534 Week 6 June 4 12 pm

Familial Chylomicronemia

  • Prevalence: 1 in 200,000 (holistic).

  • Genes: Not just LPL deficiency; other genes are implicated.

  • Characteristics:

    • Elevated chylomicrons and VLDL.

    • Reduced HDL.

    • Clinical effects: Pancreatitis, eruptive xanthomas, hepatoesplenomegaly.

Familial Hypercholesterolemia

  • Prevalence: Around 1 in a million.

  • Genes: Mutations affect LDL receptors, leading to elevated LDL.

  • Clinical signs: Xanthomas and premature atherosclerotic cardiovascular disease.

  • Genetic Mutations:

    • LDLR gene mutation

Familial Defective ApoB-100

  • Heterozygous for loss of function mutations.

  • Autosomal dominant.

Familial Dysbetalipoproteinemia

  • Autosomal recessive.

  • Biallelic carriers of APOE2 variant.

  • Elevated chylomicrons.

  • Clinical signs: Palmar and tuberoeruptive xanthomas.

PCSK9 Deficiency

  • Prevalence: 1 in 1,000.

  • Autosomal dominant.

  • Loss of function mutation.

  • Reduced LDL, reduced risk of cardiovascular disease.

  • Leads to hypolipidemic syndromes.

Hypertriglyceridemia

  • Triglycerides: >500 mg/dL.

  • Total cholesterol: >200 mg/dL.

  • HDL: <40 mg/dL.

  • LDL: Significant elevation.

  • Problem: Impaired lipolysis of triglycerides in chylomicrons.

  • Enzyme: Lipoprotein lipase (LPL).

  • LPL made by: Adipocytes, skeletal myocytes, and heart muscle cells.

  • LPL Transport: Transported to vascular endothelial surface by a protein; issues with this protein affect trilacidemia.

  • Genetic Predisposition:

    • Most patients have polygenic predisposition.

    • Influenced by obesity and insulin resistance.

  • Primary genetic causes of severe hypertriglyceridemia: Familial chylomicronemia syndrome (FCS).

  • LPL Deficiency:

    • LPL required for hydrolysis of triglycerides in chylomicrons and VLDL.

    • Deficiency leads to impaired lipolysis and elevated plasma triglycerides.

    • Turbid fasting plasma; creamy supernatant layer.

    • Fasting TG levels >500 mg/dL, often >1000 mg/dL.

    • Mutations in LPL gene, autosomal recessive inheritance.

    • Heterozygotes: Moderate elevation plasma TG levels, increased risk for coronary heart disease.

  • Other Genes:

    • APOC2 deficiency: Loss of function mutations causing functional lack of LPL activity.

    • A5 deficiency: Loss of function; helps with LPL function.

    • GPIHBP1 mutations: Interfere with LDL synthesis/folding, autoantibodies can cause severe hyperchylomicronemia.

    • LMF1 deficiency: Important for LPL maturation; proper folding is required for enzyme viability.

Hypercholesterolemia

  • Related to: Elevated LDL, associated with the risk of premature ASCVD (Artherosclerotic Cardiovascular Disease).

  • Cause: Impaired uptake of LDL by the liver.

  • Mechanism: Reduced expression/activity of the LDL receptor in the liver.

  • Factors: Diet, medical conditions, genetics.

  • Genetic Predisposition:

    • Majority of cases, is polygenic predisposition that are often increased by secondary factors like diet, etc.

  • Genetic mutations:

    • Familial hypercholesterolemia: Autosomal dominant disorder with elevated plasma LDL and relatively normal triglycerides.

    • LDL receptor mutations in the LDLR gene lead to decreased LDL clearance.

    • Homozygotes/compound heterozygotes have much higher LDL-C levels.

    • Familial Hypercholerolemia common in populations like Lancaster County Amish; founder population keeps gene running, so gene stays prevalent in that population.

    • Hypercholesterolemia from birth, diagnosed on routing lipid screening.

    • Screening during ages 9-11 important to check for abnormalities and family history, or premature ASCVD.

    • Other Mutations such as APOB one hundred are structural proteins in LDL, and their mutations reduce LDL receptor bind affinity causing LDL to circulate in the blood plasma.

    • PCSK9 mutation binds to other receptors and target the target stem for lysosomal degradation i.e too much activity is caused by mutation of this protein

  • Heterozygous familial hypercholesterolemia: 1 in 250 individuals; elevated plasma LDL, usually >100 mg/dL, with relatively normal triglyceride levels.

Xanthomas

  • Accumulation of fat tissue that eventually can crystallize, and eventually calcify under skin.

  • Typical of familial chylomicronemia syndrome with severe hypertriglyceridemia (type 1 hyperlipidemia).

  • Tuberous xanthomas: large masses at elbows, as seen in remnant hyperlipidemia (dysbetalipoproteinemia, type 3).
    Skin Condition Visualization: Dermis, Epidermis

  • Skin is continuous and not disrupted with xanthomas.

  • Foamy histiocytes of foam cells: these are macrophages or histiocytes or dendritic cells that collect fat molecule particles, storing them inside the cells and obtaining a bubble look from the inside.

  • Lymphocytes: accumulation within foamy cells

  • Collagen: accumulation of fibrous tissue.

Atherosclerosis Visualization

  • Fatty Streaks: Irregularity on surface where the surface is elevated when passed over due to collection of material. However, there are still endothelial cells covering this so the surface is mild.

  • Advanced changes: Surface is looking red, meaning inflammatory reactions. This can look like wounds, or an open wound.

  • Very Advanced: Surface is bumpy and contains many wounds, or open wounds in a rugged surface. Also contains a calcified hard surface from the aorta.

  • The mass is red indicating a coagulation activation to form a red thrombus formation.