to distinguish patients with ACS from other non-ACS conditions. METHODS: Two independent, non-randomized observational cohorts (groups 1 and 2) were examined, comprising consecutive patients who were admitted to a university teaching hospital and found to have a raised serum troponin T level (>or=0.01 microg/l). The international definition was used to confirm acute myocardial infarction. Multivariate logistic regression identified clinical variables in the first cohort, which were used to construct a score model for distinguishing between ACS and non-ACS, and this score was re-evaluated in the second cohort. RESULTS: Of the 313 patients in group 1, a score model was formulated using logarithm troponin T, ischaemic chest pain, ST depression and atrial fibrillation or flutter. Using a score of more than or equal to 1.5, sensitivity and specificity for predicting non-ACS were 0.81 and 0.84. The area under the curve was 0.900 (95% confidence interval 0.867-0.934). Sensitivity and specificity for predicting non-ACS among the 341 patients in group 2 using the same model and a score of more than or equal to 1.5 were 0.76 and 0.89, respectively, and the area under the curve was 0.918 (confidence interval 0.887-0.945). CONCLUSION: A prediction score model using simple clinical variables has been validated, and this can help clinicians in distinguishing patients with ACS from other non-ACS conditions.

Acute intermittent porphyria presenting with a subarachnoid haemorrhage.

A 47-year-old man presented with abdominal pain, neck stiffness, severe transient hypertension and unusually dark urine. Cerebrospinal fluid investigations and angiography confirmed the diagnosis of a subarachnoid haemorrhage. Porphyrin studies on the patient and his family demonstrated that the family has acute intermittent porphyria. This is the second case report of an acute hepatic porphyria presenting with a subarachnoid haemorrhage. Acute transient hypertension during the attack of porphyria caused the rupture of an intracranial arterial aneurysm.

Characteristics and mortality of severe hyponatraemia--a hospital-based study.

OBJECTIVE: To determine the characteristics, causes and outcome of severe hyponatraemia (< 125 mmol/l) in hospitalized patients, and to identify mortality predictors. DESIGN: Prospective case controlled study of sequentially presenting patients with a serum sodium (Na) < 125 mmol/l. PATIENTS AND METHODS: One hundred and four hyponatraemic and 104 randomly chosen normonatraemic (Na > 135 mmol/l) adult patients were studied. We measured hospital mortality and days in hospital, diagnoses, drug history and cause of hyponatraemia. Na was recorded at admission, as well as the closest level measured before death or discharge. In addition, the lowest Na was recorded (if this was not at admission). RESULTS: Hyponatraemic patients were older (mean age +/- 1 SD 69 +/- 14 years) than controls (61 +/- 16 years, P < 0.001), but of similar sex ratio. On admission, Na in the hyponatraemic group was 125 +/- 7 mmol/l compared with 139 +/- 3 mmol/l in controls (P < 0.0001), but fell to 120 +/- 4 mmol/l before rising at discharge to 131 +/- 7 mmol/l (all changes P < 0.001). Overall mortality was 27% in hyponatraemic patients compared with 9% in controls (P = 0.009), and length of admission was also greater (16 +/- 12 vs. 13 +/- 11 days, P < 0.005). Mortality was greater in patients whose Na levels fell during admission (34%vs. 16%, P < 0.05), and these patients appeared to have an excess of diuretic-induced and possibly iatrogenic hyponatraemia. CONCLUSIONS: 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.

Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response.

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 (20.8+/-14.7 versus 30.2+/-15.7 years; P=0.003), had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004) that remained higher during treatment with simvastatin (10.1+/-3.0 versus 6.5+/-0.9 mmol/L; P=0.006), atorvastatin (9.6+/-2.9 versus 6.4+/-1.0 mmol/L; P=0.006), or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0+/-1.6 versus 5.4+/-1.0 mmol/L; P=0.001), and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002). 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.

Drug-induced acute autoimmune hepatitis during combination therapy with atorvastatin and ezetimibe.

A case is presented of a patient who developed acute hepatitis during cholesterol-lowering treatment with atorvastatin and ezetimibe. Further investigations reveal a probable drug-induced autoimmune hepatitis, and ezetimibe is considered to be the most likely causal agent. This case is the first report of an autoimmune hepatitis associated with ezetimibe therapy.