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 lipid metabolism in children BARRY LEWIS M.D., Ph.D., M.R.C.Path., F.R.C.P. Chemical Pathology and Metabolic Disorders, St Thomas's Hospital Medical School, London SEI Summary including connective tissue, adipose tissue and other The transport of lipids 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 lipoprotein (derived from very low density lipo- levels by the age of six years. The causes of childhood protein) and chylomicrons, and the triglyceride, are hyperlipidaemia are discussed and a classification is carried from the liver 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 blood plasma- transported in the opposite direction. High density they are virtually insoluble in water. Their presence in lipoprotein is synthetized in the liver and released Protected by copyright. plasma is in the form of complex proteins, the lipo- into plasma, but as it traverses the capillary 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 lipoproteins, which tein cholesterol is the liver, from which it is excreted contain a large proportion of protein, carry about in the bile. So, high density lipoprotein concen- 1-1 3 mmol/l of cholesterol, and also phospholipids. tration may well be a determinant of cholesterol (2) The major lipoprotein of human plasma is P-lipo- mobilization while the concentration 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 concentrations 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 nutrients, vitamins, trace elements and low density lipoprotein, is the main vehicle of the energy balance influence plasma lipoprotein levels. http://pmj.bmj.com/ triglyceride present in plasma during the fasting Fat intake is the most extensively studied and, on state, i.e. the endogenous triglyceride. It also carries current knowledge, the most important to the epi- cholesterol and phospholipids, and the lipid to demiologist concerned with coronary disease. Fats 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- serum 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 enzyme lipoprotein lipase hydrolyses most of its that a minority ofnormal subjects showa pronounced triglyceride and some phospholipid, 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-coenzyme A (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 = lecithin: cholesterol acyltrans- ferase; TGFA = triglyceride fatty acids; FC = free cholesterol. reductase which regulates cholesterol biosynthesis. 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 saturated fat is replaced by steep fall in serum lipid levels precedes the attain- polyunsaturated and mono-unsaturated fats. There is ment of ideal body weight, 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 drugs. 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 Lipid metabolism 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 heart 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 fatty acid 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 carbohydrate 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.