Homozygous familial

Moorjani, S., Betard, C., Brun, D., Roy, M., Gagne, C., Davignon, J., Torres, A., Lambert, M. and Lupien, P. (1993). Mutations of the LDL receptor gene, variations in plasma cholesterol and expression of coronary heart disease in homozygous familial hypercholesterolaemia. Lancet 341, 1303-1306. 

Feher MD, Webb JC, Patel DD, Lant AF, Mayne PD, Knight BL, et al. Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia. Atherosclerosis 1993 103 171-180. 

Schaefer JR, Scharnagl H, Baumstark MW, Schweer H, Zech LA, Seyberth H, et al. Homozygous familial defective apolipoprotein B-100. Enhanced removal of apolipoprotein E-containing VLDLs and decreased production of LDLs. Arter-ioscler Thromb Vase Biol 1997 17 348-353. 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

The answer is a. (Katzung, p 590.) Bile acids are absorbed primarily in the ileum of the small intestine. Cholestyramine binds bile acids, preventing their reabsorption in the jejunum and ileum. Up to 10-fold greater excretion of bile acids occurs with the use of resins. The increased clearance leads to increased cholesterol turnover of bile acids. Low-density lipoprotein receptor upregulation results in increased uptake of LDL. This does not occur in homozygous familial hypercholesterolemia because of lack of functioning receptors. 

Homozygous familial hypercholesterolemia - 10 to 80 mg/day. Use atorvastatin as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) in these patients or if such treatments are unavailable. 

Homozygous familial hypercholesterolemia HMG-CoA reductase inhibitors are less effective in patients with the rare homozygous familial hypercholesterolemia, possibly because they have no functional LDL receptors. 

Homozygous sitosterolemia As adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia. 

This effect may be due to decreasing hepatic cholesterol and cholesterol ester levels to such an extent that hepatic formation of VLDL is impaired. The statins also have been claimed to reduce blood cholesterol levels modestly in some patients with homozygous familial hypercholesterolemia, a condition often fatal in childhood or in early adulthood. 

Homozygous familial hypercholesterol PO 40 mg once daily in evening or 80 mg/day in divided doses. 

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. 

This combination is highly synergistic in treating primary hypercholesterolemia and has some use in the treatment of patients with homozygous familial hypercholesterolemia who have some receptor function. 

Indication Adjunct to diet for the reduction of elevated total cholesterol. LDL. apo B. and TG levels in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial). mixed dyslipidemia (Fredrickson types Ila and 1 lb), elevated TG (type IV) and primary dysbetali-poproteinemia (type III) Adjunct to other lipid lowering treatments for homozygous familial hypercholesterolemia ... 

Figure 1. Pedigree pattern of the B family. Relationship of the proband (T.B.) with the clinical phenotype of homozygous familial hypercholesterolemia to her other relatives whom we studied is shown. Lipoprotein patterns were determined after ultracentrifugation using NIH outpoints (51). F indicates that fibroblast cell lines were established from skin biopsies. Males, H Females, O.

Atorvastatin calcium is used as an adjunct to diet to reduce the elevated total-cholesterol, LDL, apolipoprotein B (apo B), and triglyceride (TG) levels, and to increase the HDL-C level in patients with primary hypercholesterolemia and mixed dyslipidemia. The drug is also used for the treatment of patients with an elevated serum TG levels, and for the patients with primary dysbetaliproteinemia, which do not respond adequately to diet. Atorvastatin calcium is also indicated to reduce the total-cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia (e.g., LDL apheresis) [6]. 

Figure 19.3 Lipoprotein metabolism in the human being. Details of HDL metabolism have been omitted. LPL, lipoprotein lipase FFA, free fatty acids CM, chylomicrons A-E, apoproteins A-E HDL, LDL, IDL, and VLDL are high-density, low-density, intermediate-density, and very low density lipoproteins. (Reproduced by permission from Staff writers. Heart-liver transplantation in a child with homozygous familial hypercholesterolemia. Nutr Rev 43 274-278, 1985.)...

Grossman M, Rader DJ, Muller DWM, et al A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med 1 1148-1154,1995. 

Homozygous familial hypercholesterolemia can he treated only by a liver transplant. A more generally applicable... 

In homozygous familial hypoalphalipoproteinemia, only traces of HDL cholesterol are found in plasma, and apo A-I is undetectable. These patients have corneal clouding and are at increased risk for development of premature CHD. Heterozygotes exhibit no clinical signs but have about... 

Despite inhibition of HMG-CoA reductase by statins, cells compensate by increasing enzyme expression several fold. However, the total body cholesterol is reduced by 20-40% due to increased expression of LDL-receptors after statin administration this enhances LDL (the major cholesterol carrying lipoprotein) clearance from serum with a net reduction of serum cholesterol (Chapter 20). Individuals who lack functional LDL-receptors (homozygous familial hypercholesterolemia. Chapter 20) do not benefit from statin therapy. However, statin therapy is useful in the treatment of heterozygous familial hypercholesterolemia. Since HMG-CoA reductase plays a pivotal role in the synthesis of many products vital for cellular metabolism, inhibitors of the enzyme may have toxic effects. Monitoring of liver and muscle function may be necessary to detect any toxicity of statin drug therapy. A decreased risk of bone fractures with statin therapy has been observed in subjects age 50 years or older, who are being treated for hypercholesterolemia. The mechanism of action of statins in bone metabolism may involve inhibition of prenylation... 

---