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............................................................................................................................................................................. 9.1.2.2 Homozygous familial hypercholesterolaemia. HoFH is a rare and life-threatening disease. The clinical picture is characterized by extensive xanthomas, marked premature and progressive CVD, and TC >13 mmol/L (>500 mg/dL). Most patients develop CAD and aortic stenosis before the age of 20 years and die before 30 years of age. The frequency of HoFH is estimated to be 1/1600001/320 000. The early identification of these children and prompt referral to a specialized clinic is crucial. The patients should be treated with intensive LDL-lowering drug therapy and, when available, with lipoprotein apheresis. This treatment (every 12 weeks) can decrease plasma LDL-C levels by 5570%. The procedure frequency may be adjusted for each patient as lipid levels, symptoms, and other disease-related parameters change. Maximally tolerated pharmacological therapy must be maintained.368 For a more detailed discussion on HoFH, see the EAS consensus statements.366,368

9.1.2.3 Familial hypercholesterolaemia in children. FH is diagnosed in children based on phenotypic criteria including elevated LDL-C plus a family history of elevated LDL-C, premature CAD, and/or positive genetic testing.369 Testing during childhood is optimal to discriminate between FH and non-FH using LDL-C. In children with a family history of high cholesterol or premature CHD, an accepted cut-off is >_4.0 mmol/L (>_160 mg/dL). If a parent has a known genetic defect, the diagnostic level for the child is >_3.5 mmol/L (>_130 mg/dL). If possible, genetic testing of the child is suggested. Although there have been no placebo-controlled trials in children, observational studies have suggested that early treatment can reduce LDL-C burden, improve endothelial function, substantially attenuate the development of atherosclerosis, and improve coronary outcomes.369371 Treatment of children with FH includes a healthy lifestyle and statin treatment. A heart-healthy diet should be adopted early in life and statin treatment should be considered at 610 years of age. Statin treatment should be started with low doses and the dose should be increased to reach goals.372 The goal in children >10 years of age is an LDL-C <3.5 mmol/L (<135 mg/dL) and at younger ages a >_50% reduction of LDL-C.

9.1.3 Familial dysbetalipoproteinaemia Familial dysbetalipoproteinaemia (i.e. type III hyperlipoproteinaemia; remnant removal disease) is rare and is generally inherited as an autosomal recessive disorder with variable penetrance. Familial dysbetalipoproteinaemia produces a characteristic clinical syndrome in which both TC and TGs are elevated before treatment, usually both in the range of 710 mmol/L. In severe cases, patients develop tuberoeruptive xanthomas, particularly over the elbows and knees, and palmar xanthomata in the skin creases of the hands and wrists. The risk of CAD is very high, and accelerated atherosclerosis of the femoral and tibial arteries is also prevalent. The syndrome is usually not expressed at a young age or in women before menopause. The majority of cases are homozygous for the E2 isoform of ApoE. ApoE is important for the hepatic clearance of chylomicron remnants and IDL. ApoE2 binds less readily than the E3 and E4 isoforms to hepatic receptors. However, without some coincidental cause of dyslipidaemia such as dyslipidaemia associated with HTG, DM, obesity, or hypothyroidism,373375 ApoE2 homozygosity does not generally cause familial dysbetalipoproteinaemia. The detection of ApoE2 homozygosity in a dyslipidaemic patient is diagnostic and analysis of ApoE isoforms is now available in most clinical laboratories. The presence of cholesterol remnants characteristic of familial dysbetalipoproteinaemia can be reliably predicted on the basis of plasma levels of cholesterol, TGs, and ApoB.376 If suspicion is confirmed, ApoE genotyping can be performed. In older patients with xanthomata resembling those of familial dysbetalipoproteinaemia who prove not to be homozygous for ApoE2, a paraprotein should be sought. The treatment of familial dysbetalipoproteinaemia should be undertaken in a specialist clinic. Most cases respond well to treatment with a statin or, if dominated by high TGs, a fibrate; often a combination of a statin and a fibrate may be needed.

9.1.4 Genetic causes of hypertriglyceridaemia Although the genetic aetiology for HTG seems to be very complex, recent data have extended our genetic understanding of HTG, in particular that of chylomicronaemia.37,226,377 Moderate elevation of TG levels (between 2.010.0 mmol/L) is caused by the polygenic effect of multiple genes influencing both VLDL production and removal. Monogenic severe HTG causes chylomicronaemia, pancreatitis, and lipid deposits. Thus far, mutations in six genes (LPL, apoC2, apoA5, LMF1, GPIHBP1, and GPD1) with monogenic effects have been recognized to lead to severe elevation of serum TGs due to disruption of the chylomicron removal pathways. These mutations are inherited as autosomal recessive traits and are rare. The profound defect in the catabolism of chylomicrons and VLDL results in chylomicronaemia and TG levels >11.2 mmol/L (>1000 mg/dL), with turbid and milky serum. Severe HTG is seen in patients who are homozygous or compound heterozygous for mutations of the enzyme LPL, and in other genes linked to the catabolism of TG-rich lipoproteins. Heterozygous carriers of these same gene mutations commonly express moderate elevations of serum TG levels that expose them to increased CVD risk.378 Recently, gene therapy for LPL deficiency has been developed and tested in clinical trials,379 and the alipogene tiparvovec was approved by the EMA in 2013. However, this therapy is no longer available. A gain-of-function mutation in apoC3 that leads to high ApoC-III levels can also cause severe HTG by inhibiting the activity of LPL, whereas loss-of-function mutations are associated with a favourable lipid profile with low TG levels.380 These findings have raised the possibility of ApoC-III being a novel lipid drug target.

9.1.4.1 Action to prevent acute pancreatitis in severe hypertriglyceridaemia. The risk of pancreatitis is clinically significant if TGs are >10 mmol/L (880 mg/dL), particularly when occurring in association with familial chylomicronaemia, and actions to prevent acute pancreatitis are mandatory.381,382 Notably, HTG is the cause of 10% of all cases with pancreatitis, and patients can develop pancreatitis even when their TG concentration is 510 mmol/L (440880 mg/dL). Recent data from a prospective cohort study reported that the risk of acute pancreatitis increased significantly over the quartiles of serum TGs, highlighting the fact that, as a risk factor, serum TGs may have been underestimated.383 Any factor that increases VLDL production can aggravate the risk of pancreatitis, with alcohol consumption being the most common contributing factor. Either a patient should be admitted to hospital if symptomatic, or careful and close follow-up of the patient’s TG values should be Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026