Walter Riesen

Increased serum low-density lipoprotein cholesterol in men treated short-term with the diuretic chlorthalidone☆☆☆

The effect of the diuretic chlorthalidone (100 mg/day for 6 weeks) on serum lipoproteins was evaluated in 37 subjects. In 19 men with essential hypertension (aged 41 +/- 3 yr), 8 normal men (26 +/- 3 yr), or all of these men considered together, chlorthalidone significantly increased serum low density lipoprotein--cholesterol (LDL-C) by 20% (p less than 0.05 to less than 0.01). There was also a tendency for increased LDL-C in seven postmenopausal women (+/- 15%) but not in three premenopausal women with essential hypertension. High density lipoprotein--cholesterol was not significantly changed in hypertensive women or normal men and decreased slightly (p less than 0.05) in hypertensive men. Apolipoproteins A-I, A-II, and B were not changed significantly in women or men. Diuretic-induced lipoprotein alterations were not associated with altered plasma volume and unrelated to variations in serum potassium, glucose, insulin levels, blood pressure, and body weight. Short-term diuretic therapy with chlorthalidone may increase serum LDL-C in young or middle-aged men with normal or high blood pressure.

Diuretic treatment and serum lipoproteins: Effects of tienilic acid and indapamide

SummaryTreatment with the commonly used diuretic, chlorthalidone, has previously been found to increase the serum low-density-lipoprotein cholesterol (LDL-C) fraction. Therefore, the effects of two new agents, tienilic acid (a combined diuretic-uricosuric) and indapamide on serum lipid and lipoprotein levels were assessed. Six weeks of treatment with tienilic acid, 250 mg/day, markedly decreased serum uric acid and significantly increased LDL-C and triglycerides in 16 men. In contrast, indapamide 2.5 mg/day, had no apparent influence on serum lipids or lipoproteins in 18 men.ZusammenfassungIn einer früheren Studie fanden wir, daß eine Kurzzeitbehandlung mit dem Diuretikum Chlorthalidon eine Erhöhung der Serum Low-Density-Lipoprotein-Cholesterin Fraktion (LDL-C) bewirkt. In der vorliegenden Arbeit wurde der Einfluß von zwei neueren Substanzen auf die Serum Lipidund Lipoprotein-Spiegel untersucht. Dabei handelte es sich um Tienilsäure, das gleichzeitig diuretische und uricosurische Wirksamkeit besitzt, sowie um Indapamid. Eine 6-wöchige Behandlung mit Tienilsäure in einer Dosis von 250 mg/Tag bewirkte bei 16 Männern eine deutliche Abnahme der Serum-Harnsäure und eine signifikante Zunahme von LDL-C und Serum-Triglyzeriden. Dagegen hatte eine gleichlange Behandlung mit Indapamid in einer Dosis von 2,5 mg/Tag bei 18 Männern keinen erkennbaren Einfluß auf Serum-Lipide oder -Lipoproteine.

Quantitation of the major apoproteins of human high density lipoproteins by solid phase radioimmunoassay

Serum high density lipoprotein (HDL) plays a major role in the transport and metabolism of cholesterol which is mediated through its interaction with the enzyme lecithin: cholesterol acyltransferase (LCAT) [l] . Evidence has also been presented that HDL facilitates the uptake of cholesterol from peripheral tissues and the clearance of cholesterol from arterial wall [2] . Furthermore, decreased HDL and HDL cholesterol levels were shown to be correlated to the incidence of coronary heart disease [3,4] . HDL contains two major apoprotein components which have been designated apoprotein A-I (apo A-I) and apoprotein A-II (apo A-II) [5-71. These two protein moieties account for 90% of the total protein content of HDL [8] , and are believed to be of central importance not only for the structural but also for the functional integrity of HDL. Apo A-I has been shown to activate LCAT in vitro [9] and to remove cholesterol from the aortic smooth muscle cells [lo] . Rapid and precise measurement of apo A-I and apo A-II would be valuable in elucidating their structural and physiological functions. To this end we have

Antibodies against lipoproteins in man. Occurrence and biological significance.

SummaryHuman antibodies against lipoproteins can be divided into three types according to occurrence, specificity and the effect they exert on the concentrations of the serum lipoproteins and lipids.1. Isoantibodies against genetically determined polymorphisms of the low-density and high-density lipoproteins occurring almost exclusively in sera of patients who have received multiple transfusions of blood or plasma. They are apparently clinically irrelevant because they provoke no complications after transfusions and do not alter the lipoprotein levels.2. Autoantibodies against the lipid portion of lipoproteins. These may be monoclonal immunoglobulins with specificity towards lipids in multiple myeloma or polyclonal antibodies in essential hyperlipidemia. The antigen determinant is presumably a phospholipid. This type of autoantibody is of clinical interest because it is always associated with hyperlipidemia which can be ascribed to a retardation of the lipolysis due to a blockade of the enzyme receptors on the lipoproteins by the autoantibodies.3. Autoantibodies against the protein moiety (apoproteins) of lipoproteins, in either monoclonal or polyclonal form in multiple myeloma and other paraproteinemias, in seronegative rheumatoid arthritis and in cancer. These autoantibodies are characteristically associated with a hypolipidemia which is thought to be caused by an increase in the catabolism of the lipoprotein-autoantibody complexes.ZusammenfassungHumane Antikörper gegen Lipoproteine lassen sich auf Grund ihrer Entstehung, ihrer Spezifität und ihres Einflusses auf die Lipoprotein- und Lipidkonzentration des Serums in drei Typen unterteilen.1.Isoantikörper gegen genetisch determinierte Polymorphismen der “low density” und “high density” Lipoproteine, die vor allem im Serum Polytransfundierter auftreten. Sie sind klinisch irrelevant, da sie weder zu Transfusionszwischenfällen noch zu einer Veränderung des Lipidstoffwechsels führen.2.Autoantikörper gegen den Lipidanteil der Lipoproteine. Es handelt sich dabei entweder um monoklonale Immunglobuline mit einer Lipidspezifität bei multiplem Myelom oder um polyklonale Autoantikörper bei „essentieller“ Hyperlipidämie. Die Antigendeterminante ist vermutlich ein Phospholipid. Klinisch ist dieser Typ von Autoantikörper deshalb von Bedeutung, weil er stets mit einer Hyperlipidämie einhergeht, die ihrerseits auf eine Verzögerung der Lipolyse infolge einer Blockierung der entsprechenden Enzym-Receptoren durch den Autoantikörper zurückgeführt wird.3.Autoantikörper gegen den Proteinanteil (Apoprotein) der Lipoproteine. Sie treten als monoklonale oder polyklonale Antikörper vor allem bei Myelom und anderen Paraproteinämien, bei entzündlichem Rheumatismus mit negativer Rheumaserologie und bei bösartigen Geschwülsten in Erscheinung. Dieser Typ von Autoantikörper geht charakteristischerweise mit einer Hypolipidämie einher, wobei in diesen Fällen ein beschleunigter Katabolismus der Lipoprotein-Autoantikörper-Komplexe für die Verminderung der Serumlipide und Lipoproteine verantwortlich ist.

Reduced LDL- and increased HDL-apoproteins in patients with hypercholesterolaemia under treatment with bezafibrate.

The effect of bezafibrate on serum lipids, lipoproteins and the apoproteins A-I, A-II and B was studied in 18 patients with primary hypercholesterolaemia. Total cholesterol was lowered by 20% (P less than 0.05), LDL-cholesterol by 24% (P less than 0.05), and apo B by 14% (P less than 0.05), which is comparable to the effect obtained with anion exchange resins but with far fewer side-effects. HDL increased significantly during bezafibrate treatment both by measurement of HDL-cholesterol (+54%, P less than 0.05) and by the determination of HDL-apoproteins A-I (+ 19%, P less than 0.05) and A-II (+ 23%, P less than 0.05). This increase of HDL and the decrease of triglycerides was maintained for 6 weeks of placebo treatment after cessation of bezafibrate, while serum total and LDL cholesterol as well as apo B returned to their baseline levels.

A human myeloma protein with specificity against dinitrophenyl and nucleic acid derivatives

Abstract Immunochemical studies on a human IgG myeloma protein which precipitates with DNA-protein-conjugates are reported. This monoclonal immunoglobulin showed crossreactions with protein conjugates of a number of other compounds such as pyrimidines, purines, nucleotides and nucleosites. In addition it reacted with single stranded DNA and, to a much lesser extent, with native DNA. No reaction, however, was detectable with the free haptens DNA-lysine and 5-acetyluracil-1-caproic acid and with nucleotides and nucleosides. The binding activity could be localized in the Fab fragment of the immunoglobulin molecule.

Anti‐β‐Lipoprotein Activity of Human Monoclonal Immunoglobulins

Abstract. Human sera containing monoclonal immunoglobulins were screened for antibody‐like activity against lipoproteins by immunodiffusion tests and the passive hemagglutination of low‐density lipoprotein (LDL) coated red cells. Weak positive reactions with human LDL were observed in about 10% of fresh sera. All sera reacted with the patients own LDL and did not display any specificity against the 8 iso‐antigens of the Ag‐system. No reaction with human high‐density lipoproteins (HDL) and with LDL of animals could be detected. In the case of IgA and IgG myeloma proteins the binding activity was due to the M‐component. The Fab fragment obtained after enzymatic digestion of myeloma IgG with papain could be shown to be the reactive part of the immunoglobulin molecule. The described antibody‐like activity was associated with hypolipidemia.

Hypo‐β‐Lipoproteinaemia Associated with Auto‐Antibodies Against β‐Lipoproteins

Abstract In a 19 year old patient, presenting a severe hypo‐β‐lipoproteinaemia and a polyclonal IgG gammopathy, all known causes of hypo‐β‐lipoproteinaemia could be excluded. The patients IgG reacted with homologous and autologous low density lipoproteins like an antibody, the binding activity being localized in the Fab fragment of the IgG molecule. The reactive part of LDL appeared to be the protein moiety (apoprotein LDL). Turnover studies with radioiodinated LDL showed that the reduction of the LDL concentration in the patients serum was due to a decreased synthesis of LDL and also possibly to an immunelimination of LDL.

[Secondary hyperlipoproteinemia induced by diuretic therapy (author's transl)].

In order to study the degree and pathogenic aspects of the secondary hyperlipoproteinemia in patients under diuretic therapy we measured serum lipids, lipoproteins and the apoproteins A1, A2 and B in 12 adults after a 4 weeks placebo period and 6 weeks of treatment with chlorthalidon. There was a significant increase in atherogenic low density lipoproteins (LDL), (18%, P less than 0.05) whereas the high density lipoprotein-cholesterol Apo A1 and A2 levels were not significantly altered. The same was true for the total serum triglyceride- and the very low density lipoprotein- and LDL-triglyceride levels. The activity of lipoprotein lipase and hepatic triglyceride lipase was slightly but not significantly increased. A delayed LDL-catabolism seems to be the most probable pathogenic mechanism underlying the Chlorthalidon-induced hyperlipoproteinemia.SummaryIn order to study the degree and pathogenic aspects of the secondary hyperlipoproteinemia in patients under diuretic therapy we measured serum lipids, lipoproteins and the apoproteins A1, A2 and B in 12 adults after a 4 weeks placebo period and 6 weeks of treatment with chlorthalidon. There was a significant increase in atherogenic low density lipoproteins (LDL), (18%,P<0.05) whereas the high density lipoprotein-cholesterol, Apo A1 and A2 levels were not significantly altered. The same was true for the total serum triglyceride- and the very low density lipoprotein- and LDL-triglyceride levels. The activity of lipoprotein lipase and hepatic triglyceride lipase was slightly but not significantly increased.A delayed LDL-catabolism seems to be the most probable pathogenic mechanism underlying the Chlorthalidon-induced hyperlipoproteinemia.ZusammenfassungZur Abklärung von Ausmaß und Pathogenese der Diuretikainduzierten sekundären Hyperlipoproteinämie wurden bei 12 Probanden die Serumlipide und -lipoproteine, die Apoproteine A1, A2 und B sowie die lipolytischen Enzyme Lipoproteinlipase und hepatische Triglyzeridlipase nach einer vierwöchigen Placeboperiode und nach 6 Wochen Behandlung mit Chlorthalidon untersucht.Außer einem signifikanten Anstieg der atherogenen low density Lipoproteine (LDL), (der LDL-Cholesteringehalt nahm um 18% zu,P<0,05) waren keine signifikanten Lipoproteinveränderungen faßbar. Insbesondere blieb die high density Lipoprotein-Konzentration sowohl gemessen am HDL-Cholesteringehalt wie an den beiden Apoproteinen A1 und A2 nahezu unverändert. Der leichte statistisch nicht signifikante Anstieg der Serumtriglyzeride war begleitet von einer ebenso wenig signifikanten Zunahme der Aktivität der Lipoproteinlipase und der hepatischen Triglyzeridlipase. Pathogenetisch dürfte der sekundären Hyperlipoproteinämie unter Chlorthalidon am ehesten eine Abbaustörung der LDL zugrunde liegen.

REVERSAL OR PREVENTION OF DIURETIC-INDUCED ALTERATIONS IN SERUM LIPOPROTEINS WITH BETABLOCKERS

In 18 patients with essential hypertension serum low density lipoprotein cholesterol (LDL-C) was significantly (P less than 0.001) increased following short-term chlorthalidone therapy, but not during combination therapy with chlorthalidone and a betablocker. This tendency was similar in two subgroups which were studied with an inverse sequence of drug administration. In Group I (11 men), a 22% increase (P less than 0.01) in LDL-C during chlorthalidone monotherapy was restored to normal 6 weeks after addition to a betablocker to the diuretic; in Group II (5 men, 2 postmenopausal women) LDL-C levels were increased by 41% (P less than 0.05) 6 weeks after withdrawal of the betablocker from the combination therapy. No significant changes occurred during either the treatment phase in high density lipoprotein cholesterol or apoprotein B levels. It is concluded that combination therapy with a betablocker may prevent or reverse an increase in serum LDL-C associated with short-term chlorthalidone monotherapy.