[Disturbance of synthesis of cholesterol and its precursors in clinically serious conditions]. / Porucha syntézy cholesterolu a jeho prekurzoru u klinicky závazných stavu.

OBJECTIVE: The aim of the study was to elucidate the role and importance of hypocholesterolemia in clinically serious conditions. It was a monocentric, prospective clinical study. MATERIAL AND METHODS: Two groups of patients were recruited to the study--one group were patients with coronary heart disease (CHD), who underwent miniinvasive cardiosurgical operation without extracorporeal circulatio (n = 17) and one group of patients, who sustain polytrauma (n = 19). Thirty six patients were recruited into the study. We performed the determination of sterols (total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerols), and their precursors (beta-sitosterol, campesterol, lathosterol, skvalen), interleukin IL-6 and cortisol in the blood serum. The short version of ACTH stimulation test was performed. The oxidative burst of granulocytes was evaluated. The blood samples were taken on the day of admission, the first, the fourth and the eighth post-operative and post-traumatic day. RESULTS: There was a significant decline of total cholesterol (TC) and LDL-cholesterol level with full recovery during observed period. There was a decline of cholesterol synthesis (lathosterol and lathosterol/cholesterol ratio) together with a decline of total cholesterol. There was a significantly negative correlation between IL-6 level and total cholesterol. Despite no confirmation of disturbance of adrenal function, there was a significantly positive correlation between lathosterol/cholesterol ratio (a de novo cholesterol synthesis marker) and cortisol level after the ACTH stimulation test. There was a significant breakdown of bactericidal function of granulocytes along with a decline of cholesterol level. CONCLUSION: There was decline of endogenous cholesterol synthesis in clinically serious conditions. The cholesterol synthesis rate is negatively influenced by IL-6 level. The rate of endogenous cholesterol synthesis positively correlated with cortisol production by the adrenals and with bactericidal function of granulocytes.

Lipoprotein apheresis in the treatment of dyslipidaemia - the Czech Republic experience.

In 1984, we started using therapeutic plasmapheresis (plasma exchange) as a method of extracorporeal lipoprotein elimination for the treatment of hypercholesterolemic patients. We evaluated the results of long-term therapy in 14 patients, 8 men and 6 women. The average age was 55.6+/-13.2 (range 28-70), median 59.5 years. 14 patients were diagnosed with familial hypercholesterolemia (FH): 5 homozygous, 9 heterozygous. Ten patients in the group were treated using immunoadsorption lipoprotein apheresis and 4 using hemorheopheresis. Immunoapheretic interventions decreased LDL-cholesterol (82+/-1 %), ApoB (73+/-13 %) and even Lp(a) by 82+/-19 %, respectively. Selected non-invasive methods are important for long-term and repeated follow-up. Carotid intima-media thickness showed improvement or stagnation in 75 % of the patients. Biomarkers of endothelial dysfunction such as endoglin (in the control group: 3.85+/-1.25 microg/l, in lipoprotein apheresis-treated hypercholesterolemic individuals 5.74+/-1.47 microg/l), CD40 ligand (before lipoprotein apheresis: 6498+/-2529 ng/l, after lipoprotein apheresis: 4057+/-2560 ng/l) and neopterin (before lipoprotein apheresis: 5.7+/-1.1 nmol/l, after lipoprotein apheresis: 5.5+/-1.3 nmol/l) related to the course of atherosclerosis, but did not reflect the actual activity of the disease nor facilitate the prediction or planning of therapy. Hemorheopheresis may improve blood flow in microcirculation in familial hypercholesterolemia and also in some other microcirculation disorders via significantly decreased activity of thrombomodulin (p<0.0001), tissue factor (p<0.0001), aggregation of thrombocytes (p<0.0001) and plasma and whole blood viscosity (p<0.0001). In conclusion, lipoprotein apheresis and hemorheopheresis substantially lowered LDL-cholesterol in severe hypercholesterolemia. Our experience with long-term therapy also shows good tolerance and a small number of complications (6.26 % non-serious clinical complications).

Antioxidant defense system in familial hypercholesterolemia and the effects of lipoprotein apheresis.

Oxidative stress is thought to play an important role in the pathogenesis of disorders associated with atherosclerosis. Alpha-tocopherol is considered to be an effective lipophilic antioxidant, which protects lipid membranes against peroxidation and thus prevents cell damage by reaction with free radicals. However, measurement of alpha-tocopherol concentration in serum does not reflect the content of α-tocopherol in membranes whereas erythrocyte alpha-tocopherol may be good indicator of antioxidative status. Therefore a simple isocratic reversed phase HPLC method has been developed and validated for the determination of alpha-tocopherol in human erythrocytes in a clinical setting. The content of alpha-tocopherol in human erythrocyte membrane and lipoperoxidation were studied in patients with severe hypercholesterolemia treated by lipoprotein apheresis. The group of hypercholesterolemic patients (n = 14) treated by lipoprotein apheresis was compared to healthy adult normolipidemic controls. After lipoprotein apheresis, the content of in membrane alpha-tocopherol did not change significantly despite decreased tocopherol in serum and lipoprotein fractions. We observed significantly decreased lipoperoxidation as revealed by serum TBARS, representing end products of lipid peroxidation, which increased from third day afterwards and remained significantly higher in comparison to controls until the next LDL-apheresis. We conclude that aggressive lipid lowering procedure with lipoprotein apheresis was associated with favorable transient decrease of lipoperoxidation. Simultaneously the cell membrane bound antioxidative defense mechanisms as reflected by the content of alpha-tocopherol in human erythrocyte membrane where not depressed in spite of its decreased plasma lipid carrier. Another variables involved remain to be investigated.

Bioanalysis of PUFA metabolism and lipid peroxidation in coronary atherosclerosis.

Twenty eight men (age 34-77 years) who underwent an elective coronary angiography for coronary artery disease (CAD), were studied. They were divided into group A (luminal narrowing < 50%; n = 11) and group B (luminal narrowing > 50%; n = 17). Capillary gas chromatography was used for determination of fatty acids. Retinol and alpha-tocopherol were analyzed by reversed-phase high-performance liquid chromatography (HPLC), other parameters were determined spectrofluorometrically and spectrophotometrically. Severe coronary atherosclerosis in group B was associated with higher serum low density lipoprotein/high density lipoprotein (LDL/HDL) cholesterol ratio, triacylglycerols, and phospholipids (P < 0.05). Erythrocyte membrane fatty acids C14:0, C16:1 and C22:6n3 were significantly higher in group B (P < 0.05). We found significantly higher plasma polyunsaturated fatty acids (PUFA) C18:3n6 in group B, whereas plasma linoleic acid was not changed significantly. There was a significant increase of IDL-C18:0, LDL-C14:0 and HDL-C22:6n3 PUFA in group B. We conclude that disturbances in saturated fatty acids (SUFA) and PUFA metabolism are associated with coronary atherogenesis. Such abnormalities may include enhanced extrahepatic transport of C14:0 SUFA via LDL and its incorporation into cell membranes, and enhanced clearance of anti atherosclerotic C22:6n3 PUFA via serum HDL.

[Cholestatic icterus during parenteral nutrition and the therapeutic effect of enteral feeding--case report]. / Cholestatický ikterus na parenterální výzive a lécebný vliv enterální aplikace--kazuistika.

An acute operation was made on a 56-year woman for inflammatory perforation of colon. A series of repeated operations followed due to relapsing iatrogenic intestinal fistula and peritonitis. From the day 70 the patient was treated at the Intensive Metabolic Care Unit of the Gerontological and Metabolic Clinic of Faculty Hospital in Hradec Králové. Having cured the septic shock the authors prepared the patient to a reconstruction operation on alimentary tract by administering parenteral nutrition, treating the wounds and by motion rehabilitation. From day 150 on the patient was treated with low doses of enteral nutrition into the segment of intestine between the fistulas, in connection with the subsequent decrease of two-month lasting hyperbilirubinemia of 200-260 mumol/l. A successful reconstruction of the alimentary tract was performed on the day 205 of the treatment with the time lapse of 146 days after the last surgical intervention. A three-fold anastomosis on small intestine and a resection of the fistula on the transversal colon was made. The post-operation fistula was healed-up conservatively, while the parenteral nutrition continued, as verified on day 246 by enteroclysis. The paper draws attention to the importance of conservative metabolic care in the therapy of dishiscences of intestinal anastomoses not treated by acute surgery in time. A favourable additive effect of enteral nutrition on the persisting cholestasis during parenteral nutrition is discussed.

Extracorporeal LDL cholesterol elimination (25 years of experience in CZ).

In the Czech Republic the therapy of severe familial hypercholesterolemia (FH) by extracorporeal elimination using LDL-apheresis (immunoadsorption) and hemorheopheresis is concentrated into one center. The authors evaluate the long-term therapy (3-12 years, median 7,25) in 12 patients with FH - 3 homozygous, 9 heterozygous; Fredrickson type IIa, IIb (treated: 9 by LDL-apheresis and 3 by hemorheopheresis). Immunoapheretic interventions decrease LDL-cholesterol, ApoB and even Lp(a) by about 82 +/- 1; 73 +/- 13; 82 +/- 19 %, respectively. Selected non-invasive methods are important for a long-term and repeated follow-up. Carotid intima-media thickness showed improvement or stagnation in 75% of the patients. The level of some adhesive molecules, cytokines, endoglin and some coagulation functions were measured, but no universally accepted biomarkers informing of the actual activity of the disease were found to predict and plan the therapy. A program for procedure planning with the use of Microsoft® Excel for Windows® was developed. In summary, LDL-apheresis and hemorheopheresis substantially lower LDL-cholesterol in FH. Our experience with long-term therapy also shows good tolerance and a small number of complications (5,6% of clinically irrelevant side-effects). Hemorheopheresis may improve blood flow in microcirculation in familial hypercholesterolemia and also in some other disorders of microcirculation.