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Home , Lipid, Lipid metabolism

Postgrad Med J: first published as 10.1136/pgmj.54.629.181 on 1 March 1978. Downloaded from Postgraduate Medical Journal (March 1978) 54, 181-185.

Normal and abnormal in children BARRY LEWIS M.D., Ph.D., M.R.C.Path., F.R.C.P.

Chemical and Metabolic Disorders, St Thomas's Hospital Medical School, London SEI

Summary including connective , and other The transport of in plasma, and its dietary tissue including the smooth muscle of the arterial regulation are briefly reviewed. Plasma lipid concen- intima. So thecholesterol contained inthe low density trations are low in the neonate, rising to near-adult (derived from very low density lipo- levels by the age of six years. The causes of childhood ) and , and the , are hyperlipidaemia are discussed and a classification is carried from the and small bowel and end up in proposed. peripheral tissues. By contrast, some of the chol- esterol present in high-density lipoprotein is being LIPIDS are not carried as such in plasma- transported in the opposite direction. High density they are virtually insoluble in . Their presence in lipoprotein is synthetized in the liver and released Protected by copyright. plasma is in the form of complex , the lipo- into plasma, but as it traverses the bed of proteins (Lewis, 1976); these contain proteins with peripheral tissues, it acquires redundant free chol- the ability to solubilize lipids. There are four lipo- esterol. A major destination of high density lipopro- protein classes: (1) High density , which tein is the liver, from which it is excreted contain a large proportion of protein, carry about in the . So, high density lipoprotein concen- 1-1 3 mmol/l of cholesterol, and also . tration may well be a determinant of cholesterol (2) The major lipoprotein of human plasma is P-lipo- mobilization while the of low density protein or low-density lipoprotein. It carries some lipoprotein and very low density lipoprotein in- 3-4 mmol/l, i.e. about two-thirds of the plasma fluence cholesterol deposition in peripheral tissues. cholesterol and has a greater ratio of lipids to pro- Blood lipid are under genetic, tein than does high density lipoprotein. It also con- dietary and endocrine control. Only the second of tains a small amount of triglyceride. (3) Pre-p-lipo- these will now be discussed. A very large number of protein, a still large particle, otherwise known as very major , , trace elements and low density lipoprotein, is the main vehicle of the balance influence plasma lipoprotein levels. http://pmj.bmj.com/ triglyceride present in plasma during the fasting intake is the most extensively studied and, on state, i.e. the endogenous triglyceride. It also carries knowledge, the most important to the epi- cholesterol and phospholipids, and the lipid to demiologist concerned with coronary disease. protein ratio is about 9: 1. (4) Chylomicrons which containing saturated long chain fatty acids increase appear in plasma during absorption of fat; in ali- cholesterol and triglyceride levels; mono- mentary lipaemia they transport most of the dietary unsaturated acids such as oleate have little effect;

fat which has been absorbed. The liver is the main and polyunsaturated acids such as linoleate decrease on September 29, 2021 by guest. source of very low density lipoprotein; this lipo- cholesterol and triglyceride levels. Cholesterol intake protein, and also chylomicrons, are metabolized is of uncertain importance. The author's colleague, within the circulation (Fig. 1) (Lewis, 1977). The Mr P. Mistry, has been studying this effect. He finds lipoprotein hydrolyses most of its that a minority ofnormal subjects showa pronounced triglyceride and some , generating a rise in serum cholesterol levels when a 750 mg series of smaller and smaller "remnant" particles; cholesterol supplement is fed for 2-4 weeks; in others within the liver these are converted to low density the response is smaller or no change is observed. lipoprotein which is catabolized extra-vascularly This individual variation is of great interest. Mistry in peripheral tissues. has been studying the regulation of cholesterol syn- The cholesterol of plasma takes part in a two-way thesis in these subjects, using cultured leucocytes as traffic (Fig. 1). The cholesterol secreted in very low a model. Hyper-responders differ from hypo- density lipoprotein and later borne in low density responders in the control ofproductionofthe enzyme lipoprotein is largely transported to peripheral tissue, hydroxymethylglutaryl- (HMGCoA) Postgrad Med J: first published as 10.1136/pgmj.54.629.181 on 1 March 1978. Downloaded from 182 B. Lewis

HDL X FC A / holesterol / <; 0~~~~~~~~~~~~~~~~~L AT_FC(-(-:::~-~

/Biliary excretion Centripetal cholesterol tronsport

VLDL

TGFA_ VLDL 'remnaints' Cholester~~ j ~~~~Cholesterol;; Protected by copyright.

LDL 2

Centrifugal lipid transport FIG. 1. Plasma cholesterol pathways. HDL=high density lipoprotein; LDL=low density lipoprotein; VLDL = very low density liproprotein; LCAT = : cholesterol acyltrans- ferase; TGFA = triglyceride fatty acids; FC = free cholesterol. reductase which regulates cholesterol . density lipoprotein and low density lipoprotein

No other characteristic has been found which corre- concentrations fall. This fall may be due to a de-http://pmj.bmj.com/ lates with the response to cholesterol feeding. crease in the rate of production of these lipopro- Dietary recommendations to reduce serum lipid teins (Lewis, 1977). levels follow the general pattern of decreased satu- Correction of obesity is an essential step in treat- rated fat intake, cholesterol intake and energy ment of most common forms of hyperlipidaemia. A intake. Some of the is replaced by steep fall in serum lipid levels precedes the attain- polyunsaturated and mono-unsaturated fats. There is ment of ideal body , and usually persists after little consensus as to quantitative advice. In hospital the patient has resumed a weight-maintaining diet. practice one is concerned to maximize the percentage A negative calorie balance lowers serum lipid levels; on September 29, 2021 by guest. reduction in serum lipids in order to reduce the adipose tissue mass seems to be a separate important proportion of hyperlipidaemic patients requiring determinant of cholesterol and triglyceride concen- additional hypolipidaemic . A diet is used con- trations in plasma. taining 35°/ of energy from fats, up to 15%. from protein, and less than 300 mg/day of cholesterol. The Changes in lipid concentrations during childhood ratio of polyunsaturated to saturated fats is between Our knowledge of lipid levels during growth and 1 5: 1 and 1 8: 1, with a fairly high proportion of adolescence is somewhat incomplete. Most sources oleate. This leads to a 15-25%Y fall in serum chol- indicate that at birth mean serum cholesterol levels esterol and triglyceride levels. There is a major need are about 1-7 mmol/l, with a 95th percentile of about to define in quantitative terms the optimal diet for 2-4 mmol/l. Mean triglyceride levels are about 0 4 population use. When one changes from a saturated mmol/l. The cholesterol level in very low, low and to a polyunsaturated fat-containing diet, very low high density lipoproteins are 0 15, 0-8 and 0-8 mmol/l Postgrad Med J: first published as 10.1136/pgmj.54.629.181 on 1 March 1978. Downloaded from in children 183 respectively. Thus high density lipoprotein carries a in plasma. One is often known as familial hyper- far higher proportion of circulating cholesterol than cholesterolaemia. The disorder is severe, present in adults; but subsequently its concentration rises from birth and confers grave risk of coronary only modestly, reaching near-adult levels of about disease. It is inherited as a Mendelian dominant in 1 mmol/l by the age of 1 year. The two-fold rise in about 3/1000 of the population. A very much com- serum cholesterol during the first extra-uterine year moner cause of hypercholesterolaemia (prevalence is largely due to increased levels of low and very figures depend on the definition chosen) is a hyper- low density lipoproteins. These trends continue to cholesterolaemia which is probably due to multiple the age of 6 years, by which time median levels in genes interacting with other factors such as diet; Westernized populations are about 4 mmol/l, only and it may be that this multifactorial hyperchol- a little below those in young adults. esterolaemia is amajorreason why some communities Free concentrations are low, about have higher mean cholesterol levels than others. 0 3 mmol/l in cord blood serum (the fetus is essen- Another well defined entity is familial combined tially fed); they rise to 1-1 -2 mmol in hyperlipidaemia, in which the affected members of the first 24 hr, then decrease to typical adult levels the family may have various forms of hyperlipo- (in the fasted state) of 0-6 mmol/l. proteinaemia causing elevated levels of cholesterol, There are major differences in serum cholesterol triglyceride or both lipids. The frequency has been and triglyceride levels between adult populations, estimated at 2-3%y of the population, and this is the reflecting dietary factors; while there is some dis- commonest inherited lipoprotein disorder in patients agreement in published data, the balance of infor- with ischaemic heart disease (Goldstein et al., 1973; mation at present suggests that ethnic and geo- Nikkild and Aro, 1973). Familial hypertriglycerid- graphical differences are slight or absent at birth. aemia is seen less frequently. There is a rare entity, sometimes known as Type III or broad beta disease, Protected by copyright. Classifications of hyperlipidaemia which appears to be due in part to an accumulation The obvious first step in investigating a hyper- of lipoprotein remnants in plasma. This is inherited lipidaemic patient is to seek underlying causes, i.e. as in autosomal dominant but it seems to occur much to recognize secondary hyperlipidaemic states. Of the more commonly in families affected by endogenous very many known causes (Lewis, 1976) those of hypertriglyceridaemia. Perhaps the rarest of all especial importance in paediatric practice are shown hyperlipidaemias is due to deficiency of the enzyme in Table 1. and manifests extreme hypertri- glyceridaemia with a type I or V lipoprotein pattern. Lastly, a recently described form of familial TABLE 1. Secondary hyperlipidaemias in childhood hyperlipidaemia exists in which mild to moderate Glycogen storage disease (Types 1, 3 and 6). hypercholesterolaemia is due to elevated levels of Diabetes. high density lipoprotein. Such patients have no Idiopathic hypercalcaemia. xanthomas or other physical signs suggestive of Hypothyroidism. http://pmj.bmj.com/ Isolated growth deficiency. hyperlipidaemia. They may possess relative immunity Obstructive jaundice. to ischaemic heart disease, and often reach an advanced age. The existence of this probably un- common entity is one justification for obtaining In children, as in adults, the majority of hyper- lipoprotein analyses aswell as lipid analyses, wherever lipidaemic patients do not have any demonstrable clinically indicated. underlying cause. The hyperlipidaemia is due to The simplest classification is one which has the

various genetic disorders and, even more often, to the pragmatic goal of separating primary hyperlipidae- on September 29, 2021 by guest. interaction of genotype with diet, obesity and other mias into groups differing in their optimal treatment, factors (Leading Article, 1977). Their classification therapeutic groups 1, 2 and 3 (Table 3) (Lewis, 1976). is a matter of considerable uncertainty at the present In group 1 there is hypercholesterolaemia, but normal time. Ten years ago the Fredrickson WHO classi- triglyceride levels; and there are two groups in which fication (Fredrickson, Levy and Lees, 1967) became hypertriglyceridaemia is present, with or without a most widely known (Table 2). This depends simply rise in serum cholesterol as well. The difference be- on which lipoprotein class is responsible for the tween the common group 2 and the rare group 3 is hyperlipidaemia. Another way of classification is that in the former the triglyceride is of endogenous based upon the genetic disorders of plasma lipid origin, and requires treatment chiefly by weight metabolism, and at least six can be distinguished reduction or drugs such as clofibrate; in group 3 on current knowledge (Table 3). There are at least there is lipoprotein lipase deficiency producing exo- two disorders which produce hypercholesterolaemia, genous hypertriglyceridaemia, treated by a very low both due to a high level of low density lipoprotein fat intake. Postgrad Med J: first published as 10.1136/pgmj.54.629.181 on 1 March 1978. Downloaded from 184 B. Lewis TABLE 2. Fredrickson/WHO classification of primary hyperlipoproteinaemias Abnormality of lipoprotein Cholesterol Triglyceride Type I chylomicrons t t tt Type Ila LDLt 11 N Type IIb LDLt; VLDLf t t Type III cholesterol-rich VLDL t t t Type IV VLDL f Nt I Type V chylomicrons t; VLDL t tIt LDL =low density lipoprotein; VLDL =very low density lipoprotein; N =normal. TABLE 3. Primary hyperlipoproteincinaemia - classification Cholesterol Triglyceride Serum Therapeutic group Monogenic hypercholesteroloemia LDL Tra (dominant) N LI Multifactoriol hypercholesteroloemia (polygenic) LDL laJ

Familial combined hyperlipidoemia LDL + VLDL 3ib LDL IIa Protected by copyright. VLDL IZ VLDL + chylomicrons 7 * N or ** 2 Familial hypertriglyceridoemia VLDL iZ (endogenous) VLDL + chylomicrons Y

Remnant hyper lipoproteinoemia I DL, = broad beta disease remnant particles

Lipoprotein lipose deficiency Chylomicrons / 3N o http://pmj.bmj.com/ + VLDL : J Chylomicrons (exogenous)

LDL =low density lipoprotein; VLDL =very low density lipoprotein; N =normal. The early treatment of hyperlipidaemia the hyperlipidaemia. This perhaps constitutes the The author and his colleagues have recently been strongest argument for detection and treatment of looking at the relationship between the concentration hyperlipidaemia in childhood. There is one rider of plasma low density lipoprotein and the rate at that the author would like to make; that is, that many on September 29, 2021 by guest. which this lipoprotein enters the arterial intima in of the inborn disorders of lipid metabolism do not man (Niehaus et al., 1977). Overall there is a positive manifest in children. For example, familial combined correlation between this rate and the plasma con- hyperlipidaemia is rare until the age of 20 years and centration of lipoprotein of about r=0 5, but if we endogenous hypertriglyceridaemia (although it has separate younger individuals and older ones, then been described even in the neonate) seems to be the correlations become very much closer and in much rarer in paediatric practice than in adult young individuals the correlation coefficient is of medicine. the order of r=0 9, while in older ones it is r=0-7. Thus low density lipoprotein concentration in plasma is one of the factors determining the rate of lipid References FREDERICKSON, D.S., LEVY, R.I. & LEEs, R-S. (1967) Fat deposition in the arterial wall. But clearly chol- transport in lipoproteins: an integrated approach to esterol deposition is a of not only the lipo- mechanisms and disorders. New England Journal of protein concentrations. but also of the duration of Medicine, 276, 32, 94, 148, 215, 273. Postgrad Med J: first published as 10.1136/pgmj.54.629.181 on 1 March 1978. Downloaded from Lipid metabolism in children 185

GOLDSTEIN, J.L., SCHROTT, M.G., HAZZARD, W.R., BIERMAN, LEWIS, B. (1977) Plasma lipoprotein interrelationships. E.L. & MOTULSKY, A.G. (1973) in coronary Biochemical Society Transactions, 5, 589. heart disease. II. Journal of Clinical Investigation, 52, NIEHAUS, C.E., NICOLL, A., WOOTTON, R., WILLIAMS, B., 1540. LEWIS, J., COLTART, D.J. & LEWIS, B. (1977) Influence of lipid concentrations and age on transfer of plasma lipo- LEADING ARTICLE (1977) Diet, energy balance, and genes- protein into human arterial intima. Lancet, ii, 469. and serum cholesterol British Medical Journal, 1, 789. NIKKILA, E.A. & ARo, A. (1973) Family study of serum lipids LEWIS, B. (1976) The Hyperlipidaemias: Clinical and Labora- and lipoproteins in coronary heart disease. Lancet, i, tory Practice. Blackwell Scientific Publications, Oxford. 954. Protected by copyright. http://pmj.bmj.com/ on September 29, 2021 by guest.