Secondary causes of hyperlipidemia

0025-7125/94 $0.00 + .20

LIPID DISORDERS

SECONDARY CAUSES OF HYPERLIPIDEMIA Neil J. Stone, MD

Not invisible but unnoticed, Watson. You did not know where to look, and so you missed all that was important. SHERLOCK HOLMES

Secondary or acquired causes of hyperlipidemia can provide important clues to an underlying metabolic disorder or disease to the observant physician. A consideration of secondary causes is required before proceeding to treatment of any lipid abnormality. In addition, because secondary causes can result in either an atherogenic lipoprotein profile with heightened risk for coronary heart disease (CHD) or severe hypertriglyceridemia with the chylomicronemia syndrome and risk for acute pancreatitis, the elucidation of underlying secondary factors is crucial in any clinical evaluation of lipids and lipoproteins. The following examples show the value of considering other than primary causes of hyperlipidemia. 1. Marked or progressive elevations in lipids in the absence of a family history of hyperlipidemia. A 66-year-old man was referred for drug therapy with a striking hypercholesterolemia of 380 mg/ dL. His elevation of low-density lipoprotein cholesterol (LDL-c) was similar to that seen in a patient heterozygous for familial hypercholesterolemia. Yet there was no family history of premaThis work supported in part by the Lipid Research and Education Fund at Northwestern University School of Medicine. Note: The author has either served as a consultant or performed research for BristolMeyers Squibb, Merck and Co., Sandoz, and Parke-Davis. From the Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois MEDICAL CLINICS OF NORTH AMERICA VOLUME 78 • NUMBER 1 • JANUARY 1994

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ture CHD or hypercholesterolemia. Once a secondary cause was considered, mild symptoms of fatigue, constipation, and dry skin were elicited and a T4 thyroxine and thyroid-stimulating hormone (TSH) level confirmed the diagnosis of hypothyroidism. With appropriate therapy, his elevated TSH and characteristic deep tendon reflexes reverted to normal along with cholesterol and LDL-c levels. 2. Worsening lipid profile in a patient with primary hypercholesterolemia despite no change in lifestyle or drug adherence. A 60year-old woman being treated for mild to moderate primary hypercholesterolemia presented with higher blood pressure and mild pedal edema along with a striking increase in total cholesterol level. Before increasing lipid-lowering medication, a urine analysis was ordered. It showed 4 + albumin, suggesting superimposed nephrotic syndrome as the cause for these changes. This led to specific therapy of the underlying nephrotic syndrome. She was eventually able to return to her usual lipid-lowering therapy with good results. 3. Unresponsive hyperlipidemia. A 53-year-old woman who was not previously aware of a lipid problem (although review of older laboratory tests showed a mild to moderate hypertriglyceridemia had been present) was referred with cholesterol values of 400 to 500 mg/ dL and no response to lovastatin. She had undergone a surgical menopause 3 years earlier and was put on conjugated estrogens and norethindrone acetate. Significant hyperlipidemia occurred after the norethindrone acetate was stopped (she was thought not to require it owing to her lack of a uterus). A fasting lipid profile showed that triglycerides had jumped to the 1000 to 2000 mg/ dL range. Consideration of acquired causes of hyperlipidemia gave the necessary insights for correct management. She had a primary triglyceride removal problem, which was exacerbated by estrogen and ameliorated by progesterone.34 4. Life-threatening hyperlipidemia in a patient with previously mild hyperlipidemia. A patient who was seen at two medical centers for several pregnancies developed progressive hypertriglyceridemia and the chylomicronemia syndrome with each pregnancy. Life-threatening pancreatitis developed after one pregnancy because the patient was not adherent to the program that had been developed to deal with this acquired form of hyperlipidemia, which exacerbated her underlying mild primary hypertriglyceridemia. Careful attention to a rigid, very-Iow-fat diet allowed successful completion of subsequent pregnancies (with which she proceeded despite medical advice to the contrary). A reasonably complete list of acquired causes is given in Table 1. A simpler way for the clinician to view the secondary causes would to use the 4 D's mnemonic of diet, drugs, disorders, or diseases, as given in Table 2. Notice that secondary causes result in the following patterns of lipid and lipoprotein abnormalities.

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Table 1. LIST OF SECONDARY CAUSES OF HYPERLlPIDEMIA Predominant Lipid Abnormality

Condition Acromegaly Acute intermittent porphyria Alcohol excess Amiodarone Anabolic steroids Anorexia nervosa Alpha blockers Antiepileptics Beta blockers Burns Chlorinated hydrocarbon insecticides Cholestasis (e.g., primary biliary cirrhosis) Chronic renal failure Cyclosporine therapy Diabetes Estrogen therapy Glucocorticoids Glycogen storage diseases Growth hormone deficiency Hyperandrogenism in women Hypothyroidism Isotretinoin Lipodystrophy Myelomatosis (lgA, IgG) Nephrotic syndrome Progestins Systemic lupus and polycional gammopathy Syndrome X Thiazide diuretics Weight gain

Hypertriglyceridemia Hypercholesterolemia Hypertriglyceridemia Hypercholesterolemia Hypercholesterolemia Hypercholesterolemia Hypertriglyceridemia Hypertriglyceridemia Hypercholesterolemia

Change in High Density Lipoprotein Normal HDL Elevated HDL Low HDL Increased HDL Increased HDL Low HDL Increased HDL

Hypercholesterolemia (Lp-X) Hypertriglyceridemia Hypercholesterolemia Hypertriglyceridemia Hypertriglyceridemia Hypertriglyceridemia Hypertriglyceridemia Hypercholesterolemia Hypertriglyceridemia Hypercholesterolemia Hypertriglyceridemia Hypertriglyceridemia Hypercholesterolemia Hypercholesterolemia Hypercholesterolemia Hypertriglyceridemia

Low HDL

Hypertriglyceridemia Hypercholesterolemial hypertriglyceridemia Hypertriglyceridemia

Low HDL Low HDL

HDL ~ High-density lipoprotein; NIDDM lipoprotein seen in obstructive liver disease ..

~

Low HDL in NIDDM Increased HDL Increased HDL Low HDL Low HDL Low HDL Low HDL

Low HDL

noninsulin·dependent diabetes mellitus; Lp·X

~

special

1. They increase LDL-c. Diets rich in saturated fat and cholesterol increase LDL-c, as do diuretics. Elevations of total cholesterol over 280 mg/ dL and elevation of LDL-c above 225 mg/ dL usually are due to a primary genetic abnormality or secondary causes, such as hypothyroidism, mild to moderate nephrotic syndrome, or obstructive liver disease (e.g., primary biliary cirrhosis). 2. They increase both very-iow-density lipoprotein cholesterol (VLDL-c) and LDL-c or cause low high-density lipoprotein cholesterol (HDL-c). Often there is a primary moderate hypercholesterolemia to which is added one of a variety of secondary causes, such as excess alcohol intake, excessive calories leading to obesity,

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Table 2. EXAMPLES OF ACQUIRED CAUSES OF LIPID AND LIPOPROTEIN ABNORMALITIES

Lipidl Lipoprotein Patterns Dietary Drugs

Disorders of metabolism

Diseases

High Cholesterol Saturated fats, dietary cholesterol Diuretics, prednisone, cyclosporine

Triglyceride Excess (200-400 mg/dL)

Low HighDensity Lipoprotein Cholesterol «35 mg/dL)

Chylomicronemia Syndrome (triglyceride >1000 mg/dL)

Weight gain

Low-fat diet

Alcohol and fat plus primary disorder

Retinoic acid, beta blockers

Anabolic steroids, progestins, beta blockers Obesity, noninsulindependent diabetes

Steroids or estrogens added to primary disorder Diabetes or hypothyroidism plus primary disorder

Chronic renal failure ± dialysis

Rarely systemic lupus erythematosus, lymphoma

Hyperthyroidism, Obesity, pregnancy, noninsulindiabetes dependent diabetes, pregnancy Nephrotic Chronic renal syndrome, failure ± obstructive dialysis liver disease

pregnancy (the last two trimesters), chronic renal disease, steroids, diuretics, or beta blockers (without intrinsic sympathomimetic activity). Severe nephrosis can cause a combined elevation of both cholesterol and triglycerides, as can hypothyroidism. 3. They cause low HDL-c. This can occur with a very-Iow-fat diet (which may not be atherogenic), with anabolic or androgenic steroids, or with obesity. 4. They cause marked hypertriglyceridemia with excess VLDL and chylomicronemia. This can be a life-threatening situation because with triglyceride levels exceeding 2000 mg/ dL, the patient is prone to pancreatitis. Invariably there is a familial lipid disorder to which an acquired cause is superimposed. In fact, Chait and Brunzell24 have emphasized that a secondary cause should be looked for carefully in all patients with the chylomicronemia syndrome to prevent recurrent pancreatitis. The mechanism for the exacerbation of the underlying hypertriglyceridemia can be increased VLDL secretion, as with corticosteroid usage or alcohol, or decreased action of lipoprotein lipase, as seen in poorly controlled diabetes mellitus,9 hypothyroidism/ o6 systemic lupus erythematosus, or lymphoma. 55 DIET

Diet is covered comprehensively in another article in this issue. Dietary factors that elevate LDL-c include saturated fats, excess calories,

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and dietary cholesterol. Fish oil can also elevate LOL-c when it is given to lower triglycerides in diabetics and patients with familial combined hyperlipidemia.65 Dietary factors that lower cholesterol include soluble fiber as well as substituting unsaturated fats or complex carbohydrates for saturated fats. ~iets rich in unsaturated fats can lower HDL-c slightly in men but not in women. 94 Alcohol can raise triglycerides as well as HOL-c and can markedly aggravate hyperlipidemia in patients with preexisting hypertriglyceridemia. 24 In a survey of causes of significant hypertriglyceridemia at the Hammersmith Lipid Clinic in 1971, alcoholrelated hypertriglyceridemia was the second most common after diabetes mellitus.zs When high-fat diets are given to dieters or to fit natives living on a low-fat diet, increases in total cholesterol as well as LDL-c and HOL-c with worsening of the LOL-to-HOL ratio are seen. 91 Weight loss and anorexia are acquired causes of changes in serum lipids, which can sometimes confuse the clinician. Weight loss usually results in a prompt decline in triglycerides and an eventual rise in HOLc as ideal weight is approached. Serum cholesterol has been shown, however, to rise in humans subjected to short periods of total starvation.42 Although weight loss usually results in an increse in HOL-c, you can occasionally see an unexpected decrease in HOL-c with weight 10ss.128 Striking variability is seen with very low calorie diets when given for more than 3 months.lOs One study noted that 73% had a late rise and 36% had a rise in serum cholesterol above prediet values. Adipose tissue biopsies suggested that continued weight loss induced a major reduction in adipose mass and finally a resolution of this diet-induced hypercholesterolemia as weight loss was stopped by resumption of a eucaloric diet. Anorexia nervosa, particularly in euthyroid young women, has been known to cause in some, but not all,6 striking hypercholesterolemia with values exceeding 300 mg/ dL.84 When found, the hypercholesterolemia may be due to the diminished cholesterol and bile acid turnover secondary to the reduced caloric intake. lOl DRUGS

A comprehensive, critical analysis of drugs and their effects on lipids and lipoproteins has been published recently. 69 This article considers some of the more common and clinically important drug-lipoprotein interactions. Drug-induced lipid and lipoprotein changes can clearly improve or aggravate atherogenic risk or heighten the risk of pancreatitis when they promote severe hypertriglyceridemia. Steroid hormones can have a significant impact on lipid and lipoprotein concentrations. Cholesterol is the precursor of adrenocorticosteroids, androgens, estrogens, and progestins, so it is not surprising that these drugs affect lipid metabolism. The drug effects are not trivial; improper usage of these classes can convert a mild primary lipid abnormality into a clinically life-threatening situation. Two examples of this would be when either adrenocortical steroids ll or estrogens58 are given to someone

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with a genetic cause for impaired triglyceride clearance resulting in a marked rise in triglycerides to over 2000 mg/ dL and a full-blown chylomicronemia syndrome, often with pancreatitis. Glucocorticoids

Along with estrogens and alcohol, corticosteroids elevate triglyceride and HDL-c levels. This is in contrast to the usual situation, in which there is an inverse relationship between triglycerides and HDL-c. A study of normal men and women showed that prednisone caused total cholesterol levels to be increased by 17.3%, triglyceride levels to be increased in women only, LDL-c to be increased by 10.9% (not significant), and HDL-c to be increased by 68%.141 Prednisone increased VLDL and HDL in healthy men by increasing production of VLDL and stimulating formation of HDL.44 The most likely mechanism is increased insulin resistance. 46 Moreover, the increase in HDL-c occurs without elevation of the major protein constituents of HDL, apolipoprotein (apo) Al and A2.141 Steroids are a particular problem in the patient with impaired triglyceride removal systems (the diabetic or uremic) in whom the heightened triglyceride production can cause severe lipemia. 1O In patients post renal transplants, a change to alternate-day steroid therapy may improve hyperlipidemia if the patients are receiving minimal daily prednisone therapy.23 Anabolic Steroids

Controlled studies have shown that body builders who take these medications have a slight reduction in total cholesterol with a marked reduction in HDL-c, especially HDL2.12 Apo Al is greatly decreased as well, with only a slight increase in apo B. In some single instances, the HDL-c is barely detectable (2 to 7 mg/ dL).49 This marked reduction in HDL-c occurs within 1 to 2 weeks of beginning therapy and using Framingham risk coefficients may increase risk of a coronary event threefold to sixfold. 54 In a study designed to show the temporal relationship between hepatic triglyceride lipase (HTGL) and HDL lowering, HTGL increased dramatically and clearly with stanozolol administration before any change in HDL-c or HDL z cholestero!.S If anabolic steroid use is curtailed, there is a return to the pretreatment level in 3 to 5 weeks. One final caution: High-dose oxymetholone caused a potentially life-threatening hypertriglyceridemia in a dialysis patient treated for 51/2 weeks, with the triglycerides climbing to over 4000 mg/ dL with development of a CVA. 111 Yet when testosterone is given parenterally, the undesirable lipoprotein effects of 17-alpha-alkylated steroids given orally are not seen.127 In a comparative study, 29 mg/ day of injectable testosterone enanthate decreased HDL-c by only 9% (and mainly HDL3 ), whereas oral stanozo-

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101 decreased HDL-c and HDL2 by 33% and 71%. Importantly, LDL-c increased 29% with stanozolol but decreased 16% with injectable testosterone. The LDL-to-HDL ratio was not adversely affected by testosterone injectable. Female Hormone Preparations

Estrogens raise triglycerides and HDL-c. These are elevated 1.5-fold to 2.5-fold in proportion to the potency.8S LDL-c tends to be elevated with increasing estrogen potency in those on oral contraceptives. Progestins tend to lower triglycerides and HDL-c and in general have effects that are in the opposite direction of the estrogens. Medroxyprogesterone acetate is similar to progesterone and is used in combination with estrogen for postmenopausal estrogen replacement in women with an intact uterus. Norgestrel and norethindrone are derived from 19-nortestosterone and are used in birth control formulations with norgestrel more likely to raise LDL-c and lower HDL-c than norethindrone. In postmenopausal women, a lowering of LDL-c is expected with estrogens. One of the largest studies of women in 10 defined populations showed that premenopausal women using oral contraceptives containing a relatively low dose of estrogen combined with a medium or high dose of progestin had a 24% (P<0.05) higher median concentration of LDL-c than did those not using hormones.133 Moreover, women using oral contraceptives that are high in estrogen and low in progestin had significantly higher concentrations of HDL-c than did nonusers. Those using a low estrogen and high progestin formulation had significantly lower levels of HDL-c. Postmenopausal women using estrogen had LDL-c levels that were 11% to 19% below the levels seen in similar women who did not use replacement hormones. When two triphasic oral contraceptives were studied, it was shown that both estrogen-progestin preparations were accompanied by increases in total cholesterol, LDL, and HDL as well as apo A and B and triglycerides. There was a significant increase in the total cholesterolto-HDL but not in the LDL-to-HDL ratio in the two groups as compared with placebo. 103 Oral contraceptive users have depressed postheparin lipolytic activity and increased insulin levels to help explain the hypertriglyceridemia. 66 Exogenous estrogens affect LDL metabolism through effects on the LDL receptor and appear to retard HDL catabolism but may also increase apo Al synthesis and HDL production. Exogenous androgens appear to accelerate HDL catabolism.67 In those with an underlying primary triglyceride disorder, the addition of estrogens can lead to the chylomicronemia syndrome with acute pancreatitis as a sequela. s8 Interestingly when oral contraceptive users who exercise were compared with those who do not, there was significant improvement in triglyceride levels of the exercisers.9s Hence overweight women who do not exercise should have fasting lipids checked before birth control pills are started.

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When transdermal estrogen is given to postmenopausal women, LOL-c levels are not improved, in contrast to changes seen with oral conjugated estrogens as described earlier. 28 One small study did show a significant increase in HOL-c,122 whereas another showed that, in contrast to oral estrogens, which increase triglycerides, triglycerides declined with the use of the patch. 32 Diuretics

In short-term studies, diuretics raise total cholesterol 5% to 8%, triglycerides 15% to 25%, and LOL-c 8%? Moser lOO critically reviewed both short-term and long-term studies and demonstrated that significant elevations in total cholesterol are not seen at 1 year in most hypertension treatment trials. In the Systolic Hypertension in the Elderly Program, there was no change in total cholesterol despite a 17 mm Hg systolic and 6 mm Hg diastolic net difference in blood pressure in those randomized to chlorthalidone after 1 year. 71 It has been pointed out that small increases in lipid levels pose a greater risk to younger hypertensive subjects than to the elderly, who are more sensitive to diuretic therapy.13o There is little evidence that cholesterol concentrations increase in thiazide-treated hyperlipidemics,117 although the beneficial effects of a lowfat diet are blunted by diuretics. Nonetheless, diuretics are inexpensive, effective drugs in the therapy of hypertension. It seems reasonable that patients should be instructed on a low-fat, low-cholesterol diet along with regular exercise and that serum lipid levels be reviewed every 3 to 6 months after thiazides are started. Alpha Blackers

These antihypertensives are associated with no change in LOL-c and may cause increased HOL-c. The mechanism is thought to be diminished clearance of apo Al HOL-cYs This is in contrast to beta blockers, which tend to decrease HOL-c. In a crossover trial of an alpha blocker (prazocin) and a selective beta blocker (atenolol), the mass of intermediatedensity lipoproteins (flotation rate, 12 to 20) was significantly lower (P = 0.05) following the alpha blocker as compared with atenolol therapy. Other lipid parameters, including triglycerides and LOL-c and HOL-c, were not significantly different for the two drug treatments.124 Alpha blockers would seem to be particularly useful in diabetics or in those with abdominal obesity, in whom maintaining HOL-c would be important. Beta Blackers

Beta blockers raise triglycerides and lower HOL-c. Early studies showed a highly significant increase in basal plasma triglycerides after 3

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and 6 months treatment with propranolol, with a smaller but significant increase in atenolol-treated patients after 6 months. 36 Review of available studies suggests that all beta-blocking agents have similar effects but of different magnitudes. In a large trial of propranolol in myocardial infarction, the beta blocker group had a 17% higher mean level of triglycerides and about a 6% lower mean HDL-c with no significant effect on LDL-c. 20 Changes in lipid levels did not reduce the value of beta blockers in reducing by 20% post-myocardial infarction mortality and new events. There appears to be little difference between selective (atenolol, metopro101) and nonselective (propranolol, naldalol, or timolol) beta blockers in effects on lipids and lipoproteins. 96 The elevated triglycerides and lower HDL-c values can be countered by diet to reduce excess weight, regular aerobic exercise (often in a cardiac rehabilitation program setting), and lipid-lowering drug therapy given to achieve goals of a LDL-c approximately 100 mg/ dL and a HDL-c over 35 mg/ dL as a minimum. A carefully done study of topical beta blockers on lipid and lipoprotein concentrations showed that although there was no significant change in LDL-c, there was a 12% increase in triglycerides of borderline statistical significance and a 9% decline in HDL-c, which was significant.30 The higher the baseline HDL-c, the larger was the absolute reduction and percent decline in HDL-c level. The mean total cholesterol-to-HDL ratio increased 8% (P<0.02). Although technical factors in dosing could reduce this effect, ophthalmologists should use lowest concentration and least dosing necessary along with counseling patients on the practice of nasolacrimal occlusion or eyelid closure after drop instillation to minimize this effect. Beta blockers probably do not increase VLDL triglyceride production from the liver because free fatty acids are decreased owing to adrenergic mechanisms. 35 Decreased removal seems more likely because there is a fall in intralipid clearance, which is likely mediated through inhibition of lipoprotein lipase (LPL) activity. Beta blockers with intrinsic sympathomimetic activity are not associated with lowered HDL-c. This is also the case with labetalol,90 which is combined alpha/beta blocker and beta blocker. Sympatholytics

Clonidine is associated with either no aggravation of LDL and total cholesterol or slight improvement. Alpha methyldopa is neutral with respect to lipids. 136 Angiotensin Converting Enzyme Inhibitors

These agents are neutral with respect to lipids. Calcium Channel Blockers

These are neutral with respect to lipids.

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Retinoids (Isotretinoin)

Retinoids, which are given for acne, cause an increase in cholesterol and triglycerides, especially the latter.92 Triglyceride levels often exceed 200 mg/ dL and can rise as high as 1155 mg/ dU 6 , 81 The LDL-to-HDL ratio is elevated. The data are consistent with a hepatic oversecretion of VLDL and apo B. There is a reduction in HDL-c and HDLz and no change in apo AV04 Lipoprotein has been shown to rise with this therapy. Once retinoids are begun, peak lipid levels occur by 4 weeks of treatment in men and 12 weeks in women. 16 The lipid and lipoprotein changes seen reverse promptly with cessation of therapy. For those who begin therapy with retinoids, regular exercise, avoidance of weight gain, and limitation of alcohol help reduce the associated hypertriglyceridemia. Cyclosporine Treatment

Cholesterol increased by 21%, LDL by 31 %, and apo B by 12% in 36 men with amyotrophic lateral sclerosis receiving cyclosporine. 14 Cyclosporine is a highly lipid soluble, with 40% of cyclosporine in the intravascular compartment bound to lipoproteins.93 Also lipoprotein(a) levels are higher in renal transplant recipients treated with cyclosporine as contrasted with those receiving only azathioprine and prednisolone. 135 Severe hypertriglyceridemia has occurred after a course of cyclosporin A after bone marrow transplantation. The triglyceride level was 3215 mg/ dL with headache, visual disturbance, and neurologic disturbances. Two plasma exchange sessions lowered the triglyceride level to 486 mg/ dL.130 Clinicians are cautioned to avoid hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors with cyclosporine owing to the enhanced risk of myositis from this combination, unless it is absolutely necessary. Doses should be limited to no more than 20 mg of lovastatin or pravastatin (or 10 mg of simvastatin) with the patient aware of the need to report muscle aching or fatigue or any untoward abnormality promptly.86

H2 Blockers (Cimetidine, Ranitidine) Cimetidine was observed to raise HDL-c dramatically in a middleaged woman with remnant hyperlipidemia. 97 A controlled trial, but essentially in men, concluded that there was no significant effect,7° but in a comparison study against ranitidine, cimetidine raised HDLz cholesterol by 48% after 12 weeks in women but not in men. 60 Ranitidine had no effect on HDL in either men or women. Antiepileptic Drugs

Phenobarbital, phenytoin, and carbamazepine appear in most studies,l°z, 110 but not all,48 to increase serum HDL-c and apo Al as com-

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pared with non treated epileptic patients or controls. Women may show a greater medication effect on HDL-c. When 100 adult epileptic patients receiving long-term phenytoin treatment were compared with a like number of controls, patients showed higher HDL-c, apolipoproteins A and AI, gamma glutamyltransferase levels, and lower LDL-c and apo B values; the significance of the results was greater in women than in men. 21 Tamoxifen

HDL-c and the HDL-c-to-total cholesterol ratio rose significantly while 46 postmenopausal and 8 premenopausal women were treated for advanced breast cancer with tamoxifenY Total cholesterol did not significantly change. LDL-c was significantly decreased. Triglycerides and free fatty acids did not change markedly. The associated rise of sex hormonebinding globulin and thyroxine-binding globulin suggested that the increase of HDL-c with prolonged use of tamoxifen is likely due to an intrinsic estrogenic effect of tamoxifen on the liver. Tamoxifen is associated with a less atherogenic profile but should not be used for this reason until clinical trial data are at hand. Amiodarone

Amiodarone is a powerful antiarrhythmic that elevates cholesterol independent of its effects on thyroid hormone.137 It can cause thyroid abnormalities owing to its iodine content. DISORDERS OF METABOLISM Hypothyroidism

Although the correlation between high cholesterol and myxedema has been known for more than six decades,s1 one lipid clinic reported that 10% of those referred over a 4-year period had high TSH without previous laboratory screening for low thyroid. 56 A population screening program noted hypothyroidism in 6% of apparently healthy people with total cholesterol exceeding 272 mg/ dL.13 A similar program in Glasgow yielded a prevalence of 4.4% when individuals with total cholesterol exceeding 310 mg/ dL had thyroxine and TSH determined?3 An additional 9% were found to have raised TSH levels only, suggesting subclinical hypothyroidism. Such subclinical hypothyroidism should be treated to achieve a decrease in LDL-c and apo B levels with less atherogenic total cholesterol-to-HDL-c and LDL-c-to-HDL-c ratios? Even lipoprotein(a) levels are shown to decrease in the same direction and magnitude as apo B.38 The mechanism of the hypercholesterolemia seen with hypo-

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thyroid ism is a decrease in LDL catabolism by way of the LDL receptor pathway.l26 Thyroid deficiency is also implicated in hypertriglyceridemia. Because thyroid deficiency can lead to a decrease in LPL activity, the hypertriglyceridemia of an underlying genetic triglyceride disorder can be exacerbated, and chylomicronemia can occur. It can interfere with remnant metabolism, and so individuals with the E2/E2 genotype who would otherwise remain asymptomatic may present with marked lipid elevations and tuboeruptive xanthomas. Hypothyroidism clearly can be important in modulating the clinical expression of this rare but dramatic form of hyperlipidemia. 6s,89 Because thyroid deficiency can explain virtually any commonly appearing lipid abnormality, a thyroxine and/ora TSH level should be determined in any patient with elevated lipids. A thyroxine level alone is not sufficient because it misses cases of subclinical hypothyroidism. Obesity

Obese subjects often have increased triglycerides and low HDL-c. Obese subjects have increased synthetic rates for cholesterol and bile acids. They have increased turnover of apo LDL, but this is not necessarily associated with high LDL-c levels. S] Another way to look at lipid and lipoprotein changes in obesity is to consider what happens when the obese undergo weight loss. With weight loss, triglycerides decrease early with a delayed effect on rise of HDL-c. 13S, 14J When obese patients lose weight to nearly ideal levels, LDL-c shows no change. When body fat distribution is studied, men and women with elevated waist-hip ratios are shown to have increased levels of cholesterol, triglycerides, and apo B along with decreased levels of HDL-c. 2 The term deadly quartet has been coined to refer to the syndrome of abdominal or upper body obesity, glucose intolerance, hypertension, and hypertriglyceridemia, which is seen in those greatly inclined to premature CHD?8 Diet and exercise are needed for such patients as a first step. Diabetes Mellitus

Lipids and diabetes are covered comprehensively in another article elsewhere in this issue. Nonetheless, a few comments regarding diabetes as a secondary cause of lipid abnormalities are in order here. The treatment of both the diabetes and atherogenic lipid and lipoprotein abnormalities is important owing to the high incidence of atherosclerotic vascular disease?4, 77 In noninsulin-dependent diabetics, mild hypertriglyceridemia and low HDL-c are often seen and are due to both overproduction and removal defects. When a familial form of hypertriglyceridemia that causes enhanced production of triglyceride-rich VLDL and noninsulin-dependent diabetes coexist, removal mechanisms for dietary

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glyceride become saturated. IS This leads to the chylomicronemia syndrome, which if undetected for too long can lead to pancreatitis. 26 In these patients, the first step in therapy is to stop fat intake and use medication and exercise to improve LPL activity. For those with mild to moderate hypertriglyceridemia with low HOL-c, diet and exercise must be strongly emphasized. HMG CoA reductase inhibitors may be the drugs of choice for patients with elevated LOL-c and triglycerides under 500 mg/ dL, whereas gemfibrozil is required for those with triglycerides over 500 mg/ dL.s2 Niacin can worsen noninsulin-dependent diabetes and should usually be avoided. Fibrates can improve the triglyceride and HOL-c abnormalities, but LOL-c can elevate reciprocally. HMG CoA reductase inhibitors strikingly lower LOL-c as well as improve triglyceride and HOL-c. For those with insulin-dependent diabetes, the use of tight control via the insulin pump can lead to lower LOL-c. 41 Pregnancy and Lactation

During pregnancy, the plasma cholesterol rises on average about 50% with the major increase occurring during the second trimester. lo7 Triglycerides rise threefold, reaching a peak during the third trimester. The occurrence of hypertension or preeclampsia led to a further increase in lipids in the VLOL fraction. Women in their third pregnancy showed higher cholesterol values than women in their first. Both cholesterol and triglycerides decreased significantly within 24 hours of delivery. At 6 weeks postpartum, the total plasma triglycerides fall to baseline.98 Of interest, those women who during pregnancy have a rise in triglycerides above the 95th percentile may become overtly hyperlipidemic as they age. The increased triglycerides seen in pregnancy are likely due to overproduction of triglyceride-rich VLOL. 72 There are two important implications of the hyperlipidemia seen in pregnancy. Animal studies show that despite lower HOL-c in pregnant cynomolgus monkeys, they had only one half as much diet-induced coronary artery atherosclerosis as compared with their nonpregnant counterparts.29 Thus clinicians should reassure pregnant patients that the high cholesterol levels will not lead to an increased risk of myocardial infarction. For those who before becoming pregnant had an underlying hypertriglyceridemia owing to a genetic triglyceride removal problem, the second or third trimester of pregnancy can be complicated by acute, life-threatening pancreatitisespecially if special dietary precautions are not taken as triglycerides climb with each trimester to exceed 2000 mg/ dL. ll3 NONMETABOLlC DISEASES Liver

Cholestasis causes prominent hypercholesterolemia. Patients with primary biliary cirrhosis can present with elevated total cholesterol and

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cutaneous xanthomas that can mimic changes seen in genetic hypercholesterolemia. Total cholesterol levels can be as high as 500 to 1000 mg/ dL with significant lowering accomplished by cascade filtration plasma exchange or liver transplantation. 19 The hyperlipidemia seen is due to accumulation of an abnormal lipoprotein called lipoprotein-X (Lp_X).1I7 Lp-X is separated in the LDL density range but lacks apo B and does not interact with the LDL receptor, hence its resistance to usual modes of therapy. Its presence reflects substrate excess rather than enzyme deficiency owing to reflux of biliary lecithin into plasma. This interacts with free cholesterol, albumin, and apo C in plasma, and if this exceeds the cholesterol esterifying capacity of lecithin cholesterol acyltransferase (LCAT), Lp-X is formed. In hepatocellular damage, hepatic production of apolipoproteins and enzymes involved in lipoprotein metabolism may be impaired. 116 If LCAT is involved, cholesterol esterification is impaired, and free cholesterol levels are elevated?7 Moreover, the degree of impairment of esterification generally parallels the severity of the hepatic dysfunction. 119 An informative case study of a patient with hepatitis B showed that during the preicteric phase, there was a steady, progressive decrease in plasma cholesterol with a fall in cholesterol esterification during the acute icteric phase. 114 In advanced liver disease, lipoprotein synthesis is impaired with low levels of lipoproteins. 1 Liver disease makes the use of lipid-lowering agents more problematic. Alcohol use should be curtailed and obesity treated with a hypocaloric diet and regular exercise to see if this reduces elevated liver enzymes to the normal range before beginning lipid therapy. Gallstones should be sought as a cause of elevated enzymes in patients who have had fibric acid drugs such as clofibrate or gemfibrozil in the past. The use of reductase inhibitors must be carefully considered when any liver disease is present because concentrations of reductase inhibitors may rise owing to decreased biliary excretion causing myositis. 120 Renal Disease

Patients with chronic renal failure as well as those undergoing hemodialysis and peritoneal dialysis 8 have increased triglyceride and low HDL-c with triglyceride enrichment of HDL and LDL. The latter effect suggests decreased activity of hepatic triglyceride lipase (HTGL)Y9 Studies of patients with renal failure on hemodialysis have implicated impaired triglyceride removal with decreased LPL as an important cause of the lipid abnormalities, which is only partially corrected by increasing the efficiency of the dialysis. 22 Peritoneal dialysis causes higher, more sustained triglyceride levels owing to resorption of large amounts of glucose from peritoneal dialysis fluid that stimulate hepatic VLDL synthesis. The abnormal HDL composition seen in long-term dialysis patients is one of several factors that predispose this group to atherosclerosis.108 Similar to diabetes, atherosclerotic vascular disease is seen often in patients with renal failure. The treatment dilemma in chronic renal

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failure is that elevated triglyceride levels are not considered independent risk factors in the prevention of CHO and as such are not "primary targets for therapy." Nonetheless, the hypertriglyceridemia seen in chronic renal failure may represent atherogenic lipoproteins, such as chylomicron and VLOL remnants; intermediate density lipoproteins; and small, dense LOL. 62 Treatment of the dyslipidemia is difficult also because of lack of data concerning the benefits versus the risks or negative aspects of drug therapy in these patients. Weight reduction; reduction of carbohydrates, especially sucrose; and regular exercise should reduce overproduction of VLOL and lower triglyceride values and should be recommended. For patients with triglycerides exceeding 750 mg/ dL and risk of pancreatitis, careful use of gemfibrozil is indicated. 3 Gemfibrozil can restore LPL activity and improves HOL-c but must be used with caution at a reduced dosage of 300 mg twice daily owing to the risk of myositis because it is largely renally excreted.27 Niacin can be used if triglyceride values are under 750 mg/ dL and accompanied by low HOL-c. The side effects of niacin may limit its usefulness in these patients. Reductase inhibitors have not been tested adequately but could prove useful in decreasing the levels of atherogenic remnant lipoproteins. 62 Renal transplantation does not eliminate the problem of hyperlipidemia (see discussion of transplantation). Nephrosis

The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and hypercholesterolemia. l32 Hypertriglyceridemia usually occurs later when albumin levels are lower. An informative, recent study of 20 consecutive adult cases of uncomplicated nephrotic syndrome with more than 3 g of albumin in the urine per day showed that the mean values for lipids and lipoproteins were cholesterol 302 ± lOO, triglycerides 223±163, LOL-c 2I5±89, and HOL-c 46±18 mg/dL. 4 A significant correlation was found between the total plasma cholesterol and both the plasma albumin concentration and plasma oncotic pressure but not the plasma viscosity. Most studies agree that the mechanism is overproduction of LOL. In some patients, there is delayed catabolism of VLOL as well.l32 LOL apo B returns to normal after recovery from nephrosis?5 Loss of HOL (although intact apo Al is not found) in the urine can account for depressed values of HOL-c. Increased lipoprotein(a) has been described in nephrosis,79 which along with the lowered HOL-c and increased LOL-c could increase the risk of CHO.76 Although not all studies of nephrosis describe increased incidence of coronary disease,134 the severity of the lipid defects coupled with systemic factors, such as hypertension, corticosteroid therapy, and increased clotting tendencies, all contribute to the accelerated atherosclerosis seen at necropsy?l Treatment of proteinuria is the first step because angiotensin converting enzyme inhibitors or calcium channel blockers can be associated

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with improvement in lipid levels as proteinuria lessens. In one study using an angiotensin converting enzyme inhibitor, the reduction in proteinuria was accompanied by a decline in the excess lipoprotein(a) as welLB2 Treatment of hyperlipidemia is recommended to reduce the risk of atherosclerotic vascular disease and theoretically to reduce the chance that hyperlipidemia may further aggravate initial glomerular injury and contribute to a progressive glomerulopathy, which experimentally is primarily mediated through alterations in monocyte/macrophage function. 39 HMG CoA reductase inhibitors could prove particularly effective here because they promote a decrease in VLDL triglycerides owing to enhanced catabolism and lowered LDL-c owing to reduced input rates for LDL_c. 63 ,64 HDL-c levels are also raised, If triglyceride levels are under 250 mg/ dL addition of small doses of resin therapy may be useful as well in controlling LDL-c, Gemfibrozil, particularly when combined with resins, can lower cholesterol and triglycerides and improve LDL-to-HDL ratios.33 It is protein bound, so its use in patients with hypoalbuminemia can be difficult. Porphyria

Hypercholesterolemia occurs in some patients with inherited hepatic porphyrias, Lees et al87 documented the presence of increased LDL-c or hyperbetalipoproteinemia in acute intermittent porphyria. Systemic Lupus Erythematosus

Combined elevations of cholesterol and triglycerides are seen in lupus patients as contrasted with healthy female outpatients.43 When patients without prednisone were compared with controls, those without had lipid levels similar to controls except that HDL-c was lower. Moreover, further studies have shown that apo B may be elevated, even when lipids are normal. This atherogenic profile may increase the risk of CHD seen in these patients. 45 Rarely severe hypertriglyceridemia is seen in systemic lupus erythematosus. Glueck et al 57 described severe chylomicronemia owing to lipase deficiency caused by abnormal heparin binding in a patient with systemic lupus erythematosus. Autoimmune Hyperlipidemia

Moderate to severe hypertriglyceridemia, xanthomatosis, and hyperIgA globulinemia with the appearance late in the course of vascular disease have been described. ss Multiple myeloma did not develop. Treatment with diet and clofibrate resulted in xanthoma regression. Deposits of betalipoprotein and IgA globulin were found in atherosclerotic material biopsied from atherosclerotic plaques in peripheral vascular sites.

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Burns

Transient hypertriglyceridemia occurs in patients with severe thermal injury.l31 The mechanism is shown to be reduced levels of apoproteins necessary for triglyceride metabolism leading to impaired lipolysis with reduced clearance of exogenous triglyceride from the plasma. Transplantation

Transplant survivors have multifactorial causes for the hyperlipidemia that is seen. Often a multiplicity of factors can aggravate hyperlipidemia, including weight gain; use of steroids, cyclosporine, and antihypertensives; and development of diabetes mellitus. Kasiske and Umen80 followed 201 clinically stable renal transplant recipients a mean of 5 years posttransplant. They found that hypertriglyceridemia was less common with follow-up, whereas hypercholesterolemia had increased from 8% before transplantation to 30% at time of last follow-up. HDL-c was normall year after transplantation. Multivariate analysis showed that age, body weight, pretransplant lipids, and variables linked to allograft function (urine protein excretion, serum creatinine, and use of loop diuretics) were independently correlated with posttransplant lipids, whereas diabetes and use of alternate-day steroids, beta-adrenergic blocking drugs, and thiazide diuretics were not. The Mayo Clinic noted hypercholesterolemia (>240 mg/ dL) in more than half of the posttransplant survivors at 1 year. 59 The nondiabetic, hypercholesterolemic group had significantly greater mean values for weight gain (11.2 kg) and actual weight relative to ideal body weight (19.4 kg) than those with lower cholesterol values. Because the daily dose of prednisone and the serum creatinine levels were similar in these two subgroups, the authors recommended that weight control should be a priority after transplantation. Cattran et aF' studied young, nonobese transplant survivors and noted 44% with hypertriglyceridemia. Triglyceride turnover studies showed that overproduction was the predominant defect both in patients receiving massive steroids to reverse rejection and in stable long-term survivors. Changing to alternate-day equal dose steroid therapy showed improvement in both the absolute triglyceride concentration and triglyceride production rate. Alternate-day steroid therapy did not, however, improve hypertriglyceridemia or increase HDL-c levels in children. 40 Cardiac transplantation is associated with a marked increase in LDL-c. This seems to be explained by prednisone therapy and preoperative cholesterollevel as well as age. m , 125 A three-center study showed that 52% of heart transplant recipients were above the 75th percentile and 35% above the 90th percentile for total cholesterol, with similar elevations in LDL-c, triglycerides, and HDL-c. 1S Bivariate analysis showed cumulative prednisone exposure and cumulative cyclosporine exposure to explain best these findings. Step wise linear multiple regression analysis demonstrated cumulative prednisone to be the strongest predictor of both total choles-

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terol and LDL-c levels and percentiles independent of cyclosporine. When prednisone is removed from the posttransplantation regimen, the lipids are less elevated, and there appears to be less coronary disease.109 Not everyone faults prednisone because increased cholesterol levels were reported during the usual decrease in prednisone dosage posttransplant in another series. 121 In another large series, LDL-c, apo B100, HDL-c, and apo Al all increased such that the LDL-to-HDL ratio was constant. There was an unexpected decrease in lipoprotein(a) after transplantation, suggesting that metabolism of lipoprotein(a) is independent of LDL-c and may be affected by immunosuppressive drugs. 47 Moreover, HTGL seems to be higher and LPL is lower in these patients. m In multiple regression analysis, cyclosporine was a major cause of variation in HTGL levels. The significance of the hyperlipidemia is that despite low-fat diets, more than 50% of all patients undergoing cardiac transplantation who survive more than 3 years have vascular disease. 129 Hypercholesterolemia may play a role in the accelerated progression of the transplant coronary arteriopathy. Of note, the prevalence of accelerated coronary artery disease has been unaltered since cyclosporine has been given. 50 Therapy of hyperlipidemia after transplantation consists of a caloriecontrolled, low-saturated-fat, low-cholesterol diet and regular exercise to prevent weight gain, lower LDL-c, and improve HDL-c. Bile acid resins may interfere with cyclosporine levels; moreover, they should not be used if the triglycerides are over 250 mg/ dL. Niacin can be used cautiously but may further aggravate glucose intolerance if large doses of prednisone are used concomitantly. Myopathy can occur if niacin or gemfibrozil is added to reductase inhibitors (lovastatin, pravastatin, simvastatin). Although reductase inhibitor levels in transplant patients are 4 to 8 times that seen in normal volunteers, these potent drugs can be used to lower LDL-c if doses are kept low. For example, to avoid the myositis and possible rhabdomyolysis and renal failure that can ensue when lovastatin is used at higher dosages, no more than 10 to 20 mg/ day of lovastatin should be used in this setting.86 Patients should be reliable, closely followed, and able to recognize and report early symptoms of myositis so the drug can be stopped promptly. SUMMARY

Secondary causes of hyperlipidemia are important to recognize. In fact, hyperlipidemia may be a clue to the presence of an underlying systemic disorder. It may greatly heighten the risk of atherosclerosis with a raised LDL-c, triglyceride-rich lipoprotein excess, and increased lipoprotein(a) as well as lowered HDL-c. The search for secondary causes may provide a clue as to why patients with primary lipid disorders suddenly develop worsening lipid profiles. The point is a crucial one because some acquired causes of hyperlipidemia, such as alcohol, estrogens, steroids, or pregnancy, when superimposed on a primary familial form of hypertriglyceridemia can result in a saturated removal system

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and a buildup of chylomicrons, which can lead to life-threatening pancreatitis. A convenient way to remember secondary causes is to think of the four O's of diet, drugs, disorders of metabolism, and diseases. Although diets rich in saturated fats and cholesterol are a common cause of the mild hypercholesterolemia seen in our society, alcohol excess and weight gain can explain much of the tendency toward hypertriglyceridemia. Interestingly anorexia nervosa has long been associated with severe but reversible hypercholesterolemia. Several classes of drugs need to be considered as common causes of altered lipid profiles. Glucocorticoids and estrogens elevate triglycerides and raise levels of HOL-c. Anabolic steroids taken orally markedly reduce levels of HOL-c in contrast to injectable testosterone, which does not adversely affect the LOL-to-HOL ratio. Oral contraceptives affect atherosclerotic risk depending on the kind and doses of progestin/ estrogen. In those with an underlying primary hypertriglyceridemia and associated obesity, estrogenic medications can depress triglyceride removal mechanisms, leading to the chylomicronemia syndrome and pancreatitis. Antihypertensives have variable effects on lipids and lipoproteins. Although short-term thiazide usage raises cholesterol, triglycerides, and LOL-c, long-term usage is not necessarily associated with significant alterations in lipid levels. Alpha blockers may cause an increase in HOLc, whereas beta blockers raise triglycerides and lower HOL-c. Sympatholytics, angiotensin converting enzyme inhibitors, and calcium channel blockers are essentially lipid neutral. Retinoids can be associated with increased LOL-to-HOL ratios and occasionally striking elevations in triglycerides. Cyclosporine raises LOL-c and lipoprotein(a). Classes of drugs that may raise HOL-c include cimetidine, antiepileptic drugs, and tamoxifen, but the effect may be seen primarily in women. Hypothyroidism is the most common secondary cause of hyperlipidemia after dietary causes are considered. A thyroxine and TSH level should be obtained on all new cases of clinically important hyperlipidemia. Obesity, diabetes mellitus, and pregnancy are important hormonal disorders that have a primary effect on triglyceride and HOL metabolism. When superimposed on a familial triglyceride disorder, the chylomicronemia syndrome as described earlier can result. Systemic disorders, such as liver, kidney, and immunology disorders, can be secondary causes of hyperlipidemia. Liver disease when characterized by cholestasis can cause severe hypercholesterolemia owing to an abnormal lipoprotein, Lp-X, which lacks apo B and is not governed by the LOL receptor. Plasma exchange may be required to control its manifestations. Patients with renal failure may have heightened atherosclerosis owing to accumulation of triglyceride-rich lipoproteins as a result of impaired triglyceride clearance. Those with nephrosis have heightened LOL production rates in part driven by urinary losses of albumin and lower HOL-c owing to loss of HOL in the urine. Transplantation improves underlying organ function and lipid abnormalities owing to this, but owing to weight gain, prednisone, and immunosuppresive therapy (e.g., cyclosporine), can be associated with a complex

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form of secondary hyperlipidemia. Thus, in general, treatment of the underlying disorder or alteration or discontinuation of drug therapy can lead to improvement. Specific lipid-lowering therapy may still be required to reduce the risk of atherosclerosis or pancreatitis after the aforementioned steps are accomplished. Drug dosages may need to be modified in the setting of organ dysfunction or multiple medications. References 1. Agorastos I, Boswell C, Harry DS, et al: Plasma lipoproteins in liver disease. Biochem Soc Trans 4:593, 1976 2. Anderson AI, Sobocinski KA, Freedman DS, et al: Body fat distribution, plasma lipids, and lipoproteins. Arteriosclerosis 8:88-94, 1988 3. Anderson CF: Hyperlipoproteinemia in adults with renal disease. Mayo Clin Proc 68:358-362, 1993 4. Appel GB, Blum CB, Chien S, et al: The hyperlipidemia of the nephrotic syndrome. Relation to plasma albumin concentration, onc otic pressure and Viscosity. N Engl J Med 312:1544-1548,1985 5. Applebaum-Bowden D, Haffner SM, Hazzard WR: The dyslipoproteinemia of anabolic steroid therapy: Increase in hepatic triglyceride lipase precedes the decrease in high density lipoprotein cholesterol. Metabolism 36:949-952, 1987 6. Arden MR, Weiselberg EC, Nussbaum MP, et al: Effect of weight restoration on the dyslipoproteinemia of anorexia nervosa. J Adolesc Health Care 11:199-202, 1990 7. Arem R, Patsch W: Lipoprotein and apolipoprotein levels in subclinical hypothyroidism. Effect of levothyroxine therapy. Arch Intern Med 150:2097-2100, 1990 8. Bagdade J. Casaretto A, Albers J: Effects of chronic uremia, hemodialysis, and renal transplantation on plasma lipids and lipoproteins in man. J Lab Clin Med 87:37-48, 1976 9. Bagdade JD, Porte D, Bierman EL: Diabetic lipemia: Form of acquired fat-induced lipemia. N Engl J Med 276:427-433, 1967 10. Bagdade JD, Porte D, Bierman EL: Steroid-induced lipemia. A complication of high dosage corticosteroid therapy. Arch Intern Med 125:129-134, 1970 11. Bagdade JD, Porte D, Bierman EL: Steroid induced lipemia Arch Intern Med 125:129134, 1970 12. Baldo-Enzi G, Giada F, Zuliani G, et al: Lipid and apoprotein modifications in body builders during and after self-administration of anabolic steroids. Metabolism 39:203208, 1990 13. Ball MJ. Griffiths D, Thorogood M: Asymptomatic hypothyroidism and hypercholesterolaemia. J R Soc Med 84:527-529, 1991 14. Ballantyne CM, Podet El, Patsch WP, et al: Effects of cyclosporine therapy on plasma lipoprotein levels. JAMA 262:53-56, 1989 15. Becker DM, Chamberlain B, Swank R, et al: Relationship between corticoid exposure and plasma lipid levels in heart transplant recipients. Am J Med 85:632-638, 1988 16. Bershad S, Rubinstein A, Paterniti JR, et al: Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med 313:981-985,1985 17. Bruning PF, Bonfrer JM, Hart AA, et al: Tamoxifen, serum lipoproteins and cardiovascular risk. Br J Cancer 58:497-499,1988 18. Brunzell JD, Hazzard WR, Porte D Jr, et al: Evidence for a common saturable triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man. J Clin Invest 15:78-85, 1973 19. Busnach G, Franceschini G, Chiesa G, et al: Impaired efficacy of selective LDL-apheresis in primary biliary cirrhosis. Int J Artif Organs 14:246-250, 1991 20. Byington RP, Worthy J. Craven T, Furberg CD: Propranolol-induced lipid changes and their prognostic significance after an MI: the Beta Blocker Heart Attack Trial experience. Am J CardioI65:1287-1291, 1990

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