Hyperlipidemia Familial

After binding, the LDL-receptor complex is internalized by endocytosis. [Note A deficiency of functional LDL receptors causes a significant elevation in plasma LDL and, therefore, of plasma cholesterol. Patients with such deficiencies have type II hyperlipidemia (familial hypercholesterolemia) and premature atherosclerosis. The thyroid hormone, T3, has a positive effect on the binding of LDL to its receptor. Consequently, hypothyroidism is a common cause of hypercholesterolemia.]... 

VLDL in the plasma is converted to LDL—a much smaller, denser particle. Apo CM and apo E are returned to HDLs, but the LDL retains apo B-100, which is recognized by receptors on peripheral tissues and the liver. LDLs undergo receptor-mediated endocytosis, and their contents are degraded in the lysosomes. A deficiency of functional LDL receptors causes type II hyperlipidemia (familial hypercholesterolemia). The endocytosed cholesterol inhibits HMG CoA reductase and decreases synthesis of LDL receptors. Some of it can also be esterified by acyl CoAxholesterol acyltransferase and stored. 

LRP6 Missense mutation (familial, autosomal dominant) Autosomal dominant early coronary artery disease (hyperlipidemia, hypertension, diabetes)... 

Hyperlipidemia or significant family history Aripiprazole, ziprasidone Risperidone, quetiapine... 

A complete history and physical examination should assess (1) presence or absence of cardiovascular risk factors or definite cardiovascular disease in the individual (2) family history of premature cardiovascular disease or lipid disorders (3) presence or absence of secondary causes of hyperlipidemia, including concurrent medications and (4) presence or absence of xanthomas, abdominal pain, or history of pancreatitis, renal or liver disease, peripheral vascular disease, abdominal aortic aneurysm, or cerebral vascular disease (carotid bruits, stroke, or transient ischemic attack). 

BARs are useful in treating primary hypercholesterolemia (familial hypercholesterolemia, familial combined hyperlipidemia, type Ila hyperlipoproteinemia). 

Familial combined hyperlipidemia may respond better to a fibrate and a statin than to a fibrate and a BAR. 

Metabolic stress, familial hyperlipidemia, pancreatitis, excess IVFE dose rapid IVFE infusion rate... 

F13. Fonda, M., DaCol, P. G., La Verde, R., Battello, C., Fisicaro, M., Tonizzo, M., and Cattin, L., Lipoprotein(a) serum concentration in familial combined hyperlipidemia. Clin. Chim. Acta 223, 121-127(1993). 

Familial combined hyperlipidemia lib LDL, VLDL Chol,TG Increased VLDL production, increased conversion of VLDL to LDL. CHD, stroke... 

The fibrates are mainly used to treat two hyperlipi-demias, familial hypertriglyceridemia (type IV) and dysbetalipoproteinemia (type III). They are also useful in the treatment of hypertriglyceridemia associated with type II diabetes (secondary hyperlipidemia). The fibrates are the drugs of choice in treating hypertriglyceridemias, particularly those associated with low levels of HDL cholesterol. The fibrates additionally appear to... 

The answer is a. (Hardman, pp 875-898.) In type I hyperlipoproteinemia, drugs that reduce levels of lipoproteins are not useful, but reduction of dietary sources of fat may help. Cholesterol levels are usually normal, but triglycerides are elevated. Maintenance of ideal body weight is recommended in all types of hyperlipidemia. Clofibrate effectively reduces the levels of VLDLs that are characteristic of types 111, IV, and V hyperlipoproteinemia administration of cholestyramine resin and lovastatin in conjunction with a low-cholesterol diet is regarded as effective therapy for type 11a, or primary, hyperbetalipoproteinemia, except in the homozygous familial form. 

It is indicated as an adjunct to diet to reduce elevated total cholesterol, LDL-cholesterol and TG levels in patients with primary hypercholesterolemia, diabetic dyslipidaemia or mixed hyperlipidemia, hypertriglyceridemia, dysbetalipo-proteinemia and familial hypercholesterolemia. 

Dietary measures are initiated first—unless the patient has evident coronary or peripheral vascular disease—and may obviate the need for drugs. Patients with familial hypercholesterolemia or familial combined hyperlipidemia always require drug therapy. Cholesterol and saturated and trans-fats are the principal factors that increase LDL, whereas total fat, alcohol, and excess calories increase triglycerides. 

Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of LDL. Women with hyperlipidemia who are pregnant, lactating, or likely to become pregnant should not be given these agents. Use in children is restricted to selected patients with familial hypercholesterolemia or familial combined hyperlipidemia. 

In combination with a resin or reductase inhibitor, niacin normalizes LDL in most patients with heterozygous familial hypercholesterolemia and other forms of hypercholesterolemia. These combinations are also indicated in some cases of nephrosis. In severe mixed lipemia that is incompletely responsive to diet, niacin often produces marked reduction of triglycerides, an effect enhanced by marine omega-3 fatty acids. It is useful in patients with combined hyperlipidemia and in those with dysbetalipoproteinemia. It is clearly the most effective agent for increasing HDL and the only agent that may reduce Lp(a). 

This combination is sometimes useful in treating patients with familial combined hyperlipidemia who are intolerant of niacin or statins. However, it may increase the risk of cholelithiasis. 

Mixed hyperlipidemia is one of the most common lipid disorders, but only a minor fraction of the affected patients has a monogenic inherited disease. Most patients with mixed hyperlipidemia have a familial combined hyperlipidemia, a multifactorial disease for which the causative factors are not known. Patients have elevated remnant lipoproteins with elevated triglycerides > 3.0 mmol/1 and total cholesterol > 5.0 mmol/1. Two rare monogenic disorders lead to such a lipoprotein pattern,... 

The results of the lipoprotein electrophoresis have to be interpreted in the context of other lipid parameters, like plasma total cholesterol and triglyceride levels. Patients with normal cholesterol and triglyceride values may sometimes show electrophoresis patterns that resemble pathologic patterns but should not be classified as such. For untreated type III patients, plasma total cholesterol levels should range from 7.5 to 13.0 mmol/1 and triglycerides from 3.5 to 10.5 mmol/1. The presence of a broad-ji-band in the absence of hyperlipidemia excludes familial dysbetalipoproteinemia (type III). 

Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, Didangelos TP, Carina MV, Kranitsas DF, Kontopoulos AG. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997 80(5) 608-13. 

Transient diabetes and hyperlipidemia have been reported. Metabolic acidosis is probably a consequence of heavy, cholera-like diarrhea. Progressive reduction of libido was attributed to colchicine in patients with familial Mediterranean fever (312). 

Diabetes mellitus has been reported in patients taking olanzapine (from 10 mg for 2 months to 25 mg for 22 months) (861). All were switched to quetiapine. Five of the six had known risk factors for diabetes mellitus (positive family history, obesity, race, and hyperlipidemia) ... 

The consequences of hypertriglyceridemia are not well understood, but there may be an increased risk of cardiovascular disease and pancreatitis (SEDA-13, 123). Patients with an increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol intake, and a positive family history. With a short course (16 weeks) of isotretinoin it is sufficient to ensure there is no hyperlipidemia before the start of therapy, and to determine the triglyceride response to therapy on one occasion after 4 weeks (1207). 

Groenendijk M, De Bruin TW, Dallinga-Thie GM. Two polymorphisms in the apo A-IV gene and familial combined hyperlipidemia. Atherosclerosis. 2001, 158 369-76. 

Hausmann D, Johnson JA, Sudhir K, et al. Angiographically silent atherosclerosis detected by intravascular ultrasound in patients with familial hypercholesterolemia and familial combined hyperlipidemia correlation with high density lipoproteins, J Am Coll Cardiol I 996 27 1 562-1 570. 

---