[Genetic diseases of lipid storage and related disorders]. / Genetisch bedingte Lipidstoffwechselstörungen und Grenzgebiete.

A general account is given in this paper of genetic disorders of lipid metabolism so far known together with marginally related lesions with particular reference being made to amino acid metabolism. Somewhat closer attention is given, in this context, to pathologico-anatomic findings.

[Spongious glioneuronal dystrophy with diffuse fatty degeneration of the liver]. / Spongiöse glioneuronale Dystrophie mit diffuser Leberverfettung.

Reported in this paper are autopsy findings recorded from a boy who had died at the age of eight month. They included a spongy dystrophic tissue syndrome of the central nervous system associated with diffuse fatty degeneration of the liver. The case is considered to be in the category of glioneuronal dystrophy and is discussed under aspects of differential diagnosis.

Description of a simple method to study some aspects of the pathogenesis of arteriosclerosis by perfusion of arterial segments.

A perfusion apparatus is described which permits the perfusion of arterial segments of about 5 cm in length. It works under physiological conditions. During the perfusion, temperature and pressure constancy or pressure variation, respectively, pulsation, sufficient oxygen supply, and high sterility are guaranteed. Hitherto, the duration of the perfusion has been extended to 10 h. After this time the endothelium was well preserved. The method shall be used for the study of some problems in arteriosclerosis research.

[Cholesterol metabolism in the arteriosclerotic intima]. / Cholesterolmetabolismus in der arteriosklerotischen Intima.

Cholesterol and cholesteryl esters play an active role in the metabolism of intimal cells which are involved in the arteriosclerotic process (macrophages derived from monocytes and smooth muscle cells). LDL is the main carrier protein of both lipids and enters the vessel wall to become retained. Macrophages in cell culture have been shown to internalise LDL in an irregular fashion, if LDL is modified by oxidation, by formation of complexes with proteoglycans, malondialdehyde, etc. The development of foam cells in the intima may be interpreted in this way. Lipid-laden smooth muscle cells appear as well. Importance must be attributed to the processes of lysosomal hydrolysis of cholesteryl esters and subsequent re-esterification and hydrolysis of these lipids in cytoplasma. The free cholesterol delivered in this way may be transported by a carrier protein to the cell surface, taken up by the cholesterol acceptor HDL, and removed from the vessel wall. Phospholipids and apo E take part in this cholesterol reverse transport. But the ability of arterial tissue to release cholesterol is limited. Extracellular precipitations of cholesterol occur in the lipid accumulations which are sclerogenic. In advanced ulcerated arteriosclerosis they are the source of cholesterol crystal embolization. Cholesteryl esters extruded in the extracellular space by lysis of foam cells are taken up by monocyte-derived macrophages after interaction with albumin or fibronectin which function as opsonins.

[Carnitine deficiency and carnitine therapy]. / Karnitinmangel und Karnitintherapie.

The main function of carnitine is the transport of fatty acids across the inner mitochondrial membrane to the side of beta-oxidation. In healthy subjects no carnitine deficiency occurs. There are many inborn errors with carnitine deficiency as a primary genetic defect or secondary to other familial disorders of metabolism. Furthermore some acquired diseases are associated with secondary carnitine deficiency. Myopathic and systemic forms of carnitine deficiency have been described. Most of the carnitine deficiency syndromes leading frequently to sudden death without therapy, are treatable with L-carnitine. A beneficial influence of L-carnitine to certain hyperlipoproteinemias, hyperlipidaemic diabetes mellitus and other diseases has been reported too.

The influence of dietary low and high unsaturated fats and cholesterol on the fatty acid pattern of serum and aortic cholesteryl esters and the lipid deposits of pig aorta.

16 three-month-old female pigs were divided into 3 groups. 6 animals received a semi-synthetic diet containing 15% sunflower oil (g/100 g food) and 1.25% cholesterol (SF group). In 6 animals the sunflower oil was replaced by beef tallow (BT group). 4 control animals 1.5% sunflower oil and without cholesterol. The serum cholesterol levels of the SF group rose moderately, those of the BT group moderately or highly. The relative lipid infiltrated intima area (LIA) and the cholesteryl ester (CE) content of aortas were generally lower in the SF group than in the BT group in comparison to the serum cholesterol levels. The dietary fatty acid pattern determined the fatty acid composition of CE in the serum and extracellular lipid of the aortic lesions. With regard to the intracellular changes of fatty acid pattern of CE (decrease in dienoic acid, predominantly linoleic acid, and increase in monoenoic acids, predominantly oleic acid, and in trienoic acids and higher unsaturated fatty acids), there were important differences between the 2 dietary groups. The dienoic acid content of CE decreased intracellularly from 61% to 30.5%, at the most, in the SF group, and then stopped. In the BT group only 26-35% dienoic acid was available from the extracellular CE and was reduced intracellularly to 9% at the most. In the SF group the intracellular increase in monoenoic acid content of CE was related to the decrease in dienoic acid content. In the BT group this was true only for some lipid deposits of the aorta; in other lesions the monoenoic acid content remained nearly constant or even decreased with decrease in linoleic acid whereas the increase in trienoic acid content was especially high suggesting that an unphysiological trienoic acid (20:3 delta 5, 8, 11), originating from oleic acid, was formed in greater amounts. Our findings point to the development of an essential fatty acid deficiency in the foam cells of aortic lesions in the BT group which may result in an unfavorable influence on the cholesterol clearance from the cells and the arterial wall.

[Cholesterol ester storage disease and sea-blue histiocytes]. / Cholesterolester-Speicherkrankheit und seeblaue Histiozyten.

A case of cholesteryl ester storage disease (CESD) was found by liver biopsy in a 5-year-old boy. Hepatosplenomegaly, varying elevations of serum transaminases and hyperlipoproteinemia, type IIb, were detected clinically. The liver tissue was yellow. The cytoplasm of hepatocytes and Kupffer cells was foamy. In frozen sections these cells stained with dyes and histochemical methods for neutral lipids, unsaturated lipids, and cholesterol, but not with dyes for phospholipids and glycosaminoglycans. Under polarized light a large quantity of birefringent storage material was visible. We determined the lipid composition histochromatographically and found a very substantial increase in cholesteryl ester content and a moderate increase in triglycerides compared to control liver tissue. These findings are in agreement with our former case of CESD (1979). But in contrast to the liver tissue of the first patient there was more pronounced hepatic periportal and intralobular fibrosis in the second case. Remarkable amounts of ceroid storing histiocytes, so called "sea-blue histiocytes" were visible within the fibrous tissue. The granules of these cells stained with dyes for neutral lipids, phospholipids, glycosaminoglycans, and sea-blue with Giemsa in both frozen sections and paraffin-embedded liver tissue. They showed a yellow autofluorescence and were partly birefringent. Ceroid is believed to be the product of lipid peroxidation, binding to protein and polymerization. Therefore we suggest an additional deficiency of tissue antioxidants at the storage sites in such cases of CESD and this may potentiate liver fibrosis.

[Parameters of normal and disordered lipid metabolism in the progression and regression of arteriosclerosis]. / Parameter des normalen und gestörten Lipidstoffwechsels bei Progression und Regression der Arteriosklerose.

The processes of normal lipid metabolism in peripheral cells are regulated predominantly by LDL receptors (supply of the cells with cholesterol and essential fatty acids). Conceptions about foam cell formation in arteriosclerosis, derived from findings in cell cultures, are discussed (modified LDL lipid peroxides etc.). In prevention and regression of arteriosclerosis intracellular hydrolysis of cholesterol esters and the removal of cholesterol from the cells and the vessel wall by HDL play an important role. Further, the content of polyunsaturated fatty acids in cholesterol esters and phospholipids seems to influence the largeness of arterial lipid depositions. The manifold functions of the phospholipids within the vessel wall and the blood plasma involved in prevention and regression of arteriosclerosis (including the effect of phosphatidylcholine liposomes) are reviewed.

Histochromatographical determination of cholesteryl ester composition in the human atherosclerotic aorta.

In 14 human aortas, the cholesteryl ester (CE) composition of fatty spots was investigated histochromatographically. By a special method the intracellular lipid (foam cells) lying in the inner intima could be separated from the extracellular lipid found in the depth of the intima in many cases. The fatty acid pattern of CE of the intracellular lipid differed from that of the extracellular lipid by a relative increase in monoenoic acids (M) and trienoic acids (Tr) as well as by a relative decrease in linoleic acid (D), tetraenoic acids (Ar), and saturated fatty acids (S). In every case, the sum of the polyunsaturated fatty acids (PU) of CE (with 2 to 6 double bonds) was lower in the intracellular than in the extracellular lipid (highest difference: 23,2%, lowest difference: 5,7%). High differences of the PU-values between intra- and extracellular CE were associated with high or low D-values and with low values for Tr, Ar, and HU (high unsaturated fatty acids with more than 4 double bonds) of intracellular CE. Low differences of the PU-values between intra- and extracellular CE were accompanied with high D-values and medium or high values for Tr, Ar, and HU of intracellular CE. The results suggest that the cholesteryl esters in the intracellular lipid lose polyunsaturated fatty acids by the processes of hydrolysis and reesterification which are possibly used for other metabolic processes.

[Metabolic triglyceride storage disorders. A report of 2 cases of systemic carnitine deficiency]. / Stoffwechselstörungen mit Triglyzeridspeicherungen Ein Bericht über 2 Fälle von systemischem Karnitinmangel.

Two cases of triglyceride storage in liver, kidney, heart, and skeletal muscle are described in infants who died at the age of 1 1/2 years and 4 d, respectively. In the first patient, a previously normal girl, the clinical symptoms began two months before death with encephalopathy (vomiting, unconsciousness), liver enlargement, hypoglycemia, increase in serum transaminases. These signs disappeared within the following days. Some weeks later she died during the second attack. The 4-d-old boy, the second child of healthy consanguineous parents, showed at the third day of life an impaired sucking, muscular hypotonia, respiratory arrest and bradycardia. An intensive therapy was inefficient. At autopsy gross examination showed only a moderately enlarged yellow liver and an edematous brain in the first case and pale organs in the second one but no cause of death. The microscopial examination of all tissues of both cases showed fat storage within the four organs mentioned above. The common histochemical methods for neutral lipids were positive, the Schultz-reaction for cholesterol and cholesterol esters was negative. The lipid loaden cells did not show birefringence in polarized light. A predominance and strong fat storage of the type I fibres was found in the skeletal muscle. The storage of triglyceride could be confirmed by histochromatography, a thin-layer chromatography of tissue sections. The triglyceride accumulation in liver, heart, kidney, and skeletal muscle is a characteristic feature of systemic carnitine deficiency. The clinical symptoms of the first patient are in agreement with reports of this disease also. A carnitine deficiency in a newborn was not yet described. Family studies revealed a low carnitine concentration in the mother's serum in both cases, while the serum of father and brother resp. sister showed normal carnitine levels.

[Coincidence and biological association of diseases in autopsy findings]. / Koinzidenz und Syntropie von Krankheiten im Sektionsmaterial.

It is known that in autopsies severe arteriosclerosis and myocardial infarction are less frequently associated with liver cirrhoses and carcinomas (except bronchial carcinoma) than with other cases. This does not mean that liver cirrhosis and carcinoma protect from vascular diseases, but the higher mortality rate if liver cirrhoses, carcinomas, and vascular diseases plays an essential role and most be taken into consideration, when conclusions concerning biological connections shall be drawn from autopsy-statistical examinations. In a certain age group, e.g. in males aged 50, in the autopsy material severe arterioscleroses are more frequent than in the living population of the same age, since the death rate (number of deceased patients as related to the total number of patients) is high for cases with circulatory diseases and vascular diseases, respectively. Liver cirrhoses, carcinomas (also with high death rates), and other diseases causing death come from the total living population with healthier (less changed) vessels and, therefore, of course they must be less frequently combined with severe arteriosclerosis and myocardial infarction than the total number of death cases, for which the distribution of arteriosclerosis in all death cases is essentially determined by the number of patients who died from the sequelae of a vascular disease. The correctness of this consideration is mathematically proved by a simple model example.

Cholesteryl esters in pig liver during atherogenic diets and foreign serum protein infusions.

Eight-month-old pigs were fed a diet supplemented with 15% lard (group II) or 15% lard plus 1.5% cholesterol (group III) for 4 months. Five of the animals fed the high fat and cholesterol diet received two i.v. infusions of foreign serum protein (group IV). One group of animals was treated with the same infusions without dietary fat or cholesterol supplement (group V). Liver lipids and serum cholesterol levels were determined. In group II the concentration and fatty acid composition of hepatic cholesteryl esters showed no marked differences from controls (group I). The same findings were present in 2 of 5 animals of group III; in the other 3 animals higher hepatic cholesteryl ester concentrations and predominantly an elevation of monoenoic acid fraction, in one case also a rise of trienoic acid fraction were obtained. These alterations were found in the liver of all animals of group IV. The reverse was observed in the animals which were given the same serum infusions but only the stock diet (group V): a reduction of hepatic cholesteryl ester concentration and no striking alteration in fatty acid pattern. In cryostat sections of all liver specimens no stainable lipid could be detected. There was no correlation between liver and serum fatty acid composition of cholesteryl esters. The total cholesterol levels in serum showed no increase in group V, a slight increase in group II, a moderate increase in group IV, and a marked, partly large increase in group III. These results are discussed in relation to the effect of cholesterol and fat feeding on cholesterol metabolism and essential fatty acid requirement.

[Adrenoleukodystrophy (author's transl)]. / Adrenoleukodystrophie.

A report on clinical course and morphological findings of a case of adrenoleukodystrophy in a 10-years-old boy is given. The brain showed the typical changes of a sudanophilic, inflammatory leukodystrophy in all lobes. Pathognomic intracytoplasmatic inclusions in the perivascular macrophages were found by electron microscopic examination. The adrenal glands showed a severe atrophy, but it was impossible to detect typical cytolpasmatic inclusions within the adrenocortical cells. By thin-layer chromatography an accumulation of cholesterol esters with very long chain fatty acids was found in the demyelinated areas. Findings diagnostic facilities and theories of pathogenesis are discussed.

[Progression and regression of diet-induced arterial changes in the domestic pig]. / Progression und Regression der diätinduzierten Arterienveränderungen des Hausscheines.

Under atherogenic diet in the pig changes of the intima developed in predisposed places of the arteries which have close relations to the atherogenesis in man. 4 months after the end of a 4-month atherogenic diet no decisive regression of lipid infiltrates could be established in spontaneous thickenings of the intima, however, signs of a lipid mobilisation.

[Pathways of intracellular cholesterol metabolism in a model study]. / Wage der intrazellulären Cholesterolverarbeitung im Modellversuch.

We had concluded from former own investigations that the cells in the arteriosclerotic plaque effect a change of the ester proportion of cholesterol. One of the possible mechanisms ible bond and from double unsaturated (linoleic acid) to higher unsaturated acids. Therefore we investigated by radioactive labelling of the fatty acid moity of cholesterol esters whether such desaturation reactions take place in the model experiment. For this purpose we implanted cholesterol stearate which was 14C-labelled in the proportion of fatty acid subcutaneously into the skin of a rat. We demonstrated radiohistochromatographically that after 7 to 14 days the fraction of the cholesterol esters with 1 double bond was additionally labelled. Other fractions were not labelled. From this results that the proportion of the saturated fatty acid of the cholesterol ester is actually desaturated, in which case the desaturation as we expect only goes to the fraction with one double bond, because the double unsaturated linoleic acid is not synthetized in vivo in the mamal.

[Arteriosclerosis and liver cirrhosis (author's transl)]. / Arteriosklerose und Leberzirrhose.

The degree of arteriosclerosis in 176 autopsies of liver cirrhosis (patients in the age range of 51 to 70 years) was compared with that of controls (without liver disease). It was found that the "protective influence" of liver cirrhosis of the process of arteriosclerosis is only true for normotonic. Associated with arterial hypertension severe arteriosclerosis is predominant in liver cirrhosis. There is even some evidence that arteriosclerosis in hypertonics with liver cirrhosis is more increased than in controls without liver diseases. The factors influencing arteriosclerosis in liver cirrhosis are discussed.