Clinical mangement of HoFH, sitosterolaemia and LALD

Clinical mangement of HoFH

Importance of early diagnosis

HoFH should be suspected in people with untreated LDL-C over 10 mmol/L (>400 mg/dL), or based on medical/family history and/or genetic testing. Classic signs are xanthomas before age 10. Premature atherosclerosis often affects the aortic root, coronary ostia, and aortic valves, and may be seen in the first two decades. Aortic disease can progress even if LDL-C is lowered, highlighting the need for early diagnosis of HoFH and prompt treatment.

Children with clinically suspected HoFH (due to xanthomas or both parents having FH) should be tested early (from birth to 2 years), starting with LDL-C measurement and followed by genetic confirmation. The 2023 EAS consensus statement on HoFH proposed that paediatric guidelines should be expanded to include newborn lipid screening in high-risk settings and national screening programmes should be established where these are lacking. The EU Safe Hearts Plan supports early life lipid screening.

It is important to note that clinically defined HoFH does not necessarily mean homozygosity in a strict genetic sense, but instead includes all biallelic pathogenic variants that impair the LDL receptor pathway. Usually, a child with HoFH will have inherited one FH-causing variant from each parent, but other inheritance patterns exist. Genetic laboratory reports should clearly state that an individual has HoFH (according to all the possible genetic scenarios) to aid interpretation and treatment eligibility.

Use of cardiovascular imaging

Children with HoFH should undergo cardiovascular imaging to screen for subclinical ASCVD and aortic valve disease, as per the 2023 EAS consensus statement on HoFH. Coronary computed tomography angiography (CCTA) should be performed at least once after age 3 and thereafter as clinically indicated. Advances in CCTA, particularly photon-counting CT, allow more detailed plaque characterisation to help guide treatment decisions.

LDL-C treatment goals

The LDL-C treatment goal for children and adolescents with HoFH is ≤3.0 mmol/L (115 mg/dL) from diagnosis, as recommended by the 2023 EAS consensus on HoFH. Achieving this goal can help prevent plaque growth. For children with ASCVD, consider a lower target of ≤1.8 mmol/L (70 mg/dL).

Lifestyle measures and pharmacological treatment

A stepwise treatment algorithm for children with HoFH is shown in Figure 4. It begins with a healthy diet and initiation of high-intensity statin plus ezetimibe at diagnosis. Regular physical activity is encouraged, while smoking and vaping should be strongly discouraged. If LDL-C treatment goals are not met within a few weeks, and the child does not carry two LDLR null variants, a PCSK9 inhibitor should be added. The PCSK9 inhibitor should be continued if LDL-C is reduced by more than 15% after 1–2 doses. LDLR-independent treatments should be considered instead of adding a PCSK9 inhibitor when a child is known to have no LDLR activity or when treatment goals are not achieved with these initial treatments.

LDLR‑independent pharmacological treatments are evinacumab (administered intravenously every 4 weeks) and lomitapide (administered orally).

• Evinacumab (a monoclonal antibody that targets angiopoietin-3) reduces LDL‑C by 48% and is effective even in LDLR null/null HoFH. It is approved for children with HoFH from 6 months by the EMA and 1 year by the FDA, enabling very early treatment.
• Lomitapide (a microsomal triglyceride transfer protein inhibitor) lowers LDL‑C by ~50% but requires monitoring for hepatic and gastrointestinal adverse effects; efficacy and tolerability have been shown in children aged 5–17 years, and it is FDA‑approved from 2 years.

Lipoprotein apheresis

Lipoprotein apheresis is an effective LDLR‑independent therapy for children with HoFH and should be considered from 2–3 years of age if LDL‑C goals are not achieved with lifestyle and drug therapy. Although randomized clinical trials are lacking, evidence indicates that initiation of lipoprotein apheresis in childhood leads to longer cardiovascular event‑free survival.

Apheresis selectively removes LDL‑C (and Lp(a)) and is usually performed once every 1–2 weeks. It reduces LDL‑C by 75% acutely and 48% chronically, but levels rebound between sessions. Because LDL‑C rebounds rapidly after apheresis, the Kroon formula should be used to estimate the mean LDL‑C reduction between sessions. Treatment burden, access, cost, and quality‑of‑life issues must be considered.

The combination of lipoprotein apheresis with LDLR‑independent drugs now makes it possible for the most severely affected children with LDLR null/null variants to reach LDL‑C goals and even regress plaque. If apheresis is not feasible, plasma exchange may be considered.

Liver transplantation

In exceptional cases, liver transplantation can be considered in children with HoFH who have persistently elevated LDL-C concentrations and ASCVD despite optimal available and tolerated treatment.

Clinical management of sitosterolaemia and lysosomal acid lipase deficiency

Biallelic pathogenic variants in ABCG5 and ABCG8 cause sitosterolaemia, a recessive disease, which results in accumulation of plant sterols and stanols in the body. Clinical features include xanthomas, premature atherosclerosis, and thrombocytopenia. Individuals with sitosterolaemia should avoid plant sterols. The main treatment is ezetimibe, which acts by reducing intestinal absorption of plant sterols.

Biallelic pathogenic variants in LIPA cause lysosomal acid lipase deficiency (LALD), which is also recessive. Clinical features include liver disease (ranging from steatosis to cirrhosis) and severe dyslipidaemia. Individuals with LALD should consume a low-fat diet. The main treatment is sebelipase alfa (lipid-metabolizing enzyme-replacement), which has been shown to reduce liver and lipid abnormalities.