Heterozygous familial hypercholesterolemia

Karayan L, Qiu S, Betard C, Dufour R, Roederer G, Minnich A, et al. Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ( French Canadian mutation ) of the LDL receptor gene. Arteriosder Thromb 1994 14 1258-1263. 

A 40-year-old male with markedly elevated cholesterol, diagnosed as having heterozygous familial hypercholesterolemia, is treated with cholestyramine. What is the mechanism of action of cholestyramine ... 

Heterozygous familial hypercholesterolemia in pediatric patients 10 to 17 years of age - Recommended starting dose is 10 mg/day the maximum recommended dose is 20 mg/day. Individualize doses according to recommended goal of therapy. Make adjustments at intervals of 4 weeks or more. 

Adolescents 10 to 17 years of age with heterozygous familial hypercholesterolemia - Usual recommended starting dose is 10 mg once a... 

Children Atorvastatin, simvastatin, and lovastatin are indicated for treatment of patients 10 to 17 years of age with heterozygous familial hypercholesterolemia. Pravastatin is indicated for the treatment of patients 8 to 18 years of age with heterozygous familial hypercholesterolemia. Safety and efficacy have not been established for atorvastatin, simvastatin, and lovastatin in prepubertal patients and patients younger than 10 years of age. Safety and efficacy have not been established in patients younger than 8 years of age for pravastatin. Safety and efficacy have not been established in patients younger than 18 years of age for fluvastatin. Safety and efficacy of rosuvastatin have not been established in pediatric patients. 

Answer The patient has heterozygous familial hypercholesterolemia (type Ila) that is aggravated by lifestyle factors (obesity, high fat diet, stress, no exercise). Her LDL cholesterol is markedly elevated other lipids are normal she has angina and she has a family history of heart disease. Her hypertension would probably improve with a decrease in body weight. 

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). 

For treatment of heterozygous familial hypercholesterolemia, most patients require 2-6 g of niacin daily more than this should not be given. For other types of hypercholesterolemia and for hypertriglyceridemia, 1.5-3.5 g daily is often sufficient. Crystalline niacin should be given in divided doses with meals, starting with 100 mg two or three times daily and increasing gradually. 

This combination effectively controls VLDL levels during resin therapy of familial combined hyperlipoproteinemia or other disorders involving both increased VLDL and LDL levels. When VLDL and LDL levels are both initially increased, doses of niacin as low as 1-3 g/d may be sufficient in combination with a resin. The niacin-resin combination is effective for treating heterozygous familial hypercholesterolemia. 

The drugs may be taken together, because niacin does not bind to the resins. LDL levels in patients with heterozygous familial hypercholesterolemia require daily doses of up to 6 g of niacin with 24-30 g of resin. 

Exercise-induced muscle pain, without myopathy and a rise in creatine kinase activity, can probably be caused by statins. This has been described in seven patients with heterozygous familial hypercholesterolemia and consisted of pain during exercise and cramps in the following hours (54). 

In combination with a resin or reductase inhibitor, niacin normalizes LDL in most patients with heterozygous familial hypercholesterolemia and other forms of hypercholesterolemia. These... 

Quantitative evidence of reversal of coronary disease was demonstrated with this regimen in three major clinical trials. Effects on lipoprotein levels are sustained, and no additional adverse effects have developed other than those encountered when the drugs are used singly. The drugs may be taken together, because niacin does not bind to the resins. LDL levels in patients with heterozygous familial hypercholesterolemia are usually normalized with daily doses of up to 6.5 g of niacin with 24-30 g of resin. 

Response of total plasma cholesterol in patients with heterozygous familial hypercholesterolemia to diet (low cholesterol, low saturated fat) and hyperlipidemic drugs. 

FIGURE 17.4 Results of a study that established the dose-response relationship betwreen sinavastatin dose and percent reduction in serum cholesterol levels in patients wdth heterozygous familial hypercholesterolemia. 

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... 

Lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin fLDL catabolism inhibit LDL synthesis fCholesterol 4LDL Highly effective in heterozygous familial hypercholesterolemia and in combination with other agents... 

STATIN USE BY CHILDREN Some statins are approved for children with heterozygous familial hypercholesterolemia. Atorvastatin, lovastatin, and simvastatin are indicated for children age 11 or older. Pravastatin is approved for children age 8 or older. 

Yuan, G., Wang, J. and Hegele, R.A., Heterozygous familial hypercholesterolemia an underrecognized cause of early cardiovascular disease. CMAJ, 174, 1124—1229 (2006). 

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