[The clinical spectrum of urea cycle defects in adult patients]. / Das klinische Spektrum von Harnstoffzyklusdefekten im Erwachsenenalter.

Urea cycle defects belong to the most common metabolic disorders with a cumulative incidence of 1:8000. A common trait of urea cycle defects is a disturbed detoxification of ammonia leading to hyperammonemia in the event of a high nitrogen load. Most patients develop symptoms in the neonatal period or in infancy, e. g. vomiting, seizures and disturbed consciousness. Depending on the affected enzyme and its residual activity, patients differ in the age at first presentation, the character and severity of symptoms and in the susceptibility to metabolic derangement. The presence of hyperammonemia and an altered plasma amino acid profile give the essential diagnostic clues. Since modern therapeutic measures have prolonged the life expectancy of these patients and provided the possibility of a first presentation in adulthood, patients with urea cycle defects have become an increasing challenge in internal medicine. The reported case series illustrates the heterogeneous clinical course of these disorders from childhood to adulthood.

Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver.

Cholestasis induces down-regulation of multidrug resistance protein 2 (Mrp2, symbol Abcc2), which is localized to the canalicular membrane. Given the overlapping substrate specificities of Mrp2 and multidrug resistance protein 3 (Mrp3, symbol Abcc3), we examined the hypothesis of a different subcellular and lobular localization of these members of the Mrp family in rat liver after bile duct ligation. We raised a polyclonal antibody against rat Mrp3 and detected this protein in the basolateral plasma membrane of hepatocytes surrounding the central veins and of cholangiocytes. The Mrp3 protein level was less than 2% of the expression observed after 72 hours of obstructive cholestasis. After 48 hours of bile duct ligation, the Mrp3 protein was increased and was further enhanced after 72 hours. In 72-hour-cholestatic rat liver Mrp3 was expressed, in addition, in periportal hepatocytes. However, there was a preponderance of Mrp3 in the pericentral area of the liver lobule. In Mrp2-deficient mutant rat liver, the Mrp3 protein expression was most enhanced and its zonation was lost. The Mrp3 immunostaining of cholangiocytes was preserved in cholestatic and in Mrp2-deficient mutant liver. Canalicular Mrp2 decreased and amounted to 34% of normal after bile duct ligation for 72 hours. We conclude that the hepatocellular up-regulation of Mrp3 in cholestasis together with cholangiocellular Mrp3 may compensate for the biliary obstruction and impaired canalicular Mrp2 function by clearing cholephilic anionic substances into the blood.

Influence of atorvastatin versus simvastatin on fibrinogen and other hemorheological parameters in patients with severe hypercholesterolemia treated with regular low-density lipoprotein immunoadsorption apheresis.

Low-density lipoprotein (LDL) apheresis is a treatment option in patients with coronary artery disease and elevated LDL cholesterol concentrations if maximal drug therapy fails to achieve adequate LDL cholesterol reduction. This therapy is more effective when combined with strong lipid-lowering drugs, such as atorvastatin. However, conflicting data have been published concerning the effect of atorvastatin on fibrinogen concentration. Therefore, we investigated the effect of atorvastatin compared to simvastatin on fibrinogen concentration and other hemorheological parameters in patients treated by weekly LDL apheresis. Hemorheological parameters were, studied twice in 9 patients (4 female, 5 male, 54.0+/-8.9 years) with coronary artery disease treated by weekly LDL immunoadsorption, once during concomitant simvastatin therapy (40 mg daily) and once during atorvastatin therapy (40 mg daily). Fibrinogen concentration, plasma and blood viscosity at different shear rates, parameters of red cell aggregation at stasis and shear rate 3/s, and erythrocyte filterability were determined 7 days after the last LDL apheresis after each drug had been given for a minimum for 8 weeks. Fibrinogen concentration did not show any statistically significant difference during therapy with atorvastatin (3.09+/-0.36 g/L) compared to simvastatin (3.13+/-0.77 g/L). Plasma and blood viscosity as well as erythrocyte filterability were also unchanged. The increase in red cell aggregation at stasis during atorvastatin treatment (5.82+/-1.00 U versus 4.89+/-0.48 U during simvastatin; p < 0.05) was inversely correlated with a lower high-density liprotein (HDL) cholesterol concentration (1.17+/-0.21 mmol/L versus 1.31+/-0.30 mmol/L during simvastatin; p < 0.05). LDL cholesterol showed a strong trend to lower concentrations during atorvastatin (4.14+/-0.61 mmol/L versus 4.56+/-0.66 mmol/L during simvastatin; p = 0.07), despite a reduced plasma volume treated (3,547+/-1,239 ml during atorvastatin versus 3,888+/-1,206 mL during simvastatin; p < 0.05). In conclusion, fibrinogen concentration and other hemorheological parameters were unchanged during atorvastatin compared to simvastatin therapy with the exception of a higher red cell aggregation at stasis. Therefore, with respect to hemorheology, we conclude that atorvastatin should not be withheld from hypercholesterolemic patients regularly treated with LDL immunoadsorption.

The prevention education program (PEP). A prospective study of the efficacy of family-oriented life style modification in the reduction of cardiovascular risk and disease: design and baseline data.

We describe design and baseline data of the Prevention Education Program (PEP), a home-based and family-oriented intervention program, aimed to assess and improve cardiovascular risk factors in school children and their families during an intervention period of 10 years. Started in 1994 in the German town of Nuremberg, currently 37 elementary schools (22 control and 15 intervention schools) are enrolled including 1740 families (1740 first graders, 3046 parents, and 1521 siblings). Major cardiovascular risk factors as well as dietary behavior are evaluated yearly using structured interview, physical examination, laboratory analysis, and seven-day-dietary protocols. The intervention package is applied to all families from intervention schools using regular home visits, health curricula and group sessions. Primary outcome is any reduction in cardiovascular risk factors by dietary intervention and health education compared to the control group getting only written information on the individual risk profile. The presented baseline data showing a high prevalence of cardiovascular risk factors in adults and in their children underline the need for such an intervention program in Germany.

Low-density lipoprotein (LDL) oxidizability before and after LDL apheresis.

Oxidation of low-density lipoprotein (LDL) plays a major role in the development of atherosclerosis. Hypercholesterolemia has been associated with enhanced in vitro oxidation of LDL, and lipid-lowering therapy reduces LDL oxidizability. In the present study, we investigated whether LDL apheresis performed with different techniques affects in vitro diene formation (lag phase) and modification of apolipoprotein B-100 (apoB). Baseline and posttreatment diene formation was correlated with the baseline pattern of plasma total fatty acids. We then performed a computer-simulation study to test the hypothesis that LDL apheresis-induced changes in LDL oxidizability are related to changes in the mass ratio between freshly produced and older LDL. In 19 patients aged 49+/-7 years with heterozygous familial hypercholesterolemia (FH) regularly treated with either immunoadsorption, heparin-induced LDL precipitation (HELP), or dextran sulfate (DS) adsorption, we determined lipoprotein levels, the lag phase, apoB modification, and the fatty acid pattern in plasma samples drawn at the onset and termination of one LDL apheresis. LDL apheresis significantly decreased total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, and triglycerides by 50.4%, 14.9%, 62.6%, and 33.6%, respectively. The lag phase increased by a significant mean of 9.8%; the charge of apoB was not altered. The lag phase before treatment positively correlated with the baseline concentration of plasma total palmitic, myristic, and oleic acid. The increase in the lag phase during treatment correlated with a high pretreatment concentration of lauric, linoleic, and docosahexanoic acid. The simulation study indicates that a temporary imbalance between two LDL compartments, one representing freshly secreted LDL and the other representing older LDL, could explain the observed increase in the lag phase after LDL apheresis. In conclusion, in patients with heterozygous FH, LDL apheresis performed with different techniques decreases the susceptibility of LDL to oxidation. This decrease may be related to a temporary mass imbalance between freshly produced and older LDL particles. Furthermore, the baseline fatty acid pattern influences pretreatment and posttreatment susceptibility to oxidation.

Low density lipoprotein apheresis by membrane differential filtration (cascade filtration).

Membrane differential filtration (MDF) is an apheresis technique with which atherogenic lipoproteins can be eliminated from plasma on the basis of particle size. In 52 patients (REMUKAST Study, 1,702 treatments), low density lipoprotein (LDL) cholesterol was decreased by 61%, high density lipoprotein (HDL) cholesterol by 42%, and fibrinogen by 54%. Our own results in 3 patients show decreases of 62%, 31%, and 59%, respectively; lipoprotein (a) (Lp[a]) was reduced by 58%. The elimination of atherogenic lipoproteins was accompanied by a loss of macromolecules (IgM: 55%, IgG: 27%, alpha 2-macroglobulin: 49%) resulting in improved hemorrheologic parameters. Although HDL is eliminated with each apheresis session, pretreatment concentrations of HDL cholesterol increased by 24% during regular apheresis for 1 year (26 patients, REMUKAST Study). However, preapheresis concentrations of other macroglobulins such as immunoglobulins remained decreased compared to concentrations obtained before the first apheresis session (IgM: 34%, IgG: 23%, and IgA: 16%). We conclude that MDF apheresis is an effective method to lower elevated concentrations of atherogenic lipoproteins. The concomitant loss of other macromolecules transiently improves hemorrheology but demands a close monitoring of immunoglobulin concentrations as a safety parameter.

Three low density lipoprotein apheresis techniques in treatment of patients with familial hypercholesterolemia: a long-term evaluation.

Low density lipoprotein (LDL) apheresis is a treatment option for patients with severe hypercholesterolemia not adequately responding to drug treatment who have developed coronary heart disease. We regularly treated 18 patients with immunoadsorption, 8 with heparin induced extracorporeal LDL precipitation (HELP) and 8 with dextran sulfate adsorption for a mean of 4.6 +/- 2.6 years. The effects on LDL cholesterol, high density lipoprotein (HDL) cholesterol, and lipoprotein (a) were comparable among all 3 techniques. Twelve patients were treated for longer than 5 years and 18 patients for longer than 3 years. The evaluation of coronary angiograms (23 patients) revealed a definite regression of coronary lesions in 3 patients; in all other patients, there was a halt in progression. Three patients suffered a sudden cardiac death and 1 patient a nonfatal myocardial infarction due to the occlusion of a coronary bypass. In 9 of 11 patients, no atherosclerotic lesions developed in the coronary bypasses. No severe side effect of either procedure was observed. In conclusion, aggressive lipid lowering by LDL apheresis can stabilize coronary atherosclerosis in most patients.

[Obesity stresses blood pressure and energy metabolism. What weight reduction really accomplishes]. / Ubergewicht belastet Blutdruck und Stoffwechsel. Was Abnehmen wirklich bringt.

The increase in morbidity and mortality associated with distinct obesity is based on the one hand on the direct effects of overweight on circulatory and pulmonary function, and on the other on a higher prevalence of subsequent sequelae. The latter are, in particular, arterial hypertension and metabolic disturbances, which either arise due to overweight, or which are fostered by it. This means that weight reduction is of particular importance for the treatment of the sequelae of metabolic disorders.

Course of islet autoantibody titers during Ig-immunoadsorption in a patient with newly diagnosed type 1 diabetes.

The purpose of this study was to determine whether and to what extent diabetes-specific autoantibodies can be removed from the plasma by Ig-immunoadsorption therapy. We followed the course of islet cell antibodies (ICA), insulin antibodies (I[A]A), glutamic acid decarboxylase antibodies (GADA) and antibodies to the protein tyrosine phosphatase IA-2 (IA2A) in a patient with newly diagnosed insulin-dependent diabetes mellitus (IDDM) under multiple immunoadsorption treatments over 6 months. Autoantibodies were not removed from the plasma as efficiently as expected when compared to the removal of total immunoglobulin (IgG). Whereas IgG levels were lowered by 70-90% through each immunoadsorption treatment, antibodies to insulin were reduced by an average of 83%, IA2A by 36% and GADA by only 9% directly after treatment. ICA were > 320 JDF U at diabetes onset and remained above this level. During the 6 months of multiple immunoadsorption therapies, I[A]A levels showed a 24-fold increase due to stimulation of insulin antibody production by exogenous insulin substitution, IA2A levels remained unchanged (average 6% increase), and GADA levels were reduced by an average of 39% compared to antibody titers at onset. All four antibodies were highly positive in the eluate from the immunoadsorption columns. We showed that antibodies to pancreatic islet cells can be reduced by immunoadsorption, but as for plasmapheresis the effect is incomplete and transient for most of the antibodies. If there is clinical benefit through immunoadsorption therapy--as has been shown for newly diagnosed IDDM patients treated with plasmapheresis--our data suggest that this may be due to factors other than the sufficient removal of antibodies.

Long-term effect of low-density lipoprotein apheresis on plasma lipoproteins and coronary heart disease in native vessels and coronary bypass in severe heterozygous familial hypercholesterolemia.

Low-density lipoprotein (LDL) apheresis is a potent treatment for patients with coronary heart disease and severe hereditary forms of LDL hypercholesterolemia not adequately responsive to drug treatment. Until now, the beneficial effect of aggressive reduction of LDL cholesterol by LDL apheresis on the course of coronary heart disease has been demonstrated in one 3-year study and several studies lasting 2 years. We now report on the clinical course, lipoprotein concentrations, coronary angiograms, and side effects in patients undergoing LDL apheresis for as long as 8.6 years. Thirty-four patients (21 men and 13 women) with coronary heart disease and heterozygous familial hypercholesterolemia (FH) not adequately responsive to lipid-lowering drugs received weekly (four patients biweekly) LDL apheresis for 4.6 +/- 2.6 years under diet and lipid-lowering drug therapy; after 0.5 to 3 years, simvastatin in the maximal tolerable dose was added. The baseline LDL cholesterol concentration was 6.9 +/- 1.6 mmol/L. Combined treatment in the steady state yielded a pretreatment and posttreatment LDL cholesterol concentration of 4.8 +/- 0.9 and 1.8 +/- 0.4 mmol/L, respectively. The calculated interval mean LDL cholesterol was 3.3 +/- 0.6 mmol/L. Evaluation of the coronary angiographies revealed a definite regression of coronary lesions in four patients (11.8%); in 19 patients, there was a cessation of progression. Two patients developed atheromatous lesions in bypass grafts (L.H., 60% stenosis; S.M., occlusion). Of 23 patients eligible for the scoring of anginal symptoms, five (21.7%) reported a reduction of the frequency and severity of angina pectoris. The mean coronary symptom score in 23 patients changed from 1.65 +/- 0.83 at baseline to 1.39 +/- 0.66 at the end of the study. During the whole observation period, we observed three sudden deaths, one nonfatal myocardial infarction, and five patients requiring hospital admission because of unstable angina pectoris, one of which was followed by a transluminal coronary angioplasty. Aggressive reduction of LDL cholesterol with combined LDL apheresis and drugs induced regression of coronary lesions in four of 34 patients and prevented progression in 29 patients for as long as 8.6 years. The effect on LDL and high-density lipoprotein (HDL) cholesterol and lipoprotein(a) [Lp(a)] was comparable with all three apheresis techniques. Therefore, no obvious difference between the three techniques was found regarding changes in coronary lesions.

Plasma total homocysteine levels in patients with early-onset coronary heart disease and a low cardiovascular risk profile.

Mild hyperhomocysteinemia has been associated with an increased risk to develop premature coronary heart disease. Recently, the homocysteine concentration has been positively correlated with several main cardiovascular risk factors. We addressed the issue as to whether patients with coronary heart disease and a low cardiovascular risk profile also have a higher prevalence of hyperhomocysteinemia than matched controls. Ninety-five patients (aged 50.5 +/- 6.6 years) and 34 controls (50.0 +/- 6.7 years) less than 60 years of age were selected from a sample of patients after coronary angiography. Subjects with hypertension, diabetes, and moderate or severe hyperlipidemia were excluded. We determined plasma aminothiols (total homocysteine, cysteine, and glutathione), lipoprotein fractions, fibrinogen, and uric acid, the body mass index (weight in kilograms divided by height in meters squared), and the waist to hip ratio. Furthermore, 37 healthy subjects aged 30.8 +/- 7.5 years underwent aminothiol determinations. Patients and controls were similar with regard to age and primary cardiovascular risk factors. Total homocysteine concentrations in the patient group (9.2 +/- 2.4 micromol/L) were significantly higher than in the healthy subjects (8.0 +/- 2.0 micromol/L). However, they did not differ from the levels in the age-matched controls (9.3 +/- 3.0 micromol/L). Neither total cysteine nor glutathione concentrations were significantly different between patients and controls. Male patients (n = 85) had higher mean very-low-density lipoprotein (VLDL) triglycerides (1.36 +/- 0.90 mmol/L) and lower high-density lipoprotein 3 (HDL3) cholesterol (0.75 +/- 0.21 mmol/L) than male controls (n = 28; 1.01 +/- 0.62 and 0.88 +/- 0.26 mmol/L, respectively). Female patients did not have any significant differences in lipoprotein concentrations versus the controls. Among further cardiovascular risk factors, we found a higher prevalence of central obesity in male patients. In conclusion, there was not a higher incidence of hyperhomocysteinemia among patients with premature coronary heart disease and a low cardiovascular risk profile. The higher prevalence of hyperhomocysteinemia found in other studies may be related to the primary risk factors seen in these populations, and may therefore be an indicator of the global cardiovascular risk.

[Homocysteine and coronary heart disease. Is slight or moderate homocysteinemia related to increased risk of coronary heart disease?]. / Homocystein und koronare Herzkrankheit. Geht eine gering- oder mässiggradige Homocysteinämie mit erhöhtem KHK-Risiko einher?

Homocystinuria, a rare inherited disturbance of amino acid metabolism is associated with severe atherosclerosis and thromboembolism already in childhood. The incidence of the homozygous disease of cystathionine beta synthase is estimated to be 1:200,000, that of the heterozygous form 1:300. There are, however, numerous other causes of a mild to moderate homocysteinemia, for example, a deficiency of the cofactors vitamin B6, B12 and folic acid. The question as to whether a mild to moderate elevation of homocysteine in the plasma is also associated with an increased risk of CAD has been investigated in a number of studies in recent years. In summary, however, the presently available data do not provide a basis of proof that a mild to moderate homocysteinemia is an independent risk factor for CAD. Our present knowledge suggests that only when the family history is clearly positive does it appear reasonable to undertake a diagnostic search for possible homocysteinemia.

Long term effect of LDL apheresis on coronary heart disease.

LDL-apheresis is a treatment option for patients with coronary heart disease and severe hypercholesterolemia not adequately responding to drug treatment. 34 patients (21 men, 13 women), aged 47 +/- 9 years, with coronary heart disease and heterozygous familial hypercholesterolemia not adequately responsive to lipid lowering drugs received weekly (4 patients biweekly) LDL apheresis for 3.5 +/- 2.5 years, after 0.5 - 3.0 years simvastatin in the maximally tolerable dose was added. Baseline LDL cholesterol concentration under diet and lipid lowering drugs in the patients receiving immunoadsorption, dextran sulfate adsorption and HELP apheresis was 265.4 +/- 54.9, 230.8 +/- 75.8 and 253.7 +/- 55.7 mg/dl, respectively. The calculated mean LDL cholesterol concentration of the last 5 treatments of the observation period was 123.7 +/- 22.8, 126.8 +/- 26.7 and 138.8 +/- 19.7 mg/dl, respectively. The evaluation of coronary angiographies revealed a definite regression of coronary lesions in 3 patients (8.8%), in all other patients there was a stop in progression. 3 patients died of cardiac complications during the observation period. We conclude that aggressive lipid lowering with combined LDL-apheresis and drugs can stabilize coronary atherosclerosis in most patients with refractory hypercholesterolemia.

Elimination of islet cell antibodies and glutamic acid decarboxylase antibodies II in a patient with newly diagnosed insulin-dependent diabetes mellitus.

Islet cell antibodies and glutamic acid decarboxylase II (GAD II) antibodies have been discussed in the autoimmune pathogenesis of insulin-dependent diabetes mellitus (IDDM). Hence, immunosuppressants, intravenous immunoglobulins, and plasmapheresis have been used in an effort to modulate autoimmune activity and thereby prevent the destruction of pancreatic beta-cells. We describe the autoantibody (islet cell antibody and GAD II) kinetics and clinical course in a patient with newly diagnosed IDDM treated with a specific immunoglobulin apheresis technique. Five days after the initial diagnosis a 37-year-old patient with IDDM underwent a series of seven immunoglobulin aphereses. Immunoglobulin (IgG, IgA, IgM), islet cell antibody, GAD II, and C-peptide concentrations were monitored for a time course of 74 days. Daily insulin requirements were recorded. One single immunoglobulin apheresis decreased IgG by 66.2 +/- 9.1%, IgA by 66.8 +/- 8.7%, and IgM by 57.7 +/- 12.9%. GAD II antibodies were reduced by 61.9 +/- 12.4%. The islet cell antibody titer declined from 1:32 to 1:4 after the treatment series. There were no relevant changes in the safety parameters determined nor were there any clinical side effects. The efficient decrease in islet cell antibodies and glutamic acid decarboxylase II antibodies in a patient with IDDM encourages further investigations into the impact of this treatment on the clinical course of this autoimmune disorder.

Efficacy and safety of immunoglobulin apheresis.

Extracorporeal procedures such as plasmapheresis or protein a apheresis have been applied successfully to remove autoantibodies in the treatment of severe forms of various autoimmune diseases. A newly developed immunoapheresis technique that uses columns containing polyclonal anti human immunoglobulin (Ig) antibodies was investigated in four patients with idiopathic thrombocytopenic purpura (ITP). A series of two to four treatments were performed, and the period between the two series was dependent on the actual thrombocyte count. A total of 38 treatments was carried out. During the first apheresis, IgG declined to a mean of 52.7% of the initial concentration. The IgG subclasses one through four were decreased to the same extent. The IgA was lowered to 64.4%, and IgM was lowered to 66.7%. A series of four aphereses yielded a 75-80% decline of the different Ig species. A further decrease in Ig would have been possible, but was not aimed at in this study. All Ig fractions reincreased between the two series. In two patients, a rise in thrombocytes as a response to treatment was observed. Apart from three hypotensive reactions and one episode of hypocalcemia, no further side effects occurred in 38 treatments. The authors conclude that Ig apheresis with anti human Ig antibodies is an effective and safe form of treatment. Its effect on the clinical course of autoimmune diseases merits further investigation.

Short- and long-term effects on serum lipoproteins by three different techniques of apheresis.

Low-density lipoprotein (LDL) apheresis is applied in patients with coronary heart disease because of severe inherited forms of hypercholesterolemia, for which dietary and combined drug treatment cannot lower LDL cholesterol concentrations less than 130 mg/dl. The following article describes the changes in lipoprotein levels in a total of 19 patients undergoing weekly LDL apheresis. Immunoadsorption, operating with polyclonal antibodies against apolipoprotein B-100, was used in 6 patients. Five patients were put on heparin-induced extracorporeal LDL precipitation (HELP) therapy; 6 received dextran sulfate adsorption treatments. Under steady-state conditions a single treatment reduced LDL cholesterol by 149 + or - 3 mg/dl with immunoadsorption, 122 + or - 2 mg/dl with HELP, and 124 + or - 18 mg/dl with dextran sulfate adsorption. Lipoprotein (a) (Lp[a]) declined by 52 to 65%. Very low density lipoprotein (VLDL) cholesterol and VLDL triglycerides declined by 45 to 55% because of the activation of lipoprotein lipase and precipitation during the HELP procedure. In all procedures, there was a small reduction in the different high-density lipoprotein fractions, which had returned to normal after 24 h. The long-term HDL3 cholesterol levels increased significantly. During all procedures there was a decrease in the molar esterification rate of lecithin cholesterol acyltransferase activity. All changes in lipid fractions were paralleled by changes in the corresponding apolipoprotein levels. It is concluded that all three techniques described are powerful tools capable of lowering LDL cholesterol in severe hereditary forms of hypercholesterolemia. In HELP and dextran sulfate adsorption, the amount of plasma is limited by the elimination of other plasma constituents. Immunoadsorption may thus be preferred in very severe forms of hypercholesterolemia.