Lipid Disorders and Metabolism

Lipid Disorders

• Lipid disorders are characterized by abnormal levels of blood lipids, including triglycerides, cholesterol, and lipoproteins
• Hyperlipidemia is a high level of lipids in the blood
• Hyperlipidemia can manifest as a high level of cholesterol, a high level of triglycerides, or a combination of both
• Hypolipidemia is a low level of lipids in the blood

Lipid Metabolism

• After eating a fatty meal, cholesterol and fatty acids enter intestinal cells
• Fatty acids are assembled into triglycerides
• Triglycerides are packaged with cholesterol and lipoproteins to form chylomicrons
• Chylomicrons move into the lymphatic vessels and eventually enter into the blood
• Lipoprotein lipase breaks down chylomicrons in capillaries to release triglycerides
• Triglycerides are taken up by nearby tissues for energy or storage
• The remainder of the chylomicron (chylomicron remnant) travels to the liver
• The liver synthesizes fatty acids and cholesterol
• The liver packages fatty acids, cholesterol, and chylomicron remnants into very-low-density lipoproteins (VLDLs)
• VLDLs are released from the liver and enter the blood
• Lipoprotein lipase in capillaries breaks down VLDLs to release triglycerides for nearby tissues
• As triglycerides leave VLDLs, they become intermediate-density lipoproteins (IDLs)
• IDLs are converted to low-density lipoproteins (LDLs) as more cholesterol is present than triglycerides
• LDLs travel through the blood and are taken up by cells with LDL receptors
• This can happen in the liver or peripheral tissues

Causes of Hyperlipidemia

• Primary Hyperlipidemia - Familial/Inherited
  • Caused by inherited genetic defects
• Secondary Hyperlipidemia - Acquired
  • Caused by other diseases or medications

Clinical Manifestations of Hyperlipidemia

• Skin:
  • Xanthomas: Lipid deposits under the skin and in tendons
  • Xanthelasma: Xanthomas in the eyelid
• Eyes:
  • Corneal arcus: Brown ring of fat around the cornea
• Liver:
  • Fatty liver disease (Hepatic Steatosis): Lipid deposition in the liver
• Most worrisome: Atherosclerotic cardiovascular disease
  • Coronary artery disease
  • Stroke
  • Peripheral vascular disease
  • Carotid artery stenosis

Familial Hyperlipidemias

• Type 1: Hyperchylomicronemia (Autosomal Recessive)
  • Deficiency of lipoprotein lipase or apolipoprotein C2
  • Elevated chylomicrons
  • Eruptive xanthomas (rapidly developing xanthomas on the back/buttocks)
  • Acute pancreatitis
  • Hepatosplenomegaly
  • No increased risk of atherosclerotic cardiovascular disease
  • Chylomicrons form a creamy layer at the top of a fasting serum sample
• Type 2: Familial Hypercholesterolemia (Autosomal Dominant)
  • Elevated LDL (Type A)
  • Elevated LDL and VLDL (Type B)
  • Defective or absent LDL receptors or apolipoprotein B-100
  • Increased risk of atherosclerotic cardiovascular disease
  • Tendon xanthomas (especially Achilles tendon)
  • Corneal arcus
• Type 3: Familial Dysbetalipoproteinemia (Autosomal Recessive)
  • Defective apolipoprotein E
  • Elevated VLDL and chylomicron remnants
  • Increased risk of premature atherosclerosis
  • Xanthomas on the palms
• Type 4: Familial Hypertriglyceridemia (Hypertriglyceridemia)
  • Liver produces large amounts of VLDL
  • Decreased lipoprotein lipase activity
  • Elevated VLDL and chylomicrons
  • Increased risk of premature atherosclerosis and acute pancreatitis

Acquired Causes of Hyperlipidemia

• Diabetes Mellitus
  • Decreased insulin levels
  • Decreased lipoprotein lipase activity
  • Accumulated VLDL and LDL
• Hypothyroidism
  • Decreased LDL receptor synthesis
  • Increased LDL levels
• Nephrotic Syndrome
  • Loss of plasma proteins in the urine
  • Increased VLDL synthesis
• Medications: Estrogen-containing oral contraceptives, beta-blockers, thiazide diuretics

Hypolipidemia

• Abetalipoproteinemia (Autosomal Recessive)
  • Defective microsomal triglyceride transfer protein (MTP)
  • Deficiency of apolipoprotein B-48 and apolipoprotein B-100
  • Low levels of chylomicrons, VLDLs, and LDLs
  • Low cholesterol and triglyceride levels
  • Presents early in infancy
  • Malabsorption of fat in the small intestine
  • Failure to thrive
  • Diarrhea with large amounts of fat (Steatorrhea)
  • Malodorous stools that float in the toilet bowl
  • Fat soluble vitamin deficiencies
  • Osteomalacia
  • Retinitis Pigmentosa
  • Spinal cerebellar degeneration
  • Acanthocytosis on peripheral blood smear
  • Intestinal biopsy shows accumulation of fat in intestinal cells
• Treatment of Abetalipoproteinemia:
  • Reduce dietary fats (especially long chain saturated fatty acids)
  • Vitamin supplements
    • Vitamin E: Prevention of neurological problems
    • Vitamin A: Prevention of retinal damage

Case Summary

• Jamie presents with acute myocardial infarction at a young age
• Tendon xanthomas and elevated LDL levels point to Type 2 familial hyperlipidemia
• Type 2 familial hyperlipidemia is caused by a decrease in LDL receptors or apolipoprotein B-100 in the liver

Overview of lipid disorders, characterized by abnormal blood lipid levels, including hyperlipidemia (high lipid levels) and hypolipidemia (low lipid levels). Explanation of lipid metabolism, including the roles of chylomicrons, lipoprotein lipase, and the liver in processing and synthesizing fatty acids and cholesterol.