Relationships between homocysteine and related amino acids in chronic hemodialysis patients.

AIMS: Homocysteine (Hcy) has emerged as an important risk factor for atherosclerotic disease. Elevated levels in chronic dialysis patients may contribute to high vascular mortality, but little is known about levels of related amino acids in this group. In an observational study in the clinical setting we sought to document these. METHODS: In 114 hemodialysis patients pre-dialysis total plasma homocysteine, vitamin B12 and red blood cell (RBC) folate concentrations were measured. In a subgroup of patients (n = 42), other plasma amino acids were measured pre- and post-dialysis. All patients were routinely taking oral folic acid supplements (1.2 mg per week). RESULTS: Elevated homocysteine concentrations were found in all patients (geometric mean 33.1 umol/l, range 13.8 - 69.2 umol/l, laboratory reference range (RR) 3-13 umol/l). RBC folate levels were high (1223 +/- 54.5 nmol/l mean +/- SE, RR 300 - 710 nmol/l) and inversely related to pre-dialysis plasma Hcy (r = -0.44, p < 0.001). Hcy levels were not related to vitamin B12 levels. A history of vascular disease was not associated with higher concentrations of Hcy. Hcy clearance on dialysis was substantial (mean Hcy reduction 33 +/- 14%). While plasma methionine levels were normal, serine levels were significantly lower than the reference range (59.3 +/- 2.39 umol/l (mean +/- SE, RR 70 - 195 umol/l)) and directly related to levels of glycine (r = 0.52, p < 0.001). Glycine levels were within normal range. Although overall levels were low, higher serine levels were related to elevated homocysteine (r = 0.42, p < 0.01). Dialytic loss of glycine, serine and methionine was moderate. CONCLUSION: An inverse association between RBC folate and homocysteine levels extended to 3 times the upper limit of normal for folate, suggesting a role for high dose folic acid supplementation in the treatment of renal-failure related hyperhomocysteinemia. Low serine levels are expected as it is primarily synthesized in the kidney. The direct relationship between serine and homocysteine is consistent with the reported lack of effect of serine supplements on high Hcy levels.

Are causes of death predictable?

A random sample of death records of adult males from 1967 to 1970 was chosen from the South Australian Registry of Births, Deaths, and Marriages. The natural parents of these individuals were identified by cross-reference to birth certificates, and an extensive search was made of the death records for these parents. In this manner random families were selected for which, where possible, the cause of death and length of life of each family member were determined. From the information pertaining to the stated cause of death, each individual was assigned to one of five death categories.

A cautionary tale.

Type 2 diabetes is increasing in prevalence and is predominantly managed in general practice. This series contains case histories raising some of the metabolic problems which may be encountered in the management of these patients and indicates some of the many issues, other than glycaemic control, that need to be considered.

Monitoring glucose control.

Type 2 diabetes is increasing in prevalence and is predominantly managed in general practice. This series contains case histories raising some of the metabolic problems which may be encountered in the management of these patients and indicates some of the many issues, other than glycaemic control, that need to be considered.

A case of syndrome X.

Type 2 diabetes is increasing in prevalence and is predominantly managed in general practice. This series contains case histories which deal with some of the metabolic problems that may be encountered in the management of these patients and indicates some of the many issues, other than glycaemic control, that need to be considered.

Measurement of plasma LDL cholesterol in patients with diabetes.

OBJECTIVE: To assess the accuracy of plasma LDL cholesterol concentrations estimated by the Friedewald formula and a direct immunoseparation method by comparison with a reference ultracentrifugation procedure in patients with diabetes. RESEARCH DESIGN AND METHODS: Fasting plasma samples with triglyceride concentrations < 4.5 mmol/l were collected from 100 patients with diabetes (28 type I and 72 type II) and LDL cholesterol concentrations were compared by the three methods. RESULTS: LDL cholesterol values determined by the reference beta-quantitation procedure were highly correlated with both the Friedewald formula (r = 0.96) and a direct immunoseparation method (r = 0.92). Calculated (Friedewald) LDL cholesterol coincided with the reference method with < 10% error in 74% of the total diabetic group (82% of type I and 68% of type II diabetic patients). However, agreement between the direct LDL cholesterol and reference methods was significantly less (P = 0.02), with only 44% of patients having an error of < 10% (52% of type I and 41% of type II diabetic patients). The direct immunoseparation method for LDL cholesterol showed a positive bias with increasing triglyceride concentrations, particularly for patients with type II diabetes. CONCLUSIONS: In the group of diabetic patients studied with plasma triglyceride concentrations < 4.5 mmol/l, the Friedewald formula provided an accurate estimation of LDL cholesterol. The direct immunoseparation method significantly overestimated LDL cholesterol at triglyceride levels between 2 and 4.5 mmol/l.

Case studies in lipid management.

Seven cases are described that highlight practical aspects of lipid management in Australian general practice. The major issues are strategies for obtaining reliable lipid values, interpreting the lipids in the context of overall cardiovascular risk, and appropriate use of pharmacotherapy in high risk patients.

Sugar and fat, a recipe for disaster. New guidelines for the pharmacological management of diabetic dyslipidaemia.

Australia is embarking upon a more sophisticated approach to lipid-lowering, which is of particular relevance to those with diabetes. Diabetic dyslipidaemia is common and is usually managed in general practice. A step approach focusing on case finding, confirmation of diagnosis, lifestyle modification and pharmacological intervention should be cost effective in this high risk population (Figure 4). Although the focus of this review has been on diabetic dyslipidaemia, management should always consider overall cardiovascular risk.

Lipolysis-induced partitioning of free fatty acids to lipoproteins: effect on the biological properties of free fatty acids.

Free fatty acids (FFA) released during the lipolysis of triglyceride (TG)-rich lipoproteins in vivo are generally believed to be bound to serum albumin. When hypertriglyceridemic (HTG) sera were lipolyzed in vitro by purified bovine milk lipoprotein lipase (LpL), there was an 11- to 18-fold increase in serum FFA levels, and a major portion (> 80%) of the FFA in serum was partitioned to lipoprotein fractions. The greatest portion (33%) of FFA in lipolyzed HTG serum was associated with newly formed flocculent remnants that banded just below low density lipoproteins (LDL) in the density gradient tube. Very low density lipoprotein (VLDL), LDL, and high density lipoprotein (HDL) fractions in lipolyzed HTG serum contained 18- to 29-times more FFA molecules than those in prelipolysis serum. Analysis of the fatty acyl chain composition of FFA in lipolyzed HTG serum showed that the extent of partitioning of saturated FFA into the lipoprotein fractions relative to that of polyunsaturated FFA was about 4.5- to 11-times greater than that partitioned into the free protein fraction; most (84%) of FFA partitioned into flocculent remnants were saturated fatty acids. In vivo lipolysis of TG-rich lipoproteins in HTG subjects, induced by heparinization, resulted in only a small (2.8-fold) increase in serum FFA and little or no increase in the partitioning of FFA to lipoproteins. However, in vitro incubation of the postheparin serum at 37 degrees C for 90 min resulted in a 2.9- to 6.8-fold increase in the serum FFA level and the partitioning of > 66% of total serum FFA into lipoprotein fractions. Studies of the interaction of various plasma fractions from control and in vitro lipolyzed HTG serum with cultured mouse peritoneal macrophages (MPM) showed that FFA partitioned to lipoprotein fractions were highly cytotoxic to cultured MPM, whereas FFA partitioned to albumin at a 10 x greater concentration were not cytotoxic. The cytotoxic potencies of FFA bound to lipoproteins and albumin were further compared after in vitro incorporation of FFA (oleic acids) into LDL and to albumin. FFA bound to LDL but not to albumin were cytotoxic to cultured MPM; the cytotoxicity of FFA bound to LDL was more closely related to the FFA to LDL-cholesterol molar ratio than to the total FFA concentration in the culture dish. The ability of FFA bound to LDL and albumin to induce foam cell formation was studied in THP-1 monocyte-derived macrophages, which were less susceptible to cytotoxicity produced by FFA bound to LDL than MPM.(ABSTRACT TRUNCATED AT 400 WORDS)

Atherogenicity of triglyceride-rich lipoproteins.

The measurement of plasma triglyceride levels further refines the estimation of the risk of coronary heart disease in patients with either high levels of low-density-lipoprotein cholesterol or a high ratio of low-density-lipoprotein to high-density-lipoprotein cholesterol. Plausible mechanisms underlying the role of triglyceride-rich lipoproteins in the pathogenesis of coronary heart disease include the lipid loading of macrophages and accelerated thrombosis resulting from increases in both procoagulant and antifibrinolytic activity. Further research should include methods for better quantifying atherogenic subspecies of triglyceride-rich lipoproteins and intervention studies designed to assess the effect on the occurrence of coronary heart disease of lowering triglyceride or increasing HDL-cholesterol levels.

Lipoprotein profiling by high performance gel chromatography.

High performance gel chromatography (HPGC) was used to separate lipoproteins on the basis of their size and to generate lipoprotein profiles for plasma collected from patients with different lipoprotein phenotypes. These profiles provided a direct measurement of low density lipoprotein (LDL)-cholesterol which was more precise than LDL-cholesterol values calculated by the Friedewald equation. In addition, LDL-cholesterol concentrations were obtained in patients with combined hyperlipidemia in whom LDL-cholesterol could not be accurately calculated by the Friedewald equation. The response of LDL-cholesterol to the drug gemfibrozil was reliably monitored and in addition changes in LDL particle size could be assessed from the LDL apolipoprotein B/cholesterol ratio. HPGC also assisted in the diagnosis of type III hyperlipidemia by revealing a characteristic lipoprotein profile. HPGC-derived lipoprotein profiles provided additional useful clinical information for combined hyperlipidemia (Fredrickson lipoprotein phenotypes IIb, III).