Homozygous familial hypercholesterolemia is an inherited disorder caused by mutations in both low-density lipoprotein receptor alleles, which results in extremely elevated plasma low-density ...lipoprotein cholesterol concentrations and very early morbidity and mortality due to cardiovascular disease.
To evaluate the impact of advances in lipid-lowering (predominantly statin) therapy on cardiovascular disease morbidity and mortality in a large cohort of patients with homozygous familial hypercholesterolemia, the records of 149 patients (81 females, 68 males) from 2 specialized lipid clinics in South Africa were evaluated retrospectively. Homozygous familial hypercholesterolemia was diagnosed by confirmation of mutations in genes affecting low-density lipoprotein cholesterol or by clinical criteria. A Cox proportional hazard model with time-varying exposure was used to estimate the risk of death and major adverse cardiovascular events among statin-treated patients compared with statin-naive patients. The hazard ratio for benefit from lipid therapy, calculated with the Cox proportional hazards model for the end point of death, was 0.34 (95% confidence interval 0.14-0.86; P=0.02), and for the end point of major adverse cardiovascular events, it was 0.49 (95% confidence interval 0.22-1.07; P=0.07). This occurred despite a mean reduction in low-density lipoprotein cholesterol of only 26.4% (from 15.9±3.9 to 11.7±3.4 mmol/L; P<0.0001) with lipid-lowering therapy.
Lipid-lowering therapy is associated with delayed cardiovascular events and prolonged survival in patients with homozygous familial hypercholesterolemia.
Prevalence of Mutations in AGPAT2 Among Human Lipodystrophies
Jocelyne Magré 1 ,
Marc Delépine 2 ,
Lionel Van Maldergem 3 ,
Jean-Jacques Robert 4 ,
J. Antonie Maassen 5 ,
Muriel Meier 1 ,
Vanessa R. ...Panz 6 ,
Chong Ae Kim 7 ,
Nadia Tubiana-Rufi 8 ,
Paul Czernichow 8 ,
Eva Seemanova 9 ,
Charles R. Buchanan 10 ,
Didier Lacombe 11 ,
Corinne Vigouroux 1 ,
Olivier Lascols 1 ,
C. Ronald Kahn 12 ,
Jacqueline Capeau 1 and
Mark Lathrop 2
1 INSERM U.402, Saint-Antoine Faculty of Medicine, University of Pierre and Marie Curie, Paris, France
2 National Center of Genotyping, Evry, France
3 Center of Human Genetics, Institute of Pathology and Genetics, Loverval, Belgium
4 Department of Pediatric Diabetology, Necker Hospital, Paris, France
5 Sylvius Laboratory, University of Leiden Medical Center, Leiden, the Netherlands
6 Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
7 Department of Pediatrics, da Crianca Institute, University of Sao Paulo, Sao Paulo, Brazil
8 Department of Pediatric Endocrinology, Robert Debré Hospital, Paris, France
9 Department of Clinical Genetics, Charles University, Prague, Czech Republic
10 Department of Child Health, King’s College Hospital, London, U.K
11 Department of Medical Genetics, Pellegrin-Enfants Hospital, Bordeaux, France
12 Joslin Diabetes Center, Harvard University, Boston, Massachusetts
Abstract
Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose
tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients’
cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL
patients from 30 families with mutations in AGPAT2 . Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations
and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies,
including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations
in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and
AGPAT2 are the two major genes involved in the etiology of BSCL.
Footnotes
Address correspondence and reprint requests to Jocelyne Magré, INSERM U.402, Faculté de Médecine Saint-Antoine, 27 rue Chaligny,
75571 Paris Cedex, France. E-mail: magre{at}st-antoine.inserm.fr .
Received for publication 19 December 2002 and accepted 18 February 2003.
BSCL, Berardinelli-Seip congenital lipodystrophy; FPLD, familial partial lipodystrophy; LPA, lysophosphatidic acid.
DIABETES
The authors' goal was to document baseline pituitary-adrenal hormonal and related metabolic variables in 16 female patients with burnout. Then, following stress management intervention, to compare ...the changes with an equal number of untreated control subjects. At monthly intervals for 4 mo, 24-h urine samples were obtained for determination of free cortisol excretion. In addition, fasting blood samples were analyzed for levels of cortisol, dehydroepiandrosterone sulfate (DHEAS), ACTH, aldosterone, and catecholamines. Other biochemical measurements included growth hormone, prolactin, insulin, glucose, and lipid components. The Maslach Burnout Inventory, General Health Questionnaire- 28, and Zung depression rating scale were completed on each consecutive visit. The most striking finding was the reduction of urine free-cortisol excretion in the patients compared with controls. Initial urinary free cortisol was significantly lower in the patients (mean +/- SEM = 47.2 +/- 11.0 vs 79.0 +/- 6.8 nmol/L, p = 0.02) and remained significantly reduced at 4 mo (mean +/- SEM = 44.0 +/- 6.1 vs 91.1 +/- 8.8 nmol/L, p = 0.0001). There were no significant changes in the other hormonal and biochemical data. We conclude that there is functional hypocortisolism in burnout, which is not immediately restored on stress management intervention despite clinical and psychological improvement.
Treatment of depression is often accompanied by weight changes. Previous studies indicate that leptin plays no role in this change despite showing a strong correlation with body mass index (BMI) in ...healthy people. The aim of this study was to evaluate the effect of imipramine and fluoxetine on BMI and its correlation with leptin. Eighteen depressed female patients randomly received either drug for 3 months. BMI was calculated and fasting blood samples were assayed for glucose, leptin, insulin, free fatty acids (FFA), and lipids. The difference between the changes in BMI (imipramine + 1.0 kg/m2, fluoxetine -0.5 kg/m2) was statistically significant (P < 0.05, t = 2.106). There was a significant positive correlation between overall BMI and leptin (r = 0.784, P < 0.001) but not between BMI and insulin or FFA. However, fasting insulin levels and calculated insulin resistance levels dropped substantially in the imipramine group. We conclude that the use of tricyclic antidepressants (TCAs) in depressed patients at risk for developing type 2 diabetes remains unresolved at this stage.
The most common malignancy in men worldwide is cancer of the prostate. Androgens play a direct role in normal and malignant growth of prostate cells via the androgen receptor (AR). This study ...analyzed the polymorphic CAG repeat sequence in exon 1 of the AR gene to determine if the number of repeats might be an indicator of prostate cancer risk or aggressive disease. DNA was extracted from blood samples of 20 black and 20 white men with well-documented prostate cancer and 40 healthy controls (20 blacks and 20 whites). PCR amplification was followed by gel electrophoresis and DNA sequencing. This region normally contains between 9 and 29 repeats. Patients and controls both had minor variations in the number of repeats, which ranged from 13 to 27 with 21 being the most frequent allele. Black controls and patients both had a mean of 20 +/- 3 repeats; in whites the mean was significantly lower in patients than controls (21 +/- 2 versus 23 +/- 2; p = 0.004). Combined black and white patients also had a lower number than the combined group of controls (20 +/- 3 versus 22 +/- 3; p = 0.02). Similarly, black and white patients with aggressive disease had a lower number than patients whose disease was more slowly progressive (19 +/- 2 versus 22 +/- 3; p = 0.02). We conclude that the small differences in the number of CAG repeats in both black and white patients do not appear to be a strong indicator of risk or aggressive disease but that this size polymorphism may be one of many genetic and environmental risk factors involved in prostate cancer.
To assess whether adrenocortical function was compromised in patients with active tuberculosis (TB) during the first 5 days of therapy with either a rifampicin-based or ciprofloxacin-based regimen.
...Patients were randomised into two groups of 10 each. Adrenocortical function was compared in both groups by the measurement of biochemical indices, electrolytes, osmolality and pituitary-adrenocortical hormones. Adrenal reserve was assessed by intravenous 250 mug adrenocorticotropin hormone (ACTH) stimulation tests.
Department of Medicine, Johannesburg Hospital.
Twenty hospitalised patients who were diagnosed with TB.
Respiratory rate, pulse rate and blood pressure were recorded, and urinary sodium and osmolality were measured. Serum ACTH, cortisol, dehydroepiandrosterone- sulphate (DHEA-S) and aldosterone were assayed.
None of the patients demonstrated biochemical evidence of overt adrenal insufficiency. There were no significant differences between the two groups before or during therapy for any biochemical indices, electrolytes, hormones or calculated osmolality. Mean basal cortisol concentrations were substantially elevated and DHEA-S levels were consistently subnormal, resulting in a high cortisol/ DHEA-S ratio. In the ciprofloxacin group, cortisol responses to ACTH stimulation on day 1 were not significantly lower than on day 5. In the rifampicin group, cortisol concentrations decreased at each time point on day 5 compared with day 1 (p = 0.001). However, a significantly higher mean incremental rise from the basal cortisol concentration was measured on day 5 at 60 minutes (p = 0.04). In the entire cohort of 20 patients, 40% demonstrated an incremental cortisol rise of < 250 nmol/l after ACTH stimulation on day 1.
Rifampicin did not additionally impair adrenocortical function during the initial period of therapy. The high cortisol/DHEA-S ratio might be of clinical relevance.
Diabetes mellitus (DM) is a complication of tacrolimus therapy. This prospective study evaluated the prevalence of DM in South African black and white patients receiving tacrolimus after kidney ...transplantation and factors that could identify patients before transplantation who may be at risk of developing DM. Fasting blood samples from 17 patients (11 black, 6 white) were analyzed immediately pretransplantation and at 1 and 3 months posttransplantation for glucose, HbA sub(IC), insulin, C-peptide, free fatty acids, lipids, urea, and creatinine. Insulin resistance (IR) was calculated using the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) formulas. Eight patients (47%) became diabetic (six black, two white), and nine patients (five black, four white) remained nondiabetic. Mean glucose concentrations in the diabetic group were significantly higher at 1 month (P = 0.03) and 3 months (P = 0.01). Mean insulin level was also significantly raised at 3 months (P = 0.01) as was HbA sub(IC) (P = 0.001). C-peptide concentrations did not change significantly in either group. Significant correlations emerged between fasting glucose concentrations at 3 months posttransplantation and initial HOMA (r = 0.486; P = 0.048) and initial QUICKI (r = -0.582; P = 0.014). Occurrence of DM was high and somewhat greater in black patients. IR was the main mechanism involved, together with inadequate beta -cell compensation. IR pretransplantation predicts the subsequent development of DM.
Background. The International Diabetes Federation (IDF) introduced a new definition of the metabolic syndrome (MS) that emphasises ethnic-specific cut-offs for waist circumference (WC).
Objective. To ...compare MS prevalence rates using the National Cholesterol Education Program Adult Treatment Panel III (NCEP: ATP III) and IDF definitions.
Methods. Anthropometric data, fasting biochemical variables and MS prevalence rates were measured in 40 black patients with established coronary artery disease (CAD). Glucose metabolism was assessed using the oral glucose tolerance test (OGTT), and insulin-mediated glucose disposal (M-value) was evaluated using the hyperinsulinaemic euglycaemic clamp technique.
Results. Based on the NCEP: ATP III definition, MS prevalence was 60% and using the IDF definition, it was 57.5%. The two definitions similarly classified ∼83% of patients as being MS positive or MS negative. Lower WC cut-offs in the IDF definition classified greater numbers of men and women as having WC as a risk factor-IDF v. NCEP: ATP III men 57.6% v. 36.4%; women 100% v. 71.4%. Impaired glucose tolerance (IGT) was found in 12 of the 40 patients (30%) and diabetes mellitus (DM) in 8 (20%). Mean M-value was reduced in IGT and DM groups compared with the normal group, significantly so in the DM group (p = 0.01).
Conclusions. NCEP: ATP III and IDF definitions both generated similar MS prevalence estimates. The two definitions similarly identified the presence or absence of the MS in the majority of patients. The IDF definition classified greater numbers of men and women as having WC as a risk factor. There was a high prevalence of previously undiagnosed IGT and DM in our South African black patients with established CAD.
Faulty hypothalamic regulation (eg, via the novel Beacon protein11) might be implicated in the pathogenesis of GCL, but the gene for PPARy has been reported to be normal in this disorder. ...Nevertheless, pathways involving this receptor have been the basis for several remarkable mouse models of generalised lipodystrophy, which resemble the human counterpart. These models12 have consisted mainly of transgenic or specific- gene-knockout animals, in which the expression of the various transcription factors interacting with the PPARgammaRXR cascade (eg, SREBPlc and C/EBP) have been perturbed. Biochemically these animals show little or no white-fat mass, greatly increased serum insulin and glucose concentrations, hypertriglyceridaemia, and substantially reduced leptin concentrations. In addition, a leptin transgenic mouse, overexpressing leptin by several times, has been generated. Unlike the other variants, these "skinny mice" exhibit increased insulin sensitivity, which obliquely suggests that leptin deficiency is a major factor in insulin resistance in GCL. Although not completely analogous to the disorders in man, these mouse models signpost the direction for future research in human lipodystrophy and also constitute a valuable framework for testing novel therapeutic approaches.
Diabetes mellitus (DM) is a complication of tacrolimus therapy. This prospective study evaluated the prevalence of DM in South African black and white patients receiving tacrolimus after kidney ...transplantation and factors that could identify patients before transplantation who may be at risk of developing DM.
Fasting blood samples from 17 patients (11 black, 6 white) were analyzed immediately pretransplantation and at 1 and 3 months posttransplantation for glucose, HbAIC, insulin, C-peptide, free fatty acids, lipids, urea, and creatinine. Insulin resistance (IR) was calculated using the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) formulas.
Eight patients (47%) became diabetic (six black, two white), and nine patients (five black, four white) remained nondiabetic. Mean glucose concentrations in the diabetic group were significantly higher at 1 month (P=0.03) and 3 months (P=0.01). Mean insulin level was also significantly raised at 3 months (P=0.01) as was HbAIC (P=0.001). C-peptide concentrations did not change significantly in either group. Significant correlations emerged between fasting glucose concentrations at 3 months posttransplantation and initial HOMA (r=0.486; P=0.048) and initial QUICKI (r=-0.582; P=0.014).
Occurrence of DM was high and somewhat greater in black patients. IR was the main mechanism involved, together with inadequate beta-cell compensation. IR pretransplantation predicts the subsequent development of DM.
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