What is Familial Hypercholesterolemia (FH)?

From the Guidelines

Familial hypercholesterolemia (FH) should be treated with high-intensity statins, such as atorvastatin (40-80mg daily) or rosuvastatin (20-40mg daily), as the first line of therapy, with the goal of reducing LDL cholesterol levels below 100 mg/dL for most adults with FH, or below 70 mg/dL for those with established cardiovascular disease, as recommended by the International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia 1.

Key Considerations

• FH is a genetic disorder characterized by abnormally high levels of LDL cholesterol from birth, significantly increasing the risk of early cardiovascular disease.
• Treatment should begin at diagnosis and ideally by the age of 2 years, with counseling on heart-healthy lifestyles, psychological support for the family, and LDL-cholesterol-lowering medications.
• Lifestyle modifications are essential alongside medication, including a heart-healthy diet low in saturated fats, regular exercise, weight management, smoking cessation, and limited alcohol consumption.
• Family screening is important since FH is an autosomal dominant condition, meaning each child of an affected parent has a 50% chance of inheriting the disorder.

Treatment Options

• High-intensity statins, such as atorvastatin or rosuvastatin, as the first line of therapy.
• Ezetimibe (10mg daily) as second-line therapy if LDL targets are not achieved with statins alone.
• PCSK9 inhibitors, such as evolocumab (140mg every 2 weeks) or alirocumab (75-150mg every 2 weeks), for severe cases or those not responding to conventional therapy.
• Lipoprotein apheresis for patients with homozygous familial hypercholesterolemia (HoFH) who do not achieve guideline-recommended LDL-cholesterol goals despite maximally tolerated combination drug therapy.

Monitoring and Follow-up

• Regular monitoring of LDL cholesterol levels and adjustment of treatment as needed to achieve recommended targets.
• Comprehensive psychosocial support for patients and their families.
• Routine full blood counts and iron supplementation as needed for patients receiving lipoprotein apheresis.

From the Research

Definition and Characteristics of Familial Hypercholesterolemia

• Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism characterized by significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) 2, 3, 4, 5, 6.
• The etiology of FH includes known mutations in the gene of the LDL receptor, LDLR; the gene of apolipoprotein B, apo B; and the proprotein convertase subtilisin/kexin type 9 gene, PCSK9 2.
• Patients with FH are at very high risk for premature coronary heart disease (CHD) and other atherosclerotic sequelae 2, 3, 4, 5, 6.

Diagnosis and Screening

• Routine lipid testing should identify most patients with FH, and once an index case is identified, testing should be offered to family members 3, 5.
• Diagnostic criteria have been developed to aid the clinical diagnosis of FH, and genetic testing is now available but not widely used 5.
• Cascade screening is recommended to identify affected family members, and the benefits of early interventions are clear 5.

Treatment and Management

• Early diagnosis and aggressive treatment with therapeutic lifestyle changes and statins can prevent premature CHD and other atherosclerotic sequelae in patients with FH 2, 3, 4, 5, 6.
• Statins are the cornerstone of treatment, but patients with FH may require higher doses of statins, more potent statins, statin-based combination therapy, or adjunctive therapies 2, 6.
• Emerging therapies such as LDL apheresis, mipomersen, lomitapide, and PCSK9 inhibitors may be useful in patients with homozygous FH or treatment-resistant FH 2, 3, 4, 5, 6.
• Liver transplantation is the only effective therapy for severe cases of homozygous FH 3.