or a drunken feeling. Diagnosis This is a biochemical diagnosis from a blood glucose <50 mg/dL, but is often \201 rst picked up by the patient, their family, or their doctor from the clinical features listed in Box 112.4. Saving serum before treatment for blood glucose, insulin, and C-peptide levels will con \201 rm the diagnosis and may help determine the cause. 112-Draznin-Chap112.indd 656 3/31/2011 5:36:19 PM HYPOGLYCEMIA 657 Box 112.4 Clinical features The features of hypoglycemia can be divided into two main groups: auto- nomic symptoms and neuroglycopenic symptoms, as shown in Box 112.5. The autonomic symptoms usually occur \201 rst (when the blood glucose is <65 mg/dL), but some drugs, such as the nonselective B- blockers, and alcohol may mask these with neuroglycopenia (at blood glucose <46 mg/dL), cau sing confusion with no warning. Some patients lose these predominantly autonomic warning sy mptoms and are therefore at higher risk of injury. Box 112.5 Signs and symptoms of hypoglycemia Autonomic \200 Sweating \200 Pallor \200 Anxiety \200 Nausea \200 Tremor \200 S hivering \200 Palpitations \200 Tachycardia Neuroglycopenia \200 Confusion \200 Tiredness \200 Lack of concentration \200 Heada che \200 Dizziness \200 Altered speech \200 Incoordination \200 Drowsiness \200 A ggression \200 Coma Pathogenesis Hypoglycemia results from an imbalance between glucose supply, glucose utiliza tion, and insulin levels that results in more insulin than is needed at that time. A reduced glucose supply occurs when a meal or snack is missed, or as a late effect of alco hol. It can also be due to delayed gastric emptying with autonomic neuropathy or be associa ted with celiac disease, Addison \200\231s dis- ease, or an acute illness, such as gastroen teritis. Increased utilization occurs with exercise and high insulin levels mostly with sulfonylurea or exogenous insulin therapy. The net result of this imbalance is hypoglycemia. Human insulins have a slightly faster onset of action and a shorter dura- tion of action th an their animal predecessors, and a lot of patients report alterations in hypoglycemic awar eness when they switch from one form to the other. Even so, no de \201 nite evidence of sp eci \201 c hypoglycemic altera- tions due to human insulin itself has been reported. Sulfonylurea therapy can cause hypoglycemia due to B-cell stimulation. This is most commonl y seen from glibenclamide , especially in the elderly and those with reduced renal excretin g ability, but can occur in anyone who takes this therapy and fasts. 112-Draznin-Chap112.indd 657 3/31/2011 5:36:19 PM CHAPTER 112 Emergencies in diabetes 658 The biguanide metformin and the A-glucosidase inhibitor acarbose are unlikely to precipitate hypoglycemia. Management In the conscious patient, oral carbohydrate (20 \200\22330 g) is often suf \201 cient to resolve the problem. This can be given as 5 \200\2236 glucose tablets or as a gla ss of milk or orange juice. Having raised the sugar rapidly, the patient should then eat so mething to maintain a normal blood glucose. In the confused patient, a buccal gel (e.g., GlucoGel , a 30% glucose gel) is an alterna tive, although this should not be used in the unconscious patient as there is a risk of asp iration. In the unconscious patient, once a blood sample has been taken for glucose estimation, trea t with 25 \200\22350 mL of 50% glucose IV or 1 mg of IM or deep SC glucagon. Glucagon mobil izes glycogen from the liver and will not work if given repeatedly or in starved patients w ith no glycogen stores. In this situation or if prolonged treatment is needed, IV glucose i s better (50% initially then 10%). The worry with 50% glucose is tissue necrosis if extravasation occurs. Subsequent management Having corrected the acute event, determine why it happened and, if p os- sible, alter treatment or lifestyle to prevent recurrance. Extreme exercise may require an alteration in insulin doses for 24 hours, and alcohol causes not only initial hyperglyc emia but also a degree of hypoglycemia 3 \200\2236 hours after ingestion, and may alter ins ulin requirements the next morning. Education on how to avoid precipitating hypoglycemic episodes in these situations is advisa ble. Recurrent hypoglycemic events may also her- ald deterioration in renal or liver functi on; these conditions should be excluded. Patients on long-acting sulfonylureas who experience hypoglycemia will need careful monitor ing, as the drug may last longer than the glucose or glycogen given to correct it and repea ted hypoglycemic episodes may occur. A continuous IV glucose infusion is therefore often ne eded in this situation, particularly in overdose with these agents. Further reading Amiel SA, Tamborlane WV, Sherwin RS (1987). Defective glucose counterregula tion after strict glycemic control of insulin-dependent DM. N Engl J Med 316:1376 \200\2231 384. Cranston ICP, Amiel SA (1995). Hypoglycaemia. In Leslie RDG, Robbins DC (Eds). Diabetes: Cl inical Science and Practice. Cambridge, UK: Cambridge University Press, pp. 375 \200\223391 . Hepburn D, Deary IJ, Frier BM, et al. (1991). Symptoms of acute insulin induced hypoglycaem ia in humans with and without IDDM. Diabetes Care 14:949 \200\223957. Krentz AJ, Nattrass M (1997). Acute metabolic complications of DM: diabetic ketoacidosis, h yper- osmolar non-ketotic syndrome and lactic acidosis. In Pickup J, Williams G (Eds.), Tex tbook of Diabetes , 2nd ed. Oxford, UK: Blackwell Science, pp. 1 \200\22323. Lebovitz HE (1995). Diabetic ketoacidosis. Lancet 345:767 \200\223772. Pickup JC, Williams G (Eds.) (2003). Hypoglycaemia in diabetes. In Textbook of Diabetes , 3 rd ed. Oxford, UK: Wiley-Blackwell. 112-Draznin-Chap112.indd 658 3/31/2011 5:36:19 PM Part 12 Lipids and hyperlipidemia Barrie Weinstein and Dina Green 113 Lipids and coronary heart disease 114 Primary hyperlipidemias 115 Secondary hyperlipide mias 116 Management of dyslipidemia 660 669 674 677 113-Draznin-Chap113.indd 659 4/1/2011 6:44:37 PM CHAPTER 113 Lipids and coronary heart disease 660 Lipids and coronary heart disease Physiology The two main circulating lipids, triglycerides and cholesterol, are bound with p hospholipid and lipoproteins to make them more water soluble for transportation throughout the body. The apoproteins on the surface of these soluble masses help the body to recognize each of the different transportation complexes. Chylomicrons These contain 85% triglycerides and 4% cholesterol. Made in the mucosa of the small intestine, they are broken down in the liver and peripheral tis- sues by lipoprotein lipase. Initially they contain apoprotein B-48 (apo B-48) but also acquire apo E and apo C- II from circulating HDL. Following metabolism by lipoprotein lipase in capillary endothelial cells, which is activat ed by apo C-II, chylomicron remnants are then removed by speci \201 c apo B and apo E rece ptors in the liver. Very low \200\223density lipoproteins (VLDLs) VLDLs contain 50% triglyceride, 15% cholester ol, and 18% phospholipid. They are the main carrier of triglycerides in circulation. Made w ith triglyc- erides synthesized in the liver, they also contain apo B-100 and apo E. VLDLs are broken down by lipoprotein lipase in peripheral tissue to give IDLs, or other remnants that are removed by the liver. Intermediate-density lipoproteins (IDLs) These VLDL remnants contain mostly cholesterol and phospholipid and are either removed by the liver or metabolized to form LDLs. Low-density lipoproteins (LDLs) LDLs contain 45% cholesterol, 10% triglycerides, and 20% ph ospholipid. LDL has apo B-100 in its surface and transports most of the cholesterol in circ ulation. The liver has speci \201 c LDL receptors to extract it from the circulation. Half of the b ody \200\231s circulating LDL is removed from the plasma each day, mostly by the liver. Sma ll dense or oxidized LDL (usually only 15% of the LDL pool) is not so easily recognized by these receptors and a scavenger pathway in macrophages and liver sinusoidal endothelial cel ls removes these via an acetyl-LDL receptor. Accumulation of oxidized LDL in macrophages produces the foam cells seen in atheromatous plaques. 113-Draznin-Chap113.indd 660 4/1/2011 6:44:38 PM PATHOGENESIS 661 High-density lipoproteins (HDLs) HDLs are made in the liver and gut and contain 17% cholest erol, 4% trig- lycerides, and 24% phospholipid. HDL transports 20 \200\22350% of circulatin g cholesterol. In practice, patients are managed by their levels of cholesterol (total [TC], LDL, HDL) and triglycerides. Elevated total or LDL cholesterol with normal triglycerides is hypercholest erolemia. Isolated elevation of triglycerides is hypertriglyceridemia; both together is com bined or mixed hyperlipidemia. There is a direct linear relationship between hypercholesterolemia and coronary heart disea se (CHD). A man with a TC of 250 mg/dL has double the risk of CHD of a man with a TC of 201 mg/dL and half the risk of a man with a cholesterol of 302 mg/dL. Intervention studies sho w that reductions in total and LDL cholesterol reduce coronary and cerebrovascular events, as well as mortality. HDL cholesterol has an inverse relationship with CHD, i.e., increased levels are bene \201 cial. A low HDL cholesterol may be due to lack of physical exercise, obesity, or the prese nce of hypertriglyceridemia and occurs in smokers and the metabolic syndrome. 1 Whether iso lated hypertriglyceri- demia causes vascular disease is still debated. Mixed hyperlipidemia is clearly associated with CHD. The Helsinki Heart Study 2 showed a 4- fold greater risk of cardiac events if the LDL:HDL ratio was >5.0 and the triglycerides >20 3 mg/dL compared to the rate for those with lower levels of triglycerides. Hypertriglyceridemia is associated with a low HDL cholesterol level as well as small, dense LDL particles. The aim of keeping triglycerides <132 mg/dL is to indirectly increase the H DL cholesterol as well as for the small, dense LDL to revert to the more benign, less dense LDL. Small, dense LDL has a lower binding af \201 nity for the LDL receptor, resulting in a longer t as well as greater susceptibility to oxidation. Pathogenesis Hyperlipidemia is due to a combination of genetic factors and dietary intake a nd is secondary to other conditions. It is a major risk factor for atherosclerosis. \200 Primary hyperlipidemias are usually genetically determined. \200 Secondary hyperlipidemia s are due to a combination of other diseases, drugs, and dietary anomalies. 1 American Heart Association (2009). Harmonizing the metabolic syndrome. Circulation 120:16 40 \200\2231645. 2 Frick MH, Elo O, Haapa K, et al (1987). Helsinki Heart Study: primary-pr evention trial with gem \201 brozil in middle-aged men with dyslipidemia. Safety of treatm ent, changes in risk factors, and incidence of coronary heart disease. N Engl J Med . 317:1 237-45. 113-Draznin-Chap113.indd 661 4/1/2011 6:44:38 PM CHAPTER 113 Lipids and coronary heart disease 662 Atherosclerosis In atherosclerosis, subintimal plaques start in medium-sized blood ves- sel walls when LDL cholesterol accumulates. A cholesterol-rich necrotic core surrounded by smo oth muscle cells and \201 brous tissue then develops. These plaques can calcify. If the s urface of the plaque ulcerates, thrombo- sis occurs, which can obliterate the lumen of a bl ood vessel. Plaques may result from diffusion of elevated LDL cholesterol, a qualita- tive abnormality of LDL cholesterol, endothelial cell damage, or a combi- nation of these. Endothelial cell damage may be due to the following: \200 Physical trauma, e.g., with hypertension \200 Toxins, e.g., tobacco or alcohol \200 Low-grade infection or in \202 ammation, e.g., Chl amydia \200 Immune complex damage CHD/atherosclerosis risk factors Male sex, i age, and a positive family history are all lin ked with a greater risk for atherosclerosis, but these factors are beyond our control. Seve ral modi \201 able risk factors are, however, recognized: \200 Cigarette smoking >10 cig arettes/day increase the CHD odds ratio by 6.7-fold, while stopping smoking reduces risk of myocardial infarction (MI) by 50 \200\22370% within 5 years. Hypertension increases the CHD odds ratio by 2.7-fold. Each 1 mmHg drop in diastolic blood pressure reduces the MI risk by 2 \200\2233%. Aspirin reduces MI risk by 33%. Diabetes mellitus ( b see Epidemiology, p. 605) \200 Hyperlipidemia: A 10% fall in total cholesterol results in a 25% decrease in CHD risk, and plaque regression with reducing lipids is well documented. Other: Less strongly associated factors include type A personality, hyperuricemia, lack of exercise or sedentary lifestyle, and obesity. 113-Draznin-Chap113.indd 662 4/1/2011 6:44:38 PM ASSESSMENT OF CHD RISK 663 Assessment of CHD risk According to the Adult Treatment Panel (ATP) III guidelines, lipid-l ower- ing therapy should be based on a person \200\231s absolute risk for CHD. This risk fo r CHD is divided into three categories: established CHD and CHD risk equivalents, multiple (2+) risk factors, and 0 \200\2231 risk factor. Risk factors include cigarette smoking, hypertension (BP >140/90 mmHg or on antihypertensiv e therapy), HDL <40 mg/dL, family history of pre- mature CHD (<55 years for males and <65 y ears for females, and age (men (cid:2)45 years and women (cid:2)55 years old). One risk factor is subtracted from the count for an HDL >60 mg/dL. CHD risk equivalents inc lude diabetes and clinical atherosclerotic dis- eases such as peripheral arterial disease and carotid artery disease. If an individual is noted to have multiple (2+) risk factors for CHD, a 10-year risk assess ment for CHD should be carried out using Framingham risk scoring (see Tables 113.1 for men and 113.2 for women). The number of points for each risk factor is \201 rst calculated (r isk factors include age, smoking, TC, HDL, and systolic BP), then management is determined on the basis of risk (see Chapter 116, p. 677). Lipid measurements Measurements should not be taken during an acute illness or during perio ds of rapid weight loss as these arti \201 cially lower the results. It is therefore rec- ommended to measure a full lipid pro \201 le 8 \200\22312 weeks after the acute event. How ever, according to the ATP III guidelines, a lipid analysis should be measured within 24 ho urs of an acute coronary event. This analysis is to serve as a guideline for initiating the rapy in these individuals in which LDL lowering is crucial. Pregnancy or recent weight gain will increase lipid levels. Following rapid weight gain or weight loss, at least one month should pass before reassessing lipid levels. Full lipid pro \201 le This gives the following: \200 TC \200 HDL cholesterol \200 L DL cholesterol \200 Triglycerides 113-Draznin-Chap113.indd 663 4/1/2011 6:44:38 PM 1 1 3 D r a z n i n C h a 6 6 4 p 1 1 3 . i n d C H A P T E R d 6 6 4 1 1 3 L i p d s Table 113.1 Estimate of 10-year risk for men (Framingham point scores). Reprinted with perm ission from the Third Report of the National Cholesterol Education Program (NCEP) Expert Pa nel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Trea tment Panel III) Final Report. Circulation 2002; 106(25):3143 \200\2233421. i a n d Total Cholesterol Points at Ages 20 \200\22339 Points at Ages 40 \200\22349 Points at Ages 50 \200\22359 Points at Ages 60 \200\22369 Points at Ages 70 \200\22379 c o r o n a r y Age Points 20 \200\22334 \210\2229 <160 0 0 0 0 0 35 \200\22339 \210\2224 160 \200\223199 4 3 2 1 0 40 \200\22344 0 200 \200\223239 7 5 3 1 0 h e a r t 45 \200\22349 3 240 \200\223279 9 6 4 2 1 50 \200\22354 6 >280 11 8 5 3 1 d i s e a s e 55 \200\22359 8 60 \200\22364 10 Nonsomoker 0 0 0 0 0 65 \200\22369 11 Smoker 8 5 3 1 1 70 \200\22374 12 75 \200\22379 13 4 / 1 / 2 0 1 1 6 : 4 4 : 3 8 P M 1 1 3 D r a z n i n C h a p 1 1 3 . i n d d HDL Points Systolic BP If Untreated If Treated 6 6 (cid:2)60 \210\2221 <120 0 0 5 50 \200\22359 40 \200\22349 0 1 120 \200\223129 130 \200\223139 0 1 1 2 <40 2 140 \200\223159 1 2 (cid:2)160 2 3 Point Total 10-Year Risk Point Total 10-Year Risk <0 <1% 11 8% 0 1% 12 10% 1 1% 13 12% 2 1% 14 16% A S S E S S M E N T O F 3 1% 15 20% 4 1% 16 25% 5 2% (cid:2)17 (cid:2)30% 6 2% 7 3% C H D 8 4% 9 10 5% 6% R I S K 4 / 1 6 6 5 / 2 0 1 1 6 : 4 4 : 3 8 P M 1 1 3 D r a z n i n C h a 6 6 6 p 1 1 3 . i n d C H A P T E R d 6 6 6 1 1 3 L i p d s Table 113.2 The10-year risk estimates for women (Framingham point scores). Reprinted with p ermission from the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult T reatment Panel III) Final Report. Circulation 2002; 106(25):3143 \200\2233421. i a n d Total Cholesterol Points at Ages 20 \200\22339 Points at Ages 40 \200\22349 Points at Ages 50 \200\22359 Points at Ages 60 \200\22369 Points at Ages 70 \200\22379 c o r o n a r y Age Points 20 \200\22334 \210\2227 <160 0 0 0 0 0 35 \200\22339 \210\2223 160 \200\223199 4 3 2 1 1 40 \200\22344 0 200 \200\223239 8 6 4 2 1 h e a r t 45 \200\22349 3 240 \200\223279 11 8 5 3 2 50 \200\22354 6 (cid:2)280 13 10 7 4 2 d i s e a s e 55 \200\22359 8 60 \200\22364 10 Nonsomker 0 0 0 0 0 65 \200\22369 12 Smoker 9 7 4 2 1 70 \200\22374 14 75 \200\22379 16 4 / 1 / 2 0 1 1 6 : 4 4 : 3 9 P M 1 1 3 D r a z n i n C h a p 1 1 3 . i n d d HDL Points Systolic BP If Untreated If Treated 6 6 (cid:2)60 \210\2221 <120 0 0 7 50 \200\22359 40 \200\22349 0 1 120 \200\223129 130 \200\223139 1 2 3 4 <40 2 140 \200\223159 3 5 (cid:2)160 4 6 Point Total 10-Year Risk Point Total 10-Year Risk <9 <1% 20 11% 9 1% 21 14% 10 1% 22 17% 11 1% 23 22% A S S E S S M E N T O F 12 1% 24 27% 13 2% (cid:2)25 (cid:2)30% 14 2% 15 3% 16 4% C H D 17 5% 18 19 6% 8% R I S K 4 / 1 6 6 7 / 2 0 1 1 6 : 4 4 : 3 9 P M CHAPTER 113 Lipids and coronary heart disease 668 This should be a fasting sample, preferably after a 9- to 12-hour 1 overnight fast (water i s allowed). If nonfasting, only TC and HDL cholesterol meas- urements are accurate. Triglyc erides rise postprandially and LDL is usually calculated with the formula below, so is inac curate if not fasting. It is also invalid if triglycerides are >400 mg/dL: LDL (in mg/dL) = TC \200\223 HDL \200\223 (TG/5) ATP III introduced a new secondary target for patients with elevated trig- lycerides (cid:2 )200 mg/dL, non-HDL-C: TC-HDL = LDL + VLDL= non-HDL-C The goal for non-HDL-C is 30 mg/dL above the LDL goal. 1 1 Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detecti on, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II I) \201 nal report. Circulation 2002; 106(25):3143 \200\2233421. 113-Draznin-Chap113.indd 668 4/1/2011 6:44:39 PM FAMILIAL HYPERCHOLESTEROLEMIA (FH) 669 Primary hyperlipidemias Background There are two distinct elements in the diagnosis of primary hyperlipidemias: the genotype and the phenotype. The family history and the phenotypic \201 ndings in other f amily members are used as a surrogate for a genetic diagnosis. DNA-based technology current ly employed in research can be clinically useful, not just for initial diagnosis but also f or family screening. Polygenic hypercholesterolemia This is the most common cause of isolated hypercholesterolem ia. LDL clearance appears to be reduced by a variety of mechanisms, and the E4 allele of ap o E is a common association. Patients do not have the charac- teristic xanthelasmata or ext ensor tendon deposits (xanthomata) seen in familial hyperlipidemia. It is usually diagnosed by primary screening programs or when investi- gating some manifestation of atherosclerosis. Familial hypercholesterolemia (FH) FH is an autosomal dominant disorder. Its gene frequency is 1 in 500 in Western Europe and North America. In FH, hypercholesterolemia is mainly (>95%) due to an increase in LDL cholesterol because of an LDL receptor mutation (on the short arm of chromosome 19) reducing the number of high -af \201 nity LDL receptors by up to 50%, so reducing LDL clearance and thus prolonging th e circulating time before catabolism from the normal 2.5 days to >4.5 days. More than 1000 mutations have so far been described. Less commonly, FH is due to familial d efective apolipoprotein B-100 (3 \200\2234%) and proprotein convertase subtilisin/kexin 9 g ene ( PCSK9 ) mutation (<1%). These can lead to several situations causing elevation of circulating LDL cholesterol by \200 Not producing any LDL receptors. \200 Failure of LDL receptors to m ove to the cell surface. \200 Abnormal binding of the receptor to LDL. \200 Inability t o adequately internalize LDL for metabolism. Patients with FH have premature CHD (i.e., men <55 years old, women <65 years old) and must be treated vigorously, as their standardized mor- tality ratio is at least 9 x greater than normal. 114-Draznin-Chap114.indd 669 3/31/2011 5:38:36 PM CHAPTER 114 Primary hyperlipidemias 670 Clinical characterization \200 TC >300 mg/dL (>481 mg/dL in homozygotes), LDL is high fro m birth. \200 Normal triglycerides \200 Clinical stigmata: xanthelasmic deposits around the eyes and on the tendons (i.e., \201 ngers, hands, elbow, knee, and the Achilles tend on) Tendon xanthoma is more speci \201 c for FH than corneal arcus or xanthe- lasma. 7% of het erozygote FH patients (aged >19 years of age) have tendon xanthomas, although 75% of their parents exhibit this feature. Separate studies suggest 75% of males and 72% of females with homozygous FH have tendon xanthomas. It is important to note that tendon xanthomata may no t be present until after 40 years of age. Early onset of a corneal arcus (in the 30- to 40-year age group) may occur. Achilles tendonitis in childhood may be the \201 rst clue to the presence of FH. Homozygotes can have CHD presenting in childhood and certainly before the age of 30. Hetero zygotes usually present after 30 years of age. A strong case can be made for FH where there may not be clinical stigmata but there is a strong family history and \201 rst-degree re latives with early-onset CHD, e.g., before 50 years of age. It is estimated that >50% of heterozygous FH patients will die from CHD before reaching 60 years of age if left untreated. One in 20 patients under 60 years old surviving an MI are F H heterozygotes. FH patients need to have their families investigated and the homozygous FH may need nonphar macological therapies, such as plasmapheresis, or surgical procedures such as ileal bypass, portocaval shunts, or liver trans- plantation. These treatments are not readily available and, along with pharmacological treatments, may be superseded by gene therapy in the future . Screening is by measurement of blood lipids and looking for clinical stigmata or signs. It should involve immediate family members and can be done at any age. In newborn infants, cord blood has been used to look at LDL choles- terol levels, but this screening method may be unreliable, especially in heterozygote FH. Screening children is best carried out before 10 years of age, and then again at adolescenc e and early childhood. Between the ages of 1 and 16 years, heterozygotes will have a 2-fold higher cholesterol level than that of unaffected siblings, so standard lipid pro \201 les can be used. Over 16 years of age, a full fasting lipid pro \201 le and clinical examination should be used. 114-Draznin-Chap114.indd 670 3/31/2011 5:38:36 PM RARE GENETIC HYPERTRIGLYCERIDEMIAS 671 Familial defective apolipoprotein B-100 (FDB) FDB is an autosomal dominant trait in which a genetic defect of apo B-100 results in the delayed clearance of cholesterol. It is due to a single point mutation on apo B (e.g., Arg 3500 l Gln). This condition affects about 1/600 people. All lipids originating from the liver are bound to apo B-100. Two differ- ent mutations hav e also been described that result in i levels of an LDL more prone to oxidation, causing de layed receptor pathway clearance of LDL, which overloads the scavenger pathways, thereby in creasing circulat- ing cholesterol levels. The diagnosis is made on slowly rising cholesterol levels and DNA stud- ies for the point m utation. The management is similar to that of FH. 2% of cases previously described as FH ar e estimated to be due to FDB. Protease inhibitors have been reported to exacerbate this con dition, which may present with eruptive xanthomata. Familial hypertriglyceridemia This affects up to 1/300 people, often as an autosomal domina nt trait with elevated VLDL levels, and is frequently accompanied by hypercholesterolemia. Eruptive xanthomata (red and painful) and lipemia retinalis can accom- pany massive triglyceridemia, as can pancreatitis. Exacerbating factors include alcohol and drugs such as thiazide diuretics, glucocorticoids, and the oral contraceptive pill. Adherence to a low-fat, alcohol-free diet with weight reduction usually helps. Rare genetic hypertriglyceridemias Two rare but important familial causes of gross hypertri glyceridemia are lipoprotein lipase de \201 ciency and apolipoprotien C-II de \201 ciency . Both are autosomal recessive conditions that present in childhood and are charac- terized by the presence of hyperchylomicronemia. Lipoprotein lipase is the enzyme needed to metabolize chylomicrons; complete absence of thi s enzyme and production of an inactive form are both recognized defects. A usually heterozy gous, but much rarer and more severe homozygous form is also seen. Apo C-II is needed for the activation of lipoprotein lipase, and its de \201 - ciency resu lts in hyperchylomicronemia. Patients do not have premature CHD but can have recurrent abdo minal pain due to pancreatitis. 114-Draznin-Chap114.indd 671 3/31/2011 5:38:36 PM CHAPTER 114 Primary hyperlipidemias 672 Familial combined hyperlipidemia (FCHL) FCHL is a de \201 nite risk factor for CHD. It occ urs in 1/250 people. Patients usually present around 10 years later than those with FH. The etiology is not yet known. It is the most common type of inherited dyslipidemia, estimated to cause 10% of cases of premature CHD. It has no unique clinical manifestations and the diagnosis is based on raised lipids (>95th centile for age) and a family history of premature CHD in \201 rst-degree relatives. Familial dysbetalipoproteinemia This is also known as type III hyperlipidemia or broad beta disease. It is associated with early-onset CHD. It is an uncommon disorder affecting 0.01 \200\2230.04% of people, with ele- vated IDL and chylomicron remnants. A characteristic clinical feature is the presence of palmar striae xan- thoma (orange-yello w discolorations of the palmar creases). Tuberous xanthomata, found over the tuberosities o f the elbows and knees, may also be present. The xanthomata of this familial disease can al so be found in pressure areas, e.g., heels. Apo E is a constituent lipoprotein of IDL that has three genetically determined isoforms: E 2 , E 3 , and E 4 . \200 E 3 /E 3 occurs in 55% of people, E 2 /E 2 occurs in 1%. \200 E 2 has the lowest binding af \201 nity to the apo receptors and is therefore cleared from serum mostly slowly. Apo E 4 has the greatest af \201 nity and is more rapidly cleared. \200 Patients with fa milial dysbetalipoproteinemia are phenotype E 2 /E 2 . 114-Draznin-Chap114.indd 672 3/31/2011 5:38:36 PM RARE FAMILIAL MIXED DYSLIPIDEMIAS 673 Rare familial mixed dyslipidemias These should be considered in any patient with unexplaine d neurological symptoms, organomegaly, or corneal opacities. Two inborn metabolic disorders associated with atherosclerosis are as follows: \200 Apolipoprotein A1-CIII de \201 ciency: should be suspected if hyperlipidem ia is corrected within 24 hours of infusing 500 mL of normal fresh frozen plasma Familial lecithin:cholesterol acyltransferase (LCAT) de \201 ciency: In this recessively inherited disorder, an enzyme necessary for intravascular lipoprotein metabolis m is de \201 cient, resulting in elevated cholesterol and triglycerides. Clinically, corne al lipid deposits result in visual disturbances and renal deposits in glomerular damage, pr oteinuria, and, often, renal failure. The following disorders are not linked to the occurrence of premature atheroma formation: \200 Tangier disease (analphalipoproteinemia or familial alphalipoprotein de \201 ciency ): In this autosomal recessive condition, apo A-I, which is found on HDL, is de \201 cient . HDL level is low (<5 mg/dL), as is TC, while triglycerides are normal or high. Cholestero l accumulation gives enlarged, orange tonsils, hepatosplenomegaly, polyneuropathy, and corn eal opacities. Fish eye disease: a rare disorder from northern Sweden characterized by high VLDL levels, l ow HDL, fasting hypertriglyceridemia, and a triglyceride rich LDL. It is a variant of famil ial LCAT de \201 ciency. Dense corneal opacities occur, resulting in visual impairment. Abetalipoproteinemia: results in fat accumulation due to failure of apo B-100 production. C holesterol levels are low with, in many cases, no LDL and VLDL. This results in fat accumul ation in the gut and nerves. Vitamin E injections may prevent some of the neurological abno rmalities observed (ataxia, nystagmus, dysarthria, and motor plus sensory neuropathies), bu t usually not the retinitis pigmentosa and acanthocytes, which are also features. Hypobetalipoproteinemia: This autosomal dominantly inherited condition gives a TC of 38.5 \200\223154 mg/dL and can be associated with organomegaly and neurological changes in middle age due to fat deposition and abnormal red cells. The homozy gous state is similar to abetalipoproteinemia. Hyperalphalipoproteinemia or HDL hyperlipoproteinemia: results in mildly elevated HDL and TC, and may be bene \201 cial. No treatment is needed; raised HDL can also occur with exercise, exogenous estrogen, and phenytoin and phenobarbital use, or f rom alcohol. 114-Draznin-Chap114.indd 673 3/31/2011 5:38:36 PM CHAPTER 115 Secondary hyperlipidemias 674 Secondary hyperlipidemias Background Secondary dyslipidemias are relatively common, accounting for 10 \200\22320% of hyperlipidemic adults. These can give a mixed hyperlipidemia or a lone increase in choleste rol or triglycerides. There are multiple causes, and treatment is based on managing the pri- mary disease before making a further decision on the raised lipids. Often more than one cause is apparent in se condaryehyperlipidemias. Causes Causes include those described below and listed in Table 115.1. Table 115.1 Potential causes of secondary hyperlipidemia Elevated LDL cholesterol Elevated triglycerides Reduced HDL cholesterol Diet (high saturated fats, high calories, anorexia) Diet (weight gain + excess alcohol) Diet (some low-fat diets) Drugs (glucocorticoids, thiazide + loop diuretics, ciclosporin) Drugs (glucocorticoids, B-blockers, estrogens, isotretinoin) Drugs (anabolic steroids, tobacco, B-adrenergic blockers) Type 2 diabetes Hypothyroidism Hypothyroidism Nephrotic syndrome Type 2 diabetes Insulin resistance syndromes/obesity Chronic liver disease Insulin resistance syndromes Chronic renal failure Cholestasis + biliary obstruction Cushing \200\231s syndrome Cholestasis + biliary obstruction Cushing \200\231s syndrome Pregnancy Chronic renal failure Peritoneal dialysis Pregnancy 115-Draznin-Chap115.indd 674 4/1/2011 6:47:24 PM CAUSES 675 Diet Excessive consumption of saturated fats and carbohydrate can contribute to this condit ion. Anorexia nervosa can also cause hypercholesterolemia, as a strict low-fat, low-calorie diet results in reduced cholesterol and bile acid turnover, thus increasing circulating le vels. Obesity b See Clinical features (p. 528). Diabetes mellitus b See Lipid abnormalities found in patients with diabetes (p. 629). Hypothyroidism This is estimated to occur in 4% of tho se with hyperlipidemia, and com- pensated (subclinical) hypothyroidism in a further 10%. It usually results in hypercholesterolemia with a TC of 349 \200\223776 mg/dL. It also worsen s gen- etic dyslipidemias through d synthesis of hepatic LDL receptors. Chronic renal disea se Increased creatinine clearance is accompanied by hypertriglyceridemia and a reduction in HDL cholesterol. Proteinuria in the nephrotic syndrome is associated with hypercholesterol emia. Peritoneal dialysis may increase gut glucose load and worsen hypertriglyceridemia. Re member \200\224cyclosporine increases LDL cholesterol. Liver disease Cholestatic liver disease results in hypercholesterolemia. Primary biliary ci rrhosis produces marked increases in LDL and may elevate TC to >462 mg/dL. Severe hepatocel lular damage may lower LDL cholesterol by d production of its component parts and the enzym es that metabolize it. Cushing \200\231s syndrome Glucocorticoids increase VLDL production and thus hypertriglycer idemia. The associated weight gain and glucose intolerance can make this effect more pronou nced. Lipodystrophies This is a very rare group of congenital or acquired disorders whose hall- m ark is regional, partial, or generalized fat loss associated with hyperlipi- demia, especia lly unusually raised triglycerides. They are also associated with severe insulin resistance . Glycogen storage diseases Elevated lipids (triglycerides, cholesterol and mixed hyperlipide mia) are common, but usually only in type I (Von Gierke disease), type III (Forbes disease) , and type IV (Hers disease). Gout Hypertriglyceridemia occurs in about one-third of those with gout. Alcohol excess play s a part but it is not the sole cause. 115-Draznin-Chap115.indd 675 4/1/2011 6:47:24 PM CHAPTER 115 Secondary hyperlipidemias 676 Drugs Medications commonly implicated are as follows: \200 B -blockers, especially the no ncardioselective ones \200 Thiazide diuretics \200 Exogenous estrogens \200 Anabolic steroids \200 Glucocorticoids \200 Isotretinoin \200 Protease inhibitors (said to cau se hyperlipidemia in 50% after 10 months of treatment) Excessive alcohol consumption There is a J-shaped relationship between alcohol consumption and CHD. The American Heart Association (AHA) recommends no more than 1 alcoholic drink per day for women, and 2 drinks per day for men. Pregnancy Cholesterol rises throughout pregnancy, mostly in the second trimester, with LDL- C levels peaking mid-third trimester. Triglyceride levels follow a similar pattern to that of LDL-C. Levels decrease by 6 weeks postpartum but may take up to 1 year to return to norm al. 115-Draznin-Chap115.indd 676 4/1/2011 6:47:24 PM PRIMARY AND SECONDARY PREVENTION 677 Management of dyslipidemia Background The emphasis will depend on the cause of the hyperlipidemia and is aimed at redu cing cardiovascular, peripheral vascular, and cerebrovascular risk. There are now recommend ed target values when treating patients. Primary and secondary prevention It is universally accepted that tackling hypercholesterole mia in secondary prevention works. We now have solid evidence to support this, especially i n the context of CHD, where a 10% fall in TC is estimated to result in a 25% decrease in CH D risk. Fatty lesion regression has also been clearly demonstrated. The gain is within 2 years of l owering the cholesterol, whether by diet or a combina- tion of diet and drugs. Two groups need special mention: patients with type 2 diabetes mellitus and those with acut e coronary syndrome. Both groups show early bene \201 t with statin treatment (high-dose a torvastatin 80 mg). In post-MI patients, omega-3 fatty acids are recommended as they reduce the incidence of sudden death due to arrhythmias. Tackling cholesterol in primary prevention is controversial. There have been primary preven tion trials showing bene \201 t from lowering cholesterol. The \201 nancial burden of th is has to be confronted. Speci \201 c interventions Dietary advice All patients should see a dietitian. Total fat i ntake should constitute <35% of energy consumed (with the majority of fat intake being from polyun- saturated and monounsaturated fats) and saturated fats must be <30% of the total f at content. Vegetable and marine mono- and polyunsaturated fats should be i in the diet. To tal dietary cholesterol should not exceed 200 mg/day. Foods advocated include fresh fruits and vegetables, which are also important sources of an tioxidants. These foods should be tried for 3 months to see if dietary manipulation will wo rk (monitor at 6-week inter- vals). It is unusual to see >15% fall in cholesterol from diet ary measures; a reduction of 5% is more likely in free-living individuals on a diet. Alcohol intake should be no more than 1 drink per day for a female and no more than 2 drink s per day for a male. At this level, alcohol intake con- fers CHD protection in men >40 yea rs old and postmenopausal women. 116-Draznin-Chap116.indd 677 4/1/2011 6:52:41 PM CHAPTER 116 Management of dyslipidemia 678 Plant sterols and stanols, 2 g daily, can reduce blood cholesterol by 10 \200\22315%. They are available commercially in enriched margarine spreads, yogurt, and milky drinks. Weight control All overweight patients must be encouraged to lose weight. Weight reduction is closely attuned to dietary advice and physical exercise. Most weight is lost in the \201 rst 4 months of a regimen. A 10 kg weight loss in an obese subject can reduce LDL chol esterol by 7% and increases HDL cholesterol by 13%. Physical activity Physical activity, especially aerobic exercise, is recommended. This shou ld involve moderate intensity exercise performed for a minimum of 30 min- utes, at least 5 times per week. Acute exercise will transiently change lipoprotein levels and increase lipoprotein lipase a ctivity. These effects become more permanent with regular training. Triglyceride levels fall, HDL cholesterol levels rise, especially the HDL 2 subfraction, wi th more vigorous exercise, and the LDL cholesterol is of the less-dense variety, which is n ot so atherogenic. The changes are dose dependent with i exercise, and a 20% alteration in each variable is achiev- able after 6 weeks. Modi \201 cation of other risk factors Other risk factors such as hypertension, smoking, a nd diabetes mellitus must also be addressed. Drug therapy Numerous agents can be used for both primary and secondary prevention in patie nts in whom diet has been ineffective. HMG CoA reductase inhibitors (statins) Indications These include high LDL or VLDL, i.e., pr imary hypercholesterolemia, heterozygous + homozygous FH, mixed hyperlipidemia. Not all of these medications are licensed for use in children and should be used with cau- tion in wom en of childbearing age because of insuf \201 cient safety data on pregnancy and of potenti al teratogenicity. The medication should be stopped for at least 3 months before pregnancy is planned. Women m ust be warned about pregnancy when on these drugs.