Chapter 11. Atherosclerosis and cirrhosis of the liver

Chapter 11. Atherosclerosis and cirrhosis of the liver R. VANE(EK Atherosclerosis of the aorta and coronary arteries and myocardial infarction were studied post mortem in 390 males and 190 female cirrhotic subjects in the 5 towns. Comparison with the reference groups revealed that calcification of the aorta and coronary arteries was more frequent (in the case ofmales) and more extensive (in the case of males and females) in cirrhotics than in noncirrhotics. Raised and complicated lesions were not increased. Coronary stenosis (in females), fresh myocardial infarction (in both sexes), and large myocardial scar (in both sexes) were less frequent in cirrhotics. " Obesity " was similar in cirrhotics and non-cirrhotics. Study of the relationship between liver cirrhosis and atherosclerosis is confused by the question of what effect alcoholism may have on the development and extension of this condition. The results of a number of studies have suggested that atherosclero- sis is less extensive in subjects with cirrhosis and that myocardial infarction is less frequent (4, 5, 8, 9, 10, 12, 17). Only a few observations have failed to corroborate this finding (15, 16). The negative cor- relation between the two conditions was assumed to result from a favourable effect of alcohol consump- tion on atherosclerosis. It is now known that a number of factors may play a role in the etiology of liver cirrhosis and that this condition cannot be used as a criterion of alcoholism. Moreover, most of the analyses so far published are based on routine hospital material and have therefore been subject to errors arising from selection factors (3, 6, 13). Nevertheless, the relation- ship between liver cirrhosis and atherosclerosis is of great interest in view of the importance of the liver in the general metabolism on the one hand and the metabolic component of atherosclerosis on the other. This relationship was therefore examined in an autopsy series where selection factors could be at least partly controlled. MATERIAL AND METHODS The study was confined to persons aged be- tween 40 and 79 since only very few cases were available outside this age range. A total of 12424 autopsies were analysed (6903 males and 5551 fe- males). Liver cirrhosis was found in 507 subjects (317 males and 190 females), i.e., 4.07% of the total. The age, sex, and geographical distribution of the cirrhotics is shown in Table 32. The methods of evaluation of atherosclerosis and other lesions, as well as the statistical procedures used, are described in Chapter 1. RESULTS The age-standardized values for the prevalence of atherosclerotic lesions in cirrhotics and in the low and high atherosclerosis groups is shown in Table 33. Cirrhotics had average values for raised and complicated lesions in both the aorta and the coronary arteries, but male cirrhotics had high values for calcified lesions. Male and female subjects with cirrhosis of the liver had significantly less extensive raised lesions than subjects in the standardized average athero- sclerosis group but mostly more extensive than the low atherosclerosis group. The same trend was, in general, found also in the different towns, but the differences were not always significant. The pattern for the extent of calcified lesions was different. Men with liver cirrhosis had significantly more extensive lesions than subjects in the standard- ized group, but less extensive than the high athero- sclerosis group. In contrast, women showed no such difference. The geographical differences tended to follow this pattern, but the differences were rarely significant. The extent of complicated lesions was similar to that for the standardized group, in both the aorta and the coronary arteries. Coronary stenosis in men with liver cirrhosis was as common as in the standardized group, but women showed the same prevalence as the low athero- BULL. WORLD HEALTH ORGAN., Vol. 53, 1976-5673474 R. VANtCEK Table 32. Number of cases of liver cirrhosis, by age and sex, in each town % of Age group Malm6 Prague Ryazan Yalta Tallin Total natural deaths Males 40-44 6 2 1 0 2 111 4.5 45-49 6 2 1 3 5 171 50-54 16 10 7 3 5 41 5.3 55-59 18 13 3 6 7 47 60-64 28 16 5 5 6 60 4.8 65-69 28 24 4 3 2 61 70-74 15 21 1 0 5 42 4.2 75-79 17 14 1 1 5 38 134 102 23 21 37 317 4.7 Females 40-44 2 2 3 3 3 13 ) 4.3 45-49 3 0 1 0 3 71 50-54 7 3 3 5 2 20 ) 3.3 55-59 7 1 1 2 3 141 60-64 3 11 1 0 4 19 3.0 65-69 16 15 5 3 6 45 70-74 19 12 4 0 6 41 ) 3.4 75-79 13 11 1 1 5 311 70 55 19 14 32 190 3.3 sclerosis group. The same trends were found for the individual towns, with the exception that Malmo women had as much stenosis as the standardized group. Significant differences between the groups under comparison were, however, found in the frequency of ischaemic lesions of the myocardium. While the prevalence of fresh myocardial infarction in men of the standardized average atherosclerosis group was 14%, it was found in only 4% of subjects with liver cirrhosis. Also, fresh myocardial infarction was found significantly less frequently in cirrhotic women. Similar results were obtained for the indi- vidual towns. The findings were analogous for large myocardial scars, which were significantly less frequent in sub- jects of both sexes with liver cirrhosis. Here, too, this pattern was observed in each town, but the differ- ences were significant only in men and women in Malmo and Prague and in men in Yalta. As regards average body weight and thickness of the subcutaneous fat, no significant differences were observed between cirrhotics as a whole and the standardized atherosclerosis group, or for women in the different towns. Men from Malm6, however, were significantly heavier than those in the standard- ized average atherosclerosis group and men from Prague were significantly lighter. DISCUSSION The results of the analysis revealed an inverse relation between liver cirrhosis and the extent of atherosclerosis, measured as raised lesions of the 568 ATHEROSCLEROSIS AND CIRRHOSIS OF THE LIVER Table 33. Prevalence (%) of atherosclerotic lesions in cirrhotics and the low and high atherosclerosis groups (age-standardized values) Fatty streak Fibrous plaque Complicated Calcified Raisedlesions lesions lesions M F M F M F M F M F Abdominal Cirrhotics 96.1 93.5 97.5 92.2 58.4 29.7 64.9 46.6 97.5 92.2 aorta Low atherosclerosis group 96.0 95.1 95.6 90.2 40.6 c 21.3 40.9 c 31.3 b 95.6 90.2 High atherosclerosis group 89.6 c 89.0 99.0 96.0 71.7 b 54.0 c 50.2 c 51.6 99.1 96.0 Left anterior Cirrhotics 80.0 83.4 93.6 88.5 13.7 6.3 51.9 24.7 93.9 88.5 descending coronary Low atherosclerosis group 85.6 87.3 95.2 81.0 7.8 a 1.6 28.8 c 17.8 95.2 81.2 artery High atherosclerosis group 72.8 a 81.3 99.0 a 93.6 32.8 c 22.4 c 56.6 39.0 a 99.0 a 93.6 a Significance of the difference: P< 0.05. b Significance of the difference: P< 0.01. c Significance of the difference: P< 0.001. aorta and coronary arteries and as myocardial le- sions. In this respect, the results coincide with those of other authors, who have analysed routine hospital material (4, 5, 8, 9, 10, 12, 17). Since this study was based on post-mortem findings of a majority of the subjects from the different populations, and thus selection factors were greatly reduced, the inverse relation found seems to be valid. Its cause remains unclear, however. The solution to the problem can hardly be limited to the question of alcohol, as stated by Grant et al. (5) for instance. Such a theory is not in line with current concepts of a multifac- torial etiology for liver cirrhosis. The evidence presented by Hirst et al. (9) indicates that coronary atherosclerosis or its complications were less frequent only where chronic alcoholism had been accompanied by liver cirrhosis. In contrast, no difference from the control group was found in alcoholics without cirrhosis. These findings indicate that cirrhosis itself rather than alcohol acted as the " protective" factor. The mechanism whereby liver cirrhosis acts as such a factor is also unclear. The complicated role of the liver in general metabolism suggests a number of possibilities. Particular factors may be abnormalities of blood coagulation and fibrinolysis (1), the effect of the liver on lipid metabolism (4, 5, 8, 18), dis- orders in the inactivation of estrogen (2, 4, 5, 9), effects of malnutrition (5), or even abnormalities of haemodynamics (8, 11, 19). The fact that body weight and thickness of the subcutaneous fat in cirrhotics showed no significant difference from the standardized average athero- sclerosis group seems to indicate that these factors are not related to the differences in the extent of atherosclerosis found between the two groups. The morphological variety of atherosclerotic le- sions clearly shows that atherosclerosis is a process of an apparently diverse biological nature develop- ing in stages. Any analysis of the various aspects of atherosclerosis must take this fact into account. Individual atherosclerotic lesions do not all behave in the same way. The reduced extent of atherosclero- sis in cirrhotics was significant only for raised le- sions, mainly fibrous plaques. The prevalence and extent of calcified lesions, when analysed separately, were found to be high in cirrhotics, especially males. Geographical differences in the body build of cirrhotics were not related to differences in extent of arterial calcification. The reason for this phenomenon is thus unclear, but the same finding has been reported by :danov (20). In the experiments of Haas et al. (7), rabbits with liver cirrhosis induced by carbon tetrachloride, appeared to respond to treatment with vitamin D and choles- terol by being far more prone to deposit calcium in vascular walls than rabbits without liver cirrhosis given the same treatment. On the other hand, the cirrhotic group displayed an abatement of the fibrous proliferation of the intima as well as the growth of intercellular matrix with a reduction of lipoid deposits. The cause of this phenomenon remains unclear and calls for more experimental studies. 569 570 R. VANttEK The inter-town differences observed in the relation between liver cirrhosis and atherosclerosis were not very striking and may be partly explained by the low number of cases in some towns. Such differences have, however, also been reported by Restrepo et al. (16); they may be a reflection of the diverse etiology of liver cirrhosis in different geographical regions. RESUME CHAPITRE 11. ATHE'ROSCLE'ROSE ET CIRRHOSE DU FOIE L'atherosclerose de l'aorte et des arteres coronaires, et l'infarctus du myocarde ont fait l'objet d'etudes post- mortem chez 390 hommes et 190 femmes cirrhotiques dans les 5 villes considerees. La comparaison avec les groupes de reference a reve1 que la calcification de l'aorte et des coronaires etait plus frequente (dans le sexe masculin) et plus etendue (dans les deux sexes) chez les cirrhotiques. I1 n'y a pas d'augmentation des 1lsions saillantes ou compliquees. La stenose coronaire (chez la femme), l'infarctus myocardique recent (dans les deux sexes), et les cicatrices etendues du myocarde (dans les deux sexes) sont moins frequents chez les cirrhotiques. <L'obesite ) est analogue chez les cirrhotiques et les non-cirrhotiques. REFERENCES 1. ASTRUP, T. ET AL. Nature (Lond.) 185: 619 (1960). 2. BARR, D. P. J. Chronic Dis., 1: 63 (1965). 3. BERCKSON, J. Biom. Bull., 2: 47 (1946). 4. CREED, D. L. ET AL. Am. J. med. Sci., 230: 385 (1955). 5. GRANT, W. C. ET AL. Ann. intern. Med., 51: 774 (1959). 6. GROSSE, H. Z. Kreislaufforsch., 53: 667 (1964). 7. HAAs, G. M. ET AL. Am. J. Pathol., 57: 405 (1969). 8. HALL, E. M. ET AL. Am. J. Pathol., 29: 993 (1953). 9. HIRST, A. R. ET AL. 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