Types of Lipid Metabolism Disorders
Fredrickson Classification (by blood lipids)
Types of Lipid Metabolism Disorders
Fredrickson Classification (by blood lipids)
Classification of Lipid Metabolism Disorders by Lipid Composition
The Fredrickson classification of lipid metabolism disorders is based on lipid composition:
Type I Hyperlipoproteinemia (Hyperchylomicronemia):
Triglycerides are significantly elevated, total cholesterol is normal, and both LDL-C and HDL-C are reduced.
The cause is an enzyme defect. This condition is very rare.
Type IIa Hyperlipoproteinemia (Hypercholesterolemia):
Total cholesterol and LDL-C are elevated, triglycerides are normal, and HDL-C is often reduced.
The cause may be a defect in the LDL receptor: either the ApoB protein on the LDL particle does not function properly and cannot bind to the receptor, or the liver cell produces too much proprotein convertase subtilisin/kexin type 9 (PCSK9).
Type IIb Hyperlipoproteinemia (Mixed Hyperlipidemia):
Triglycerides are elevated, HDL-C is reduced. Total cholesterol and LDL-C may be normal but are often elevated.
This is the typical lipid disorder seen in metabolic syndrome and type 2 diabetes mellitus.
Type III Hyperlipoproteinemia (Familial Dysbetalipoproteinemia):
Total cholesterol and triglycerides are elevated; LDL-C may be normal but is often elevated, and HDL-C is reduced.
This is due to a genetic defect.
Type IV Hyperlipoproteinemia (Hypertriglyceridemia):
Triglycerides are elevated due to endogenous overproduction and reduced breakdown of VLDL triglycerides.
Type V Hyperlipoproteinemia (Endocrine-exogenous Hypertriglyceridemia):
Triglycerides are significantly elevated; total cholesterol and LDL-C may be normal but are often elevated; HDL-C is reduced.
4.7.3 Classification of Primary Lipid Metabolism Disorders
Primary lipid metabolism disorders are divided into three groups:
4.7.3.1 Primary Hypercholesterolemia
Disorders primarily affecting LDL-C metabolism and familial hypercholesterolemia (FH)
The homozygous form of familial hypercholesterolemia (HoFH) is much rarer. Its prevalence is estimated at about 1 in 160,000 to 1 in 1 million,.
Familial hypercholesterolemia is classified into a homozygous and a heterozygous form. About 1 in 250 people suffers from heterozygous familial hypercholesterolemia. It is among the most common, if not the most common, genetic disease seen in general practice.
The prevalence of familial hypercholesterolemia (FH) is similar across many populations, but detection rates and actual diagnosed cases vary widely depending on region, healthcare access, and awareness.
Region | Prevalence | Estimated Number of People Affected |
Europe | 1 in 250 | ~2.8 million (population ~700 million) |
USA | 1 in 250 | ~1.3 million (population ~330 million) |
Conclusion: The prevalence is the same (~1:250) across regions, but the absolute number of cases scales with population size.
Region | Prevalence | Estimated Number of People Affected |
Europe | 1 in 160,000–1 million | ~700–4,400 |
USA | 1 in 160,000–1 million | ~330–2,000 |
Conclusion: HoFH remains extremely rare everywhere, but potentially underdiagnosed.
Important Notes:
FH is associated with elevated LDL-C levels in the blood and rapidly progressive atherosclerosis—even in the absence of other cardiovascular risk factors.
It often becomes symptomatic only upon the occurrence of an acute myocardial infarction.
FH is defined as a disorder in LDL-C degradation due to functionally significant mutations in the genes for the LDL receptor (LDL-R), ApoB-100, or PCSK9 (proprotein convertase subtilisin/kexin type 9).
In 93% of patients, mutations occur in the LDL-R gene; in 5%, in the receptor-binding domain of ApoB-100; and in 2%, gain-of-function mutations of PCSK9 are present. PCSK9 is a protease involved in the cellular degradation of LDL receptors.
If it has increased activity due to genetic alterations (gain-of-function), more LDL receptors are broken down than normal, leading to increased LDL-C levels.
Between 5% and 10% of coronary artery disease patients under 55 years of age are affected by heterozygous FH.
FH should always be considered when LDL cholesterol levels exceed 190 mg/dl (4.91 mmol/l), and in children under 16 years at levels above 155 mg/dl (4 mmol/l).
For heterozygous men, the cumulative risk of developing manifest coronary artery disease is 90% by age 60, and for women, 40%—representing a 12- to 13-fold increase in risk and a reduction in life expectancy by around 15 years.
As with other diseases with dominant inheritance, half of the first-degree relatives are also affected.
Homozygous patients typically have LDL-C levels between 600 and 1,000 mg/dl (15.5 to 25.9 mmol/l).
Coronary artery disease often manifests in the first decade of life, and heart attacks may occur as early as the second decade.
Approximately half of all homozygous patients suffer a fatal myocardial infarction before age 40.
Diagnosis is based on clinical presentation, laboratory findings, and molecular genetics.
Familial hypercholesterolemia (FH) is likely when LDL-C is above 190 mg/dl (4.9 mmol/l), xanthomas are present, and half of the first-degree relatives also have elevated
An update on familial hypercholesterolaemia.” Annals of Medicine 1999;31(Suppl 1):13–18. doi:10.1080/07853890.1999.11904394.
The indication for genetic testing can be established using the Dutch Lipid Clinic Network point system.
The Dutch Lipid Clinic Network (DLCN) Score is a widely used clinical diagnostic tool for familial hypercholesterolemia (FH).
Dutch Lipid Clinic Network Scoring System
Familial hypercholesterolaemia (FH): report of a second WHO consultation, Geneva, 4 September 1998.
“Autor”/Herausgeber: World Health Organization, Human Genetics Programme.
Publikationstyp / „Journal“: WHO-Bericht (kein Journal).
Erscheinungsjahr/Ort: 1999, Genf.
Publikations-Nr.: WHO/HGN/FH/CONS/99.2
Leiv Ose. “An update on familial hypercholesterolaemia.” Annals of Medicine 1999;31(Suppl 1):13–18. doi:10.1080/07853890.1999.11904394.
Result Interpretation:
0–2 points → FH unlikely
3–5 points → FH possible
6–8 points → FH probable
8 points → Definite FH
* For cholesterol values in the family history, the original score uses age-specific 95th percentiles. This has been simplified by using average values for adults and children. In children, LDL-C levels are relatively high at the age of two, then decrease, and rise again to the values of two-year-olds by age 17. Average values were used here to simplify application.
A score of 6 or more makes molecular genetic testing appropriate.
Genetic mutations responsible for FH can be identified in more than 70% of cases.
If a mutation is already known in a family, identifying other affected members becomes straightforward.
Diagnosing FH based solely on lipid levels would overestimate its prevalence in the general population.
Only about 1 in 10 patients with isolated elevated LDL-C actually have FH.
Differential diagnoses include polygenic hypercholesterolemia, rare autosomal recessive hypercholesterolemia, familial combined hyperlipidemia (FCHL), and secondary hypercholesterolemias (e.g., from hypothyroidism).
Even within affected families, FH is often underdiagnosed because other genetic and environmental factors can compensate for the mutation, leading to normal cholesterol levels.
In such cases, identifying a known mutation is particularly valuable.
For patients with confirmed FH, cardiovascular risk calculators like Framingham or ESC HeartSCORE underestimate total risk.
Therefore, European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines classify asymptomatic individuals with isolated high cholesterol >310 mg/dl (8 mmol/l) (e.g., in FH) as high-risk patients, even without additional risk factors.
The LDL-C target for these individuals is <70 mg/dl (1.8 mmol/l) with ≥50% reduction from baseline.
The 2019/2021 ESC guidelines recommend:
Treatment should begin with a high-intensity statin, usually combined with ezetimibe.
PCSK9 inhibitors should be used in patients with very high cardiovascular risk who do not reach target levels, or in cases of statin intolerance.
Patients with heterozygous FH generally respond well to statins.
If statins are insufficient, additional medications like ezetimibe, bempedoic acid, PCSK9 inhibitors, or PCSK9 synthesis inhibitors can be added.
A confirmed pathogenic mutation in LDL-R, ApoB, or PCSK9 is a cardiovascular risk factor independent of LDL-C levels.
An LDL-C <190 mg/dl does not exclude FH.
Approved Therapies:
These medications are approved for:
Often used in combination with other lipid-lowering therapies (especially statins), or as monotherapy in case of statin intolerance:
The exact indications and study data are available in the respective product information.
Genetic Testing Use:
Genetic documentation of FH provides objective confirmation of high familial risk, justifying treatment with PCSK9 antibodies.
These therapies allow most patients to reach target LDL-C levels.
If drug therapy is insufficient and atherosclerotic vascular changes are proven, LDL apheresis may be considered.
Autosomal Recessive Hypercholesterolemia (ARH)
Patients with ARH show a clinical picture similar to homozygous FH, with:
However, parents and grandparents are usually normolipidemic, which distinguishes ARH from classical homozygous FH.
Not all patients who meet the clinical criteria for possible or probable familial hypercholesterolemia (FH) show detectable mutations in the typical FH-related genes.
If no mutations in LDL-R, ApoB, or PCSK9 are found in patients with the clinical features of FH, the condition is not autosomal dominant FH, but in 90% of these cases, it is polygenic hypercholesterolemia.
Patients with ARH show a clinical picture similar to homozygous FH, with:
However, parents and grandparents are usually normolipidemic, which distinguishes ARH from classical homozygous FH.
Not all patients who meet the clinical criteria for possible or probable familial hypercholesterolemia (FH) show detectable mutations in the typical FH-related genes.
If no mutations in LDL-R, ApoB, or PCSK9 are found in patients with the clinical features of FH, the condition is not autosomal dominant FH, but in 90% of these cases, it is polygenic hypercholesterolemia.
Primary Hypertriglyceridemia
In adulthood, primary hypertriglyceridemias are caused by genetic polymorphisms and rare variants in genes affecting triglyceride metabolism.
Most cases correspond to Fredrickson type IV, rarely to type V.
Typical triglyceride levels range from 200–500 mg/dl (2.3–5.7 mmol/l).
LDL-C and HDL-C levels are typically low.
The individual expression of the disorder is influenced by factors such as:
Treatment:
Chylomicronemia
Chylomicronemia is a rare, mostly autosomal recessive disorder affecting the breakdown of triglyceride-rich lipoproteins.
Fasting plasma shows chylomicrons, and triglycerides are elevated (Type I HLP).
VLDL levels are normal or slightly elevated.
Diagnosis is usually made in childhood, based on:
Therapy is dietary, using medium-chain triglycerides (MCTs), which are not incorporated into chylomicrons.
Familial Combined Hyperlipoproteinemia (FCHL)
The prevalence of familial combined hyperlipoproteinemia (FCHL) varies across populations and regions.
FCHL is the most common form of primary hyperlipoproteinemia, with a prevalence of up to 1 in 100, and is one of the leading causes of coronary heart disease (CHD).
About 10% of myocardial infarction patients have FCHL.
In FCHL, different lipoprotein phenotypes (types IIa, IIb, and IV) can occur within the same family.
LDL-C and/or triglycerides are elevated.
The presence of xanthomas makes the diagnosis unlikely.
Family members with hypertriglyceridemia may have the same risk for CHD as those with hypercholesterolemia.
FCHL is a heritable disorder caused by mutations in various genes that regulate lipid metabolism.
Although diet and physical activity can improve the condition, medication (primarily statins) is generally required.
PCSK9 InhibitorsElevated Lipoprotein (a)
Lipoprotein(a) [Lp(a)] is a complex of LDL and apolipoprotein(a).
There are more than 30 isoforms of Apo(a), differing in molecular size.
The plasma concentration of Lp(a) is largely genetically determined and varies greatly among individuals:
The larger the Apo(a) isoform, the lower the plasma concentration.
The function of Lp(a) remains unknown.
However, it is considered an independent cardiovascular risk factor.
Meta-analyses and genetic studies support a causal role of Lp(a) in the development of atherosclerosis.
Lp(a) testing is indicated in:
It is recommended to measure Lp(a) at least once in every adult’s life to identify individuals with a hereditary high lifetime risk for ASCVD, comparable to the risk associated with heterozygous FH.
Lp(a) is a negative acute-phase protein, so testing immediately after a heart attack may result in false-negative values.
Medications to lower Lp(a) are under development.
PCSK9 inhibitors lower Lp(a) by about 30%.
Regardless of Lp(a) level, conventional risk factors (like LDL-C and blood pressure) should be treated more aggressively when Lp(a) > 20 mg/dl (50 nmol/l).
In relevant clinical scenarios, Lp(a) elimination by LDL apheresis may be considered.
Due to the various Apo(a) isoforms, Lp(a) level alone is not sufficient to assess risk.
Not all isoforms raise cardiovascular risk equally.
Therefore, in addition to crossing a threshold level, progression of cardiovascular disease is also required to justify apheresis treatment.