RESUMEN
Familial hypobetalipoproteinemia is an autosomal codominant trait that can be caused by mutations in the apo B gene. Here we report a novel apo B gene mutation causing hypobetalipoproteinemia, that is associated with the synthesis of a truncated apo B protein in a young healthy male subject and his mother. The mutation is an A deletion at position 6627 of the apo B cDNA leading to a truncated protein of 2166 amino acids (apo B-48.4). This truncated apo B was detected mainly in VLDL, LDL and in trace amounts in HDL, but not in the lipoprotein deficient plasma fraction. Affected family members present with elevated levels of HDL-cholesterol, mainly due to an increase in HDL2 particles. Postprandial triglycerides and retinyl esters in the d < 1.006 g/ml lipoprotein in the proband showed a normal response to an oral fat load compared to a group of eight matched healthy controls. In summary this novel mutation is associated with hypobetalipoproteinemia with a normal fat absorption as expected for a protein with a length similar to that of apo B-48.
Asunto(s)
Apolipoproteínas B/genética , Hipobetalipoproteinemias/genética , Oligopéptidos/genética , Adulto , Anciano , Apolipoproteína A-I/sangre , Apolipoproteína A-II/sangre , Apolipoproteína B-48 , Apolipoproteína C-II , Apolipoproteína C-III , Apolipoproteínas B/análisis , Apolipoproteínas B/sangre , Apolipoproteínas B/química , Apolipoproteínas C/sangre , Apolipoproteínas E/sangre , Apolipoproteínas E/genética , Secuencia de Bases , Colesterol/sangre , HDL-Colesterol/sangre , HDL-Colesterol/genética , LDL-Colesterol/sangre , LDL-Colesterol/genética , VLDL-Colesterol/sangre , VLDL-Colesterol/genética , Análisis Mutacional de ADN , ADN Complementario/análisis , ADN Complementario/genética , Electroforesis en Gel de Poliacrilamida , Salud de la Familia , Femenino , Eliminación de Gen , Humanos , Inmunoquímica , Masculino , Persona de Mediana Edad , Madres , Oligopéptidos/química , Linaje , Fenotipo , Mutación Puntual/genética , Mutación Puntual/fisiología , Dodecil Sulfato de Sodio , Triglicéridos/sangreRESUMEN
We describe a case of central retinal vein and branch artery occlusion associated with inherited type I plasminogen deficiency (68%) and permanent elevation of Lp(a) (460 mg/l, S2 phenotype) in a 45 year old white woman with no associated local or systemic risk factors. Pedigree analysis revealed inheritance of plasminogen deficiency from the deceased father and of high Lp(a) levels from the mother. Both the patient's sons had plasminogen deficiency, but they had normal Lp(a) levels. In a series of 40 consecutive patients with central retinal vein occlusion we previously reported the observation of high Lp(a) levels--consistently associated with the S2 phenotype--in 30% of the patients as compared to a 10% incidence in controls. This case emphasizes the importance of screening patients with occlusion of the retinal vessels and no associated risk factors for coagulation abnormalities predisposing to thrombosis.
Asunto(s)
Lipoproteína(a)/sangre , Plasminógeno/deficiencia , Oclusión de la Arteria Retiniana/complicaciones , Oclusión de la Vena Retiniana/complicaciones , Femenino , Humanos , Persona de Mediana Edad , Oclusión de la Arteria Retiniana/sangre , Oclusión de la Arteria Retiniana/genética , Oclusión de la Vena Retiniana/sangre , Oclusión de la Vena Retiniana/genéticaRESUMEN
In order to evaluate the effect of a combined kidney-pancreas (KP) transplantation in insulin-dependent diabetes mellitus (IDDM) patients on the lipid and lipoprotein profile, 15 KP patients were compared with 11 kidney (K)--transplanted IDDM patients, 19 IDDM patients on hemodialysis (HD), and 15 nondiabetic control subjects. Cholesterol, triglycerides, apo AI, and apo B were measured in total plasma and in VLDL, LDL, and HDL of all participants. VLDL cholesterol, VLDL-triglycerides, and VLDL-apo B were significantly lower in KP patients, but not in K patients, than in HD patients. In addition, patients in the K, but not in the KP, group showed high levels of apo B in LDL and an increased triglyceride/apo B ratio in VLDL, compared with patients in the HD group. The percentage of apo AI associated with HDL was significantly higher in both transplanted groups than in the HD group. However, compared with a nondiabetic control population, an increase in VLDL particles and in triglyceride content in LDL and HDL still persisted following combined KP transplantation. Insulin resistance (probably due to steroid therapy) associated with high peripheral and potentially low hepatic insulin levels (due to the systemic drainage of the transplanted pancreas) could be the main causes of the remaining lipoprotein abnormalities.
Asunto(s)
Diabetes Mellitus Tipo 1/cirugía , Trasplante de Riñón , Lípidos/sangre , Lipoproteínas/sangre , Trasplante de Páncreas , Adulto , Femenino , Humanos , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Páncreas/metabolismoRESUMEN
Whereas the importance of plasma lipoprotein(a) [Lp(a)] levels as a risk factor for premature coronary artery disease (CAD) is certain, it is not clear if the apolipoprotein(a) [apo(a)] phenotype plays an additional and independent role. To investigate the possible effect of apo(a) phenotype on premature CAD (in patients < 55 years of age), plasma Lp(a) concentrations, the apo(a) phenotypes, and their relation with many recognized CAD risk factors were examined in 96 non-diabetic male patients with angiographically defined CAD and in 83 age-matched male control subjects with no angiographic evidence of CAD. Results demonstrate that patients with premature CAD are characterized by higher Lp(a) levels (24 +/- 21 vs 17 +/- 15 mg/dl, p < 0.01) and a higher frequency of S2 phenotype (32% vs 15%, p < 0.01). Patients with an S2 phenotype exhibited significantly higher plasma Lp(a) concentrations than control subjects with the same isoform (37 +/- 22 vs 22 +/- 17 mg/dl, p < 0.05). A significant correlation was found between apo B and Lp(a) levels in patients with an S2 phenotype. In addition, patients had a low frequency of S1 and S4, and a high frequency of double-band phenotypes of apo(a). Multivariate analysis did not demonstrate an independent role for apo(a) phenotype as a risk factor for premature CAD. In conclusion, CAD patients < 55 years of age have a very different pattern of apo(a) phenotypes than subjects with no angiographic evidence of CAD; this study confirms the hypothesis that apo(a) phenotype may play an additional role in the etiology of premature CAD.
Asunto(s)
Apolipoproteínas/genética , Enfermedad Coronaria/epidemiología , Lipoproteína(a)/sangre , Apolipoproteínas/análisis , Apoproteína(a) , Estudios de Casos y Controles , Angiografía Coronaria , Enfermedad Coronaria/sangre , Enfermedad Coronaria/genética , Humanos , Lípidos/sangre , Lipoproteínas/sangre , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fenotipo , Factores de RiesgoRESUMEN
A series of coagulation parameters and lipoprotein(a) (Lp(a)) were explored in plasma from 40 patients with central retinal vein occlusion (CRVO, non-ischemic type n = 12; ischemic type n = 28) free of local and systemic predisposing factors, 1 to 12 months after the acute event. Forty age- and sex-matched patients with cataract served as controls. Prothrombin fragment 1.2 (F1.2), D-dimer, FVII:C--but not FVII:Ag--were higher and fibrinogen was lower in CRVO patients than in controls. Patients with non-ischemic CRVO had higher F1.2 and FVII:C and lower heparin cofactor II than patients with ischemic CRVO. Lp(a) levels greater than 300 mg/l were observed in 12 patients with CRVO and in 4 controls (30% vs 10%, p < 0.025). Patients with high Lp(a)--consistently associated with the S2 phenotype--had higher FVII:C, FVII:C/Ag ratio, and fibrinogen than the remaining CRVO patients. Plasma F1.2 and D-dimer correlated fairly in controls (r = 0.41) and patients with normal Lp(a) levels (r = 0.55), but they did not in the group of patients with high Lp(a) (r = 0.19), where the latter parameter was negatively related to D-dimer (r = -0.55). There was no dependence of the abnormalities observed on the time elapsed from vein occlusion. The findings of activated FVII and high F1.2, D-dimer, and Lp(a) are not uncommon in patients with CRVO. Increased thrombin formation with fibrin deposition and impaired fibrinolysis may play a role in the pathophysiology of CRVO and require specific treatment.
Asunto(s)
Trastornos de la Coagulación Sanguínea/sangre , Lipoproteína(a)/sangre , Oclusión de la Vena Retiniana/sangre , Adulto , Anciano , Femenino , Humanos , Incidencia , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Prevalencia , Oclusión de la Vena Retiniana/epidemiologíaAsunto(s)
Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/cirugía , Lípidos/sangre , Trasplante de Páncreas/métodos , Trasplante de Páncreas/fisiología , Apolipoproteína A-I/análisis , Apolipoproteínas B/análisis , Colesterol/sangre , HDL-Colesterol/sangre , Hemoglobina Glucada/análisis , Humanos , Terapia de Inmunosupresión/métodos , Lipoproteínas VLDL/sangreRESUMEN
OBJECTIVE: To characterize the effects of intraperitoneal insulin pump therapy on lipoprotein composition and lipolytic enzyme activity in patients with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: Ten IDDM patients were studied 3 times: when receiving conventional subcutaneous insulin therapy and at 3 and 9 months from the initiation of intraperitoneal insulin regimen. Ten nondiabetic subjects matched for age, sex, and body weight were studied as controls. Levels of cholesterol, triglycerides, apolipoprotein A-I (apoA-I) and B (apoB) were measured in total plasma and lipoprotein fractions (very-low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], low-density lipoprotein [LDL], and high-density lipoprotein [HDL]: HDL2 and HDL3). Postheparin plasma lipoprotein lipase and hepatic lipase activities were determined by an immunochemical method. RESULTS: IDDM patients showed higher levels of HDL3 and lower levels of HDL2 particles during intraperitoneal insulin therapy in comparison with subcutaneous insulin therapy. Both cholesterol and apoA-I significantly increased in HDL3 and decreased in HDL2 during intraperitoneal treatment. Plasma total cholesterol significantly decreased in the diabetic patients at 3 months of intraperitoneal insulin therapy compared with both subcutaneous insulin regimen and control subjects. IDL triglyceride concentrations during intraperitoneal treatment were significantly lower than those seen with subcutaneous therapy. Furthermore, triglyceride:apoB ratio in VLDL and cholesterol:apoB ratio in LDL significantly decreased in IDDM patients treated by intraperitoneal insulin. A significant increase in the activity of hepatic lipase with intraperitoneal insulin therapy by 9 months compared with subcutaneous insulin therapy has been shown. CONCLUSIONS: The increased activity of hepatic lipase after intraperitoneal insulin administration in IDDM patients appears to be one of the main determinants of lipoprotein changes observed, resulting in the normalization of lipoprotein composition during this mode of therapy. The normal inverse relationship between VLDL triglycerides and HDL cholesterol, which was not present in IDDM patients with subcutaneous therapy, was restored with intraperitoneal insulin regimen.
Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Sistemas de Infusión de Insulina , Insulina/administración & dosificación , Lipoproteínas/sangre , Adulto , Apolipoproteína A-I/análisis , Apolipoproteína A-I/metabolismo , Apolipoproteínas B/análisis , Apolipoproteínas B/metabolismo , Colesterol/sangre , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Inyecciones Subcutáneas , Insulina/uso terapéutico , Lipasa/sangre , Masculino , Valores de Referencia , Triglicéridos/sangreAsunto(s)
Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/cirugía , Nefropatías Diabéticas/cirugía , Dieta para Diabéticos , Trasplante de Riñón/fisiología , Lípidos/sangre , Trasplante de Páncreas/fisiología , Adulto , Apolipoproteína A-I/metabolismo , Apolipoproteínas B/sangre , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Nefropatías Diabéticas/sangre , Estudios de Seguimiento , Humanos , Factores de Tiempo , Triglicéridos/sangreRESUMEN
Type 1 and type 2 diabetes mellitus are both characterized by increased cardiovascular mortality and morbidity. Since several reports have indicated that apolipoprotein (a) [apo(a)] levels are positively associated with an increased risk of macrovascular disease, we investigated whether apo(a) levels are elevated in both types of diabetes mellitus and may thus represent an independent risk factor for atherosclerotic disease. Apo(a) concentrations in type 1 diabetic patients were not significantly different from matched controls (276 +/- 78 vs 149 +/- 46 units/l). Type 2 diabetic patients had considerably higher levels of apo(a) than matched controls (471 +/- 89 vs 221 +/- 61 units/l, P = 0.06), though the difference was not statistically significant. However, concentrations of apo(a) were above 300 units/l in 36% of type 1 and 67% of type 2 diabetic patients, but in only 14% and 25% respectively of matched control subjects. Plasma triglycerides were positively and independently correlated with apo(a) levels in both diabetic and non-diabetic subjects. On the other hand, no significant correlation was found between apo(a) levels and glycosylated haemoglobin, total cholesterol or high density lipoprotein cholesterol in any of the groups studied. In conclusion, apo(a) levels are not significantly elevated either in type 1 or type 2 diabetic patients without proteinuria and in moderate metabolic control; however, levels above 300 units/l were 2.6 times more frequent in both types of diabetes mellitus than in carefully age-, sex-, and weight-matched control subjects.
Asunto(s)
Apolipoproteínas/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Angiopatías Diabéticas/diagnóstico , Lipoproteína(a) , Adulto , Anciano , Apoproteína(a) , Biomarcadores/sangre , Colesterol/sangre , HDL-Colesterol/sangre , Angiopatías Diabéticas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Factores de Riesgo , Triglicéridos/sangreRESUMEN
A common accuracy-based standardization program is indispensable for establishing reference intervals for the clinical use of apolipoproteins. The development and distribution of reference materials and quality-control materials that do not exhibit matrix effects between methods is essential to the standardization process. We examined the suitability of lyophilized material as a common reference material for the measurement of apolipoproteins A-I and B. We determined values for apolipoproteins A-I and B in frozen and lyophilized serum pools, using different immunochemical approaches. We found little or no differences in apolipoprotein A-I values between frozen and lyophilized pools as determined by the different methods. In contrast, values for apolipoprotein B in lyophilized samples were consistently lower than those obtained for frozen samples. After adjusting for the effect of dilution due to reconstitution, the difference in the apolipoprotein B values for lyophilized as compared with frozen samples ranged from -26% to 4%, depending upon the assay method. Evidently, serum pools in lyophilized from are not a suitable matrix for reference materials for apolipoprotein B measurements but can be used for apolipoprotein A-I measurements.
Asunto(s)
Apolipoproteínas A/sangre , Apolipoproteínas B/sangre , Liofilización , Apolipoproteína A-I , Apolipoproteínas A/normas , Apolipoproteínas B/normas , Conservación de la Sangre/métodos , Colesterol/sangre , Congelación , Humanos , Estándares de Referencia , Triglicéridos/sangreRESUMEN
The appearance of seminiferous tubules and interstitial cells of children, aged 2.5 to 13 years, affected by acute lymphoblastic leukemia was analyzed in sections. The testicular biopsies were performed at the end of therapy (vincristine, prednisone, L-asparaginase, 6-mercaptopurine, intrathecal methotrexate), which was affected for the same period and at the same doses. Three age groups were considered (I, 2.5 to 5 years; II, 6 to 9 years; III, 12 to 13 years). Age groups I and II presented damage of some tubules (25-35%) and areas of degeneration. Histometric analysis performed for A type spermatogonial population gave a mean value corresponding to controls in age group I and a mean value significantly lower with respect to controls in age group II. Moreover, age group II presented a lack of increase in tubular cross section. These results suggest that there is a vulnerability both of whole tubules and of some areas of Sertoli cells and germ cels to cytotoxic-induced damage. Leydig cells appear to be the cells least sensitive to drugs, and hormonal data indicate that the hypothalamic pituitary function appears to be intact, despite chemotherapy. Long-term prospective studies of reproductive function in children receiving cancer chemotherapy are needed to determine the magnitude and duration of damage resulting from therapeutic treatment.