Plasma or serum 5-hydroxyindoleacetic acid can be used interchangeably in patients with neuroendocrine tumours.

5-hydroxyindole acetic acid, a metabolite of serotonin, is used in the diagnosis and monitoring of patients with neuroendocrine tumours, in particular patients with small intestinal neuroendocrine tumours associated with the carcinoid syndrome. Analysis of 5-hydroxyindole acetic acid was commonly performed in urine, but blood-based assays are now becoming available. The objective of this study was to assess how 5-hydroxyindole acetic acid compares in plasma and serum as a biochemical marker of neuroendocrine tumours. Twenty-four-hour urine, plasma and serum samples were obtained from 80 patients with neuroendocrine tumours and 30 healthy volunteers. We developed a liquid chromatography tandem mass spectrometry assay for plasma and serum 5-hydroxyindole acetic acid. Comparison was made between them, and their cut-off was determined using a receiver-operating characteristic curve. A close correlation was shown between plasma and serum 5-hydroxyindole acetic acid. At a cut-off of 135 nmol/l, a sensitivity of 91.2% with a specificity of 61.9% was obtained for both compared to the urinary assay. A statistically significant agreement was shown when plasma and serum 5-hydroxyindole acetic acid were compared with the currently used urine assay in patients with neuroendocrine tumours; κ = 0.675 (95% CI 0.49 to 0.86), p < 0.001 and healthy volunteers; 0.967 (95% CI 0.828 to 0.999), p = <0.001. In conclusion, 5-hydroxyindole acetic acid in plasma and serum were comparable, hence either sample type can be used interchangeably.

Assessment of non-alcoholic fatty liver disease (NAFLD) severity with novel serum-based markers: A pilot study.

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) represents a significant public health issue. Identifying patients with simple steatosis from those with non-alcoholic steatohepatitis (NASH) is crucial since NASH is correlated with increased morbidity and mortality. Serum-based markers, including adipokines and cytokines, are important in the pathogenesis and progression of NAFLD. Here we assessed the usefulness of such markers in patients with NAFLD. METHODS: This prospective, cross-sectional study included 105 adult patients with varying severity of NAFLD. Twelve serum-based markers were measured by 3 biochip platforms and 2 enzyme-linked immunosorbent assay (ELISA) methods. We also developed a NAFLD individual fibrosis index (NIFI) using the serum-based markers mostly correlated with fibrosis severity. RESULTS: Sixty-one out of 105 patients were male (58.1%) with mean age was 53.5 years. Higher Interleukin-6 (IL-6) increased (p = 0.0321) and lower Matrix Metalloproteinase-9 (MMP-9) serum levels (p = 0.0031) were associated with higher fibrosis as measured by Fibroscan® in multivariable regression analysis. Using receiver-operating characteristic (ROC) curve analysis for the NIFI, area under the curve for predicting Fibroscan values ≥ 7.2 kPa was 0.77 (95%CI: 0.67, 0.88, p<0.001), with sensitivity of 89.3%, specificity of 57.9% and a positive likelihood ratio of 2.8. CONCLUSIONS: Increasing fibrosis severity in NAFLD is associated with differential expression of IL-6 and MMP-9. NIFI could be valuable for the prediction of advanced NAFLD fibrosis and potentially help avoid unnecessary interventions such as liver biopsy in low-risk patients.

Proposed low-density lipoprotein cholesterol goals for secondary prevention and familial hypercholesterolemia in India with focus on PCSK9 inhibitor monoclonal antibodies: Expert consensus statement from Lipid Association of India.

BACKGROUND: Rates of atherosclerotic cardiovascular disease (ASCVD) are strikingly high in India compared to Western countries and are increasing. Moreover, ASCVD events occur at a younger age with only modest hypercholesterolemia, most commonly with low levels of high-density lipoprotein cholesterol. The course of ASCVD also appears to be more fulminant with higher mortality. OBJECTIVE: In light of these issues, the Lipid Association of India (LAI) endeavored to develop revised guidelines with more aggressive low-density lipoprotein cholesterol (LDL-C) goals in secondary prevention and for patients with familial hypercholesterolemia compared to guidelines in the United States and other countries. METHODS: Owing to the paucity of clinical outcomes data in India, it was necessary to place major emphasis on expert opinion as a complement to randomized placebo-controlled data generated mostly in non-Indian cohorts. To facilitate this process, the LAI conducted a series of 19 meetings among 162 lipid specialists in 13 cities throughout India over a period of 11 months before formulating this expert consensus statement. RESULTS: The LAI recommends an LDL-C goal <50 mg/dL in all patients in secondary prevention or very high-risk primary prevention but proposes an optional goal ≤30 mg/dL in category A extreme-risk patients (eg, coronary artery disease + familial hypercholesterolemia) and a recommended goal ≤30 mg/dL in category B extreme-risk patients [coronary artery disease + (1) diabetes and polyvascular disease/≥3 major ASCVD risk factors/end organ damage, or (2) recurrent acute coronary syndrome within 12 months despite LDL-C <50 mg/dL, or (3) homozygous familial hypercholesterolemia]. CONCLUSIONS: More aggressive LDL-C goals are needed for prevention of ASCVD in India, as described in this expert consensus statement. Use of statins and ezetimibe needs to increase in India in combination with improved control of other ASCVD risk factors. Proprotein convertase subtilisin kexin type 9 inhibitors can improve LDL-C goal achievement in patients with refractory hypercholesterolemia.

Duration of type 2 diabetes mellitus and systolic blood pressure as determinants of severity of coronary stenosis and adverse events in an asymptomatic diabetic population: PROCEED study.

BACKGROUND: Evidence from imaging studies suggests a high prevalence of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). However, there are no criteria for initiating screening for CAD in this population. The current study investigated whether clinical and demographic characteristics can be used to predict significant CAD in patients with T2DM. METHODS: Computed tomography coronary angiography (CTCA) and laboratory assessments were performed in 259 patients diagnosed with T2DM attending clinics in Northwest London, UK. Coronary artery calcium (CAC) was calculated during CTCA. Significant plaque was defined as one causing more than 50% luminal stenosis. Associations between groups and variables were evaluated using Student's t test, Chi-square tests and univariate and multivariate regression analysis. P < 0.05 was considered statistically significant. RESULTS: Among patients with a median duration of T2DM of 13 years and a mean age of 62.0 years, median CAC score was 105.91 Agatston Units. In a multivariate analyses, duration of diabetes, CAC score and the presence and number of coronary artery plaques and presence of significant plaque were significant predictors of cardiovascular adverse events. Systolic blood pressure (SBP) had borderline significance as a predictor of cardiovascular events (p = 0.05). In a receiver operating characteristic curve (ROC) analysis, duration of diabetes of > 10.5 years predicted significant CAD (sensitivity, 75.3%; specificity 48.2%). Area under the ROC curve was 0.67 when combining duration of T2DM > 10.5 years and SBP of > 139 mm Hg. Adverse cardiovascular events after a median follow-up of 22.8 months were also significantly higher in those with duration of T2DM > 10.5 years and SBP > 140 mm Hg (log rank p = 0.02 and 0.009, respectively). CONCLUSIONS: Routine screening for CAD using CTCA should be considered for patients with a diagnosis of T2DM for > 10.5 years and SBP > 140 mm Hg. Trial registration Clinicaltrials.gov identifier: NCT02109835, 10 April 2014 (retrospectively registered).

Correlation between PAI-1, leptin and ferritin with HOMA in HIV/AIDS patients.

BACKGROUND: Data about correlation of interleukins (IL-1 α, IL-1 ß, IFN γ, IL-2, IL-4, IL-6, IL-8, IL-10), adipocytokines (leptin, adiponectin, monocyte chemoattractant protein-1 (MCP-1), resistin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNFα), ferritin, C reactive protein (CRP) and vascular endothelial growth factor (VEGF) with homeostasis model assessment (HOMA) in HIV/AIDS patients are still limited. Therefore the aim of this study was to evaluate the possible correlations of serum levels of PAI-1, leptin and ferritin with HOMA in HIV/AIDS patients treated with combined antiretroviral therapy (cART). METHODS: This cross-sectional study included 64 HIV/AIDS patients, all Caucasians, receiving cART at the HIV/AIDS Centre, Belgrade, Serbia. PAI-1, leptin, ferritin and insulin levels were measured using the Metabolic Syndrome Array I (Randox Laboratories Ltd., London, UK), while adiponectin and resistin levels were measured using Metabolic Syndrome Array II (Randox Laboratories Ltd., London, UK), interleukins (IL-1 α, IL-1 ß, IFN γ, IL-2, IL-4, IL-6, IL-8, IL-10), MCP-1, TNF-α as well as VEGF was measured using Cytokine Array I (Randox Laboratories Ltd., London, UK). Insulin resistance was determined using the homeostasis model assessment index (HOMA). Multicollinearity of independent variables in multivariate model was analyzed using Variance Inflation Factor. RESULTS: Correlation analysis revealed significant correlations between HOMA and waist circumference, body mass index, patients' age, number of cART combinations and triglycerides (p = 0.001, p = 0.001, p = 0.050, p = 0.044, p = 0.002, respectively). HOMA negatively correlated with levels of high density lipoprotein (HDL) (Rho = -0.282; p = 0.025). PAI-1 (Rho = 0.334; p= 0.007) and leptin (Rho = 0.492; p = 0.001) together with ferritin (Rho = 0.396, p = 0.001) positively and significantly correlated with HOMA. Levels of IL-1 α, IL-1 ß, IFN γ, IL-2, IL-4, IL-6, IL-8, IL-10, adiponectin, MCP-1, resistin, TNF-α, CRP and VEGF did not significantly correlate with HOMA. Further, multiple logistic regression showed that there is a statistically significant correlation between PAI, leptin and ferritin with HOMA levels (p = 0.042; p < 0.001, p = 0.009). CONCLUSIONS: We showed significant correlation between PAI-1, leptin and ferritin, independently of each other with HOMA, in HIV/AIDS patients on cART.

Short-term abstinence from alcohol and changes in cardiovascular risk factors, liver function tests and cancer-related growth factors: a prospective observational study.

OBJECTIVE: To assess changes in metabolic risk factors and cancer-related growth factors associated with short-term abstinence from alcohol. DESIGN: Prospective, observational study. SETTING: Single tertiary centre. PARTICIPANTS: Healthy subjects were recruited based on intention to: (1) abstain from alcohol for 1 month (abstinence group), or (2) continue to drink alcohol (control group). Inclusion criteria were baseline alcohol consumption >64 g/week (men) or >48 g/week (women). Exclusion criteria were known liver disease or alcohol dependence. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was change in insulin resistance (homeostatic model assessment (HOMA) score). Secondary outcomes were changes in weight, blood pressure (BP), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and liver function tests. Primary and secondary outcomes were adjusted for changes in diet, exercise and cigarette smoking. RESULTS: The abstinence group comprised 94 participants (mean age 45.5 years, SD ±1.2) and the control group 47 participants (mean age 48.7 years, SD ±1.8). Baseline alcohol consumption in the abstinence group was 258.2 g/week, SD ±9.4, and in the control group 233.8 g, SD ±19.0. Significant reductions from baseline in the abstinence group (all p<0.001) were found in: HOMA score (-25.9%, IQR -48.6% to +0.3%), systolic BP (-6.6%, IQR -11.8% to 0.0%), diastolic BP (-6.3%, IQR -14.1% to +1.3%), weight (-1.5%, IQR -2.9% to -0.4%), VEGF (-41.8%, IQR -64.9% to -17.9%) and EGF (-73.9%, IQR -86.1% to -36.4%). None of these changes were associated with changes in diet, exercise or cigarette smoking. No significant changes from baseline in primary or secondary outcomes were noted in the control group. CONCLUSION: These findings demonstrate that abstinence from alcohol in moderate-heavy drinkers improves insulin resistance, weight, BP and cancer-related growth factors. These data support an independent association of alcohol consumption with cancer risk, and suggest an increased risk of metabolic diseases such as type 2 diabetes and fatty liver disease.

HIV infection and lipids.

PURPOSE OF REVIEW: We comment on the role of dyslipidaemia in cardiovascular disease (CVD) in HIV-infected patients. We have discussed various risk factors, including traditional CVD risk factors, HIV-related risk factors and antiretroviral therapy (ART)-induced dyslipidaemia. RECENT FINDINGS: HIV-infected individuals are prone to lipid and lipoprotein abnormalities as a result of the infection itself and the effect of ART. The older drugs used for the treatment of HIV were associated with an increased risk of these abnormalities. New therapies used to treat HIV are lipid friendly. Calculating CVD risk in the HIV population is complex due to the infection itself and the ART-related factors. The advancement in ART has helped to increase the life expectancy of HIV patients. As a result, a growing number of patients die of non-HIV related complications such as CVD, hepatic and renal disease. Outcome studies with intervention for dyslipidaemia in HIV are underway. SUMMARY: The implications of the above findings suggest that all patients with HIV should undergo a CVD risk assessment before starting ART. Appropriate lipid-friendly ART regimen should be initiated along with intervention for associated CVD risk factors (e.g. lipids, hypertension and smoking).

Higher Levels of Cystatin C in HIV/AIDS Patients with Metabolic Syndrome.

Data about Cystatin-C levels in HIV-infected patients with metabolic syndrome (MetS) are still limited. Therefore, the aim of this study was to evaluate the possible correlations of serum levels of Cystatin-C in HIV/AIDS patients treated with combined antiretroviral therapy (cART) with or without MetS. This cross-sectional study included 89 HIV/AIDS Caucasian patients receiving cART at the HIV/AIDS Centre Belgrade, Serbia, divided into two groups according to the presence of MetS. Cystatin-C and other biochemical parameters were measured using Cytokine-Array-I, Metabolic-Array-I and Metabolic-Array-II, at the Department of Clinical Biochemistry, Royal Free Hospital and University College London, UK. A linear regression model was performed to evaluate which clinical and laboratory variables had an independent effect on Cystatin-C levels in HIV/AIDS patients. There were 33 (37%) patients with MetS and 56 (63%) without MetS. Patients with and without MetS were homogenous for age, duration of cART, number of cART combinations and CD4+ T cell count. Statistically increased Cystatin-C levels were observed in HIV/AIDS patients with MetS (p = 0.017), when compared to patients without MetS. Data showed a positive correlation of Cystatin-C and C-reactive protein (r = 0.349, p = 0.001). Using linear regression modelling, significant correlations were obtained between Cystatin-C and MetS in univariate analysis (p < 0.001). Cystatin-C levels were significantly higher in HIV/AIDS patients with MetS versus without MetS. Early assessment of MetS using Cystatin-C as a marker may ultimately help increase the lifespan of HIV/AIDS patients, as these patients appear to be at high risk of cardiovascular diseases.

Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. METHODS: FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. RESULTS: 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7-0.79) vs. 0.66 mm (0.61-0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4-41.8) vs. 2.65 (0.94-7.44), p = 0.0004]. CONCLUSIONS: In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.

Genetic Architecture of Familial Hypercholesterolaemia.

PURPOSE OF REVIEW: Familial hypercholesterolaemia (FH) is an inherited disorder of low-density lipoprotein cholesterol (LDL-C) which is characterised by a raised cholesterol level from birth and a high risk of premature coronary heart disease. In this paper, we review the genetic basis of FH and its impact on the clinical presentation. RECENT FINDINGS: Mutations in any of three genes (LDLR, APOB and PCSK9) are known to cause autosomal dominant FH, but a mutation can be found in only ∼40% of patients with a clinical diagnosis of FH. In the remainder, a polygenic aetiology is most likely, due to the co-inheritance of common LDL-C-raising variants. The cardiovascular presentation and management of FH will differ between patients based on their underlying genetic factors. New genotyping methods such as next-generation sequencing will provide us with better understanding of the genetic architecture of FH.

Correlation of Leptin, Adiponectin, and Resistin Levels in Different Types of Lipodystrophy in HIV/AIDS Patients.

BACKGROUND: Leptin, adiponectin, and resistin may play an important role in the development of lipodystrophy (LD) in HIV/AIDS patients. The aim of this study was to correlate levels of leptin, adiponectin, and resistin between HIV/AIDS patients with LD and without lipodystrophy (non-LD), as well as between subgroups of LD [lipoatrophy (LA), lipohypertrophy (LH), and mixed fat redistribution (MFR)] and non-LD patients. METHODS: Cross-sectional study of 66 HIV/AIDS patients. Serum levels of leptin, adiponectin, and resistin were measured. The associations between adipocytokine levels and metabolic variables were estimated by Spearman correlation. Analysis of covariance with bootstrapping method was used to examine the relationship between adiponectin and leptin and lipodystrophy categories. RESULTS: The LD was observed in 29 (44%) patients, while 15 (52%) of them had LA, 4 (14%) had LH, and 10 (34%) patients had MFR. No significant differences regarding leptin, adiponectin, and resistin levels, between LD and non-LD patients, were observed. LH patients had significantly higher levels of leptin and adiponectin in comparison with non-LD patients (P = 0.039, P = 0.011, respectively). Within the LD group, LA patients had significantly lower levels of leptin (LA vs. LH, P = 0.020; LA vs. MFR, P = 0.027), while LH patients had significantly higher levels of adiponectin (LH vs. LA, P = 0.027; LH vs. MFR, P = 0.028). Correlation of adiponectin with LD remains significant in the LH subgroup after adjustment for age, body mass index, cystatin-C, plasminogen activator inhibitor-1 (PAI-1), and interferon gamma (IFN-γ) (P = 0.001). CONCLUSIONS: Adiponectin and leptin levels differ significantly between LH patients and non-LD patients, as well as between the LD subgroups. Adiponectin may be a more useful marker of LD in HIV/AIDS patients.

Lower levels of IL-4 and IL-10 influence lipodystrophy in HIV/AIDS patients under antiretroviral therapy.

BACKGROUND: The role of interleukins in the pathogenesis of lipodystrophy in HIV/AIDS-patients is still not understood. The aim of this study was to evaluate the relationship between serum levels of interleukins between HIV/AIDS-patients with or without lipodystrophy, as well as between different subgroups of lipodystrophy (lipoatrophy, lipohypertrophy, mixed-fat-redistribution) and patients without lipodystrophy. METHODS: Cross-sectional study of 66 HIV/AIDS patients, all Caucasians. Serum levels of interleukins (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10) were measured using Cytokine-Array-1 on Evidence Investigator, Biochip Array Technology. The associations between interleukins and anthropometric and metabolic variables were estimated by Spearman-correlation. Analysis of covariance with bootstrapping method (ACBM) was used to examine relationship between interleukins and lipodystrophy categories adjusted for confounding variables. RESULTS: The lipodystrophy was observed in 29 (44%) patients, while 15 (52%) had lipoatrophy, 4 (14%) lipohypertrophy and 10 (34%) patients had mixed fat redistribution. There were 37 (56%) patients without lipodystrophy. Significantly lower levels of IL-4 and IL-10 were observed in lipodystrophy vs. non-lipodystrophy (p=0.008; p=0.027, respectively). No differences were found relating IL-1α, IL-1ß, IL-2, IL-6 and IL-8 levels in lipodystrophy vs. non-lipodystrophy. In patient subgroup with lipoatrophy, significantly lower levels of IL-4 and IL-10 were found when compared to non-lipodystrophy (p=0.043; p=0.031, respectively). In lipohypertrophy subgroup significantly lower levels of IL-4 were found when compared to non-lipodystrophy (p=0.003). In order to estimate the correlation of IL-4 and IL-10 and the presence of lipodystrophy, ACBM showed that correlation of IL-4 levels in patients with lipodystrophy remains statistically significant (p=0.004) in all types of lipodystrophy: lipoatrophy, lipohypertrophy and mix-fat-redistribution (p=0.027; p=0.009; p=0.017, respectively) after adjustment for age, BMI. CONCLUSIONS: IL-4 and IL-10 levels were significantly lower in lipodystrophy vs. non-lipodystrophy. According to our knowledge, we showed for the first time significant correlation between IL-4 levels and lipodystrophy development in HIV/AIDS patients.

Cardiovascular risk stratification in familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is a common autosomal-dominant disorder in most European countries. Patients with FH are characterised by a raised level of low-density lipoprotein cholesterol and a high risk of premature coronary heart disease (CHD). Currently there is no consensus regarding the clinical utility to predict future coronary events or testing for the presence of subclinical atherosclerotic disease in asymptomatic patients with FH. Family screening of patients with FH as recommended by the UK National Institute of Health and Care Excellence guideline would result in finding many young individuals with a diagnosis of FH who are clinically asymptomatic. The traditional CHD risk scores, that is, the Framingham score, are insufficient in risk prediction in this group of young individuals. In addition, a better understanding of the genetic aetiology of the FH phenotype and CHD risk in monogenic FH and polygenic hypercholesterolaemia is needed. Non-invasive imaging methods such as carotid intima-media thickness measurement might produce more reliable information in finding high-risk patients with FH. The potential market authorisation of novel therapeutic agents such as PCSK9 monoclonal inhibitors makes it essential to have a better screening programme to prioritise the candidates for treatment with the most severe form of FH and at higher risk of coronary events. The utility of new imaging techniques and new cardiovascular biomarkers remains to be determined in prospective trials.

Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.

BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation. METHODS AND RESULTS: Exomes of 125 unrelated DFH patients were sequenced, as part of the UK10K project. First, analysis of known FH genes identified 23 LDLR and two APOB mutations, and patients with explained causes of FH were excluded from further analysis. Second, common and rare variants in genes associated with low-density lipoprotein cholesterol (LDL-C) levels in genome-wide association study (GWAS) meta-analysis were examined. There was no clear rare variant association in LDL-C GWAS hits; however, there were 29 patients with a high LDL-C SNP score suggestive of polygenic hypercholesterolaemia. Finally, a gene-based burden test for an excess of rare (frequency <0.005) or novel variants in cases versus 1926 controls was performed, with variants with an unlikely functional effect (intronic, synonymous) filtered out. CONCLUSIONS: No major novel locus for FH was detected, with no gene having a functional variant in more than three patients; however, an excess of novel variants was found in 18 genes, of which the strongest candidates included CH25H and INSIG2 (p<4.3×10(-4) and p<3.7×10(-3), respectively). This suggests that the genetic cause of FH in these unexplained cases is likely to be very heterogeneous, which complicates the diagnostic and novel gene discovery process.

Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction.

Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme.

Familial hypercholesterolaemia.

PURPOSE OF REVIEW: Familial hypercholesterolaemia is associated with lifelong elevated cholesterol levels and is an important cause of premature coronary heart disease (CHD). This condition is often underdiagnosed and undertreated. Awareness of this condition is poor among nonlipid specialists. Treatment of elevated cholesterol levels with statins reduces the risk for CHD. The review will increase the awareness of this condition among nonspecialists. RECENT FINDINGS: Recently, several guidelines have been produced by different countries, but a unified approach to this global problem is addressed through a recent guideline facilitated by the Familial Hypercholesterolaemia Foundation. Although the widespread use of statins has been successful in reducing the risk for CHD in familial hypercholesterolaemia, there have been difficulties in getting to targets, especially in those with established vascular disease. New therapies such as mipomersen, a second-generation antisense oligonucleotide, microsomal triglyceride transfer protein inhibitors that decrease the synthesis of apolipoprotein B-containing lipoproteins and proprotein convertase subtilisin/kexin type 9 inhibitors hold promise in reducing cholesterol levels in those patients in whom low density lipoprotein cholesterol (LDL-C) reduction is required beyond the use of statins, especially in those with severe heterozygous familial hypercholesterolaemia or homozygous familial hypercholesterolaemia. SUMMARY: Increased awareness and wider availability of guidance to treat familial hypercholesterolaemia will improve management of familial hypercholesterolaemia. New therapies, if they become available after appropriate outcome studies, will reduce LDL-C levels in both homozygous familial hypercholesterolaemia and severe heterozygous familial hypercholesterolaemia, thus reducing the risk for premature CHD.

Point of care testing is appropriate for National Health Service health check.

BACKGROUND: The Department of Health launched a cardiovascular disease risk assessment initiative with particular reference to reducing health inequalities in ethnic minorities. Collaboration between HEART UK, Royal Free Hampstead NHS Trust and Hindu Temples resulted in vascular screening in North London. METHODS: Subjects of South Asian origin were screened. A full lipid profile and glucose were measured using a point of care testing (POCT) Cholestech LDX analyser (LDX). Venous samples were analysed in our hospital laboratory. RESULTS: The results (215 men; 191 women) were divided into tertiles and Bland-Altman plots were used to assess agreement. At high-density lipoprotein cholesterol (HDL-C) concentrations < 1.0 mmol/L the LDX underestimated values by -0.2 mmol/L (P<0.0001). At HDL-C concentrations >1.3 mmol/L this bias disappeared. For total cholesterol the concentration-dependent negative bias was evident at concentrations of < 4.1 mmol/L (P < 0.0001). This bias was less evident at higher concentrations. A similar pattern was seen for low-density lipoprotein cholesterol. There were also small variations in glucose and triglyceride values. However, there was excellent agreement in calculated cardiovascular disease risk using kappa analysis for JBS2, QRISK2, ETHRISK and Framingham (κ = 0.86, 0.92, 0.94 and 0.88, respectively). This was a high-risk population since 9.7-19.4% had a ≥ 20% 10-y probability of a vascular event depending on the risk engine and assay method used. The corresponding values for intermediate risk (11-19%) were 18.6-25.7%. CONCLUSIONS: There was a minimum mismatch irrespective of the type of risk calculator used. POCT measurements are adequate for the National Health Service Health Check.

Comparison of cystatin C and creatinine-based glomerular filtration rate formulas with 51Cr-EDTA clearance in patients with cirrhosis.

BACKGROUND AND OBJECTIVES: Renal function is an important predictor of survival in cirrhosis and liver transplantation. GFR estimates using serum cystatin C (CysC) are proposed as better predictors of renal function than ones on the basis of serum creatinine (Cr). Our aims were: (1) evaluate correlations between serum CysC and different methods of creatinine measurements; (2) compare CysC and Cr GFR formulas with (51)Cr-EDTA; and (3) evaluate liver-related parameters potentially influencing GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 254 blood samples in 65 patients with cirrhosis correlating CysC with four Cr methods were used; another 74 patients comparing (51)Cr-EDTA GFR to Modification of Diet in Renal Disease and Larsson and Hoek formulas for CysC were also included. Agreement was assessed using Bland-Altman plots and concordance correlation coefficients. Multivariate linear regression analysis was used for GFR predictors. RESULTS: Serum CysC correlated modestly with O'Leary modified Jaffe, compensated kinetic Jaffe, enzymatic creatinine, and standard kinetic Jaffe 0.72/0.71/0.72/0.72 (all P < 0.001). Bland-Altman agreement with (51)Cr-EDTA GFR was poor; the best agreement was Modification of Diet in Renal Disease (concordance 0.61; 95% CI, 0.47 to 0.71); the worst agreement was the Hoek formula (concordance 0.46; 95% CI, 0.27 to 0.61). A new GFR formula including the Child-Pugh score improved the accuracy of Cr GFR formulas compared with (51)Cr-EDTA GFR. CONCLUSIONS: Estimated GFR in cirrhosis is not better with CysC formulas compared with creatinine ones: specific formulas may be necessary.

Prediction of ESRD and death among people with CKD: the Chronic Renal Impairment in Birmingham (CRIB) prospective cohort study.

BACKGROUND: Validated prediction scores are required to assess the risks of end-stage renal disease (ESRD) and death in individuals with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study with validation in a separate cohort. SETTING & PARTICIPANTS: Cox regression was used to assess the relevance of baseline characteristics to risk of ESRD (mean follow-up, 4.1 years) and death (mean follow-up, 6.0 years) in 382 patients with stages 3-5 CKD not initially on dialysis therapy in the Chronic Renal Impairment in Birmingham (CRIB) Study. Resultant risk prediction equations were tested in a separate cohort of 213 patients with CKD (the East Kent cohort). FACTORS: 44 baseline characteristics (including 30 blood and urine assays). OUTCOMES: ESRD and all-cause mortality. RESULTS: In the CRIB cohort, 190 patients reached ESRD (12.1%/y) and 150 died (6.5%/y). Each 30% lower baseline estimated glomerular filtration rate was associated with a 3-fold higher ESRD rate and a 1.3-fold higher death rate. After adjustment for each other, only baseline creatinine level, serum phosphate level, urinary albumin-creatinine ratio, and female sex remained strongly (P < 0.01) predictive of ESRD. For death, age, N-terminal pro-brain natriuretic peptide, troponin T level, and cigarette smoking remained strongly predictive of risk. Using these factors to predict outcomes in the East Kent cohort yielded an area under the receiver operating characteristic curve (ie, C statistic) of 0.91 (95% CI, 0.87-0.96) for ESRD and 0.82 (95% CI, 0.75-0.89) for death. LIMITATIONS: Other important factors may have been missed because of limited study power. CONCLUSIONS: Simple laboratory measures of kidney and cardiac function plus age, sex, and smoking history can be used to help identify patients with CKD at highest risk of ESRD and death. Larger cohort studies are required to further validate these results.