Essential Familial Hypercholesterolemia

The level of serum cholesterol concentration of any given individual at a certain time obviously depends on a number of factors. Some exogenous influences on serum cholesterol are well recognized as e.g. age, sex, body weight, diet etc. 

Others, particularly endogenous factors, which influence cholesterol synthesis and degradation are incompletely understood. It is not at all surprising, therefore, that the distribution of the serum cholesterol concentration in the population is continuous and generally unimodal as must be expected as a consequence of multifactorial determination. 

Unpublished data of Heuschebt (1964) also demonstrated a high degree of concordance in a group of ten uniovular pairs of twins of older age (55—75 years of age) some living together and some apart. 

Gedda and Poggi (1960) studied 50 pairs of identical twins and 50 pairs of binovular twins aged 6 to 19 years, all living together with their parents. Definite differences in variation of identical and nonidentical twins were considered evidence for the dependence of the cholesterol concentration on the genotype. 

Thomas et al. (1964) approached the question of distribution by studying 1018 white male medical students. They concluded that the observed distribution could 

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Keys et al. (1965) have recently reviewed the evidence on the effect of dietary cholesterol on the plasma cholesterol level, which has been a controversial subject for many years. They came to the conclusion that there is a predictable effect of exogenous cholesterol on plasma cholesterol. This has to be considered in the dietary approach to the treatment of essential familial hypercholesterolemia. 

Piper, J., and L. Orrild Essential familial hypercholesterolemia and xanthomatosis. Followup study of twelve danish families. Amer. J. Med. 21, 34 (1956). 

Dehydrogenase Deficiency, Biotinidase Deficiency, and Adrenoleukodystrophy. Catabolism of essential amino acid skeletons is discussed in the chapters Phenylketonuria and HMG-CoA Lyase Deficiency. The chapters Inborn Errors of Urea Synthesis and Neonatal Hyperbilirubinemia discuss the detoxification and excretion of amino acid nitrogen and of heme. The chapter Gaucher Disease provides an illustration of the range of catabolic problems that result in lysosomal storage diseases. Several additional chapters deal with key aspects of intracellular transport of enzymes and metabolic intermediates the targeting of enzymes to lysosomes (I-Cell Disease), receptor-mediated endocytosis (Low-Density Lipoprotein Receptors and Familial Hypercholesterolemia) and the role of ABC transporters in export of cholesterol from the cell (Tangier disease). 

Bile acids have two major functions in man (a) they form a catabolic pathway of cholesterol metabolism, and (b) they play an essential role in intestinal absorption of fat, cholesterol, and fat-soluble vitamins. These functions may be so vital that a genetic mutant with absence of bile acids, if at all developed, is obviously incapable of life, and therefore this type of inborn error of metabolism is not yet known clinically. A slightly decreased bile acid production, i.e., reduced cholesterol catabolism, as a primary phenomenon can lead to hypercholesterolemia without fat malabsorption, as has been suggested to be the case in familial hypercholesterolemia. A relative defect in bile salt production may lead to gallstone formation. A more severe defect in bile acid synthesis and biliary excretion found secondarily in liver disease causes fat malabsorption. This may be associated with hypercholesterolemia according to whether the bile salt deficiency is due to decreased function of parenchymal cells, as in liver cirrhosis, or whether the biliary excretory function is predominantly disturbed, as in biliary cirrhosis or extrahepatic biliary occlusion. Finally, an augmented cholesterol production in obesity is partially balanced by increased cholesterol catabolism via bile acids, while interruption of the enterohepatic circulation by ileal dysfunction or cholestyramine leads to intestinal bile salt deficiency despite an up to twentyfold increase in bile salt synthesis, to fat malabsorption, and to a fall in serum cholesterol. 

An isolated defect in bile acid production has been found so far only in familial hypercholesterolemia (62), though even in this entity cholesterol catabolism as a whole may be decreased. Essential hypercholesterolemics (11) and hypothyroid patients (11,89) also tend to have a low bile salt elimination, though the excretion of cholesterol as such appears to decrease, too, particularly in the latter condition. In the circumstances in which bile salt elimination is decreased as a result of decreased hepatic function, elimination of cholesterol as such is also reduced (11). Under these conditions, serum cholesterol apparently increases only when the amount of elimination is decreased more than the feedback mechanism(s) are able to suppress synthesis, i.e., when the production exceeds elimination. 

Another group of hypercholesterolemic (type II) patients, indicated in Table II by the term essential hypercholesterolemia, was also studied. These patients differed from familial hypercholesterolemia patients in that the family history was less clear, serum cholesterol was less elevated, and xanthomata were not present. Hypercholesterolemia may be primarily caused by environmental, primarily dietary, factors. Bile acid production in this group is less significantly reduced than in the familial group, and the relative catabolism of cholesterol by way of bile acids is within normal limits. Sodhi (151) observed in this type of hypercholesterolemia a markedly low fecal bile acid excretion. 

Fasoli, a., and A. Cesana Serum lipid and lipoprotein changes after treatment with Atromid in patients with atherosclerosis, essential hyperlipemia and familial hypercholesterolemia. J. Atheroscler. Kes. 3, 475 (1963). 

Figures in parentheses indicate the number of subjects in each group. In essential hypercholesterolemia (type II), familial history is unclear, tendon xanthomata are absent, and serum cholesterol is usually only moderately increased. 

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