Perspective:

The following are 10 points to remember about homozygous familial hypercholesterolemia (HoFH):

1. HoFH is a rare (recent studies range estimates of 1/160,000 to 1/300,000 people) life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C), extensor tendon xanthomas, and premature atherosclerotic cardiovascular disease (ACVD) developing before age 20 years, with survival generally <30 years.

2. Studies in cultured fibroblasts show a severe defect in the ability to bind and internalize LDL particles. The defect can be receptor-negative (<2% residual activity) or receptor-defective (2-25% residual activity), which influences the severity of the HoFH phenotype. HoFH is caused by mutations in both alleles of the gene encoding the LDL receptor. Mutations in alleles of other genes including APO-B, PCSK9, and LDLRAP1 (autosomal recessive) may be present in some individuals with HoFH who may be double heterozygotes (e.g., LDL-R + PCSK-9).

3. Diagnostic criteria include genetic confirmation of two mutant alleles; or untreated LDL-C >500 mg/dl or treated LDL-C ≥300 mg/dl with cutaneous or tendon xanthomas before age 10 years or untreated LDL-C levels consistent with HoFH in both parents. Lower LDL-C levels do not exclude HoFH in children or treated patients, particularly when on multiple lipid-lowering agents.

4. Triglycerides are frequently within the normal range, but hypertriglyceridemia can be observed, and may be more common with an increasing prevalence of the metabolic syndrome. Decreased catabolism of triglyceride-rich lipoproteins may result from deficient LDL receptor function. Familial hypercholesterolemia is also associated with increased plasma levels of lipoprotein (a) and low levels of HDL-C.

5. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. Statins + ezetimibe usually provide a 30-40% reduction in LDL-C in HoFH. There is additional value of the bile resins, niacin, and fibrates.

6. LDL-C targets are <100 mg/dl in adults, <135 mg/dl in children, and <70 mg/dl if clinical ACVD. As patients rarely achieve LDL-C targets, adjunctive weekly or biweekly lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. There is evidence that LDL apheresis reduces coronary disease progression and outcome.

7. The Food and Drug Administration has approved lomitapide, an oral inhibitor of microsomal triglyceride transport protein, for patients with an HoFH phenotype. Lomitapide lowers LDL-C by about 50% when added to optimal therapy including LDL apheresis, but is poorly tolerated because of the need for a diet with <20% fat, severe gastrointestinal distress, and diarrhea which are dose related, and accumulation of liver fat.

8. Mipomersen, an anti-sense to apo B, has also been approved and requires a subcutaneous injection weekly. It reduces LDL by about 25%, but has not been evaluated in combination with LDL apheresis. Its tolerance is limited by site reactions, flu-like symptoms, and hepatic steatosis. The long-term consequences of increasing liver fat from each of these agents are unknown, but appears to be reversible. Whether the CV benefits in patients with HoFH and established ACVD outweigh the theoretical risk of steatohepatitis and fibrosis is not known. Neither drug has been evaluated in very young children.

9. Given the severity of ACVD, regular follow-up should include Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary.

10. Contraception and pregnancy should be discussed for female patients; as hormonal control is generally contraindicated in HoFH, other contraceptive methods are strongly recommended. The consequences of pregnancy include complications from ACVD and aggravation of hypercholesterolemia due to discontinuation of pharmacotherapy, and the effects of high levels of estrogen and progesterone on lipoprotein metabolism. Where pregnancy is not contraindicated, lipoprotein apheresis is strongly recommended.