Lipid Disorders

An abnormal amount of lipid in blood is called dyslipidemia, which includes abnormal levels of cholesterol, triglycerides, and/or lipoproteins. Dyslipidemia may be primary (familial) or secondary (acquired). Both primary and secondary causes can lead to the development of premature cardiovascular ( atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis) disease. Familial causes are classified according to the Fredrickson system, which looks into the pathology and the lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids that are elevated. Certain types do not increase the risk of premature atherosclerotic disease but still impact overall cardiac risk and chance of cardiovascular events in the future. Screening, early diagnosis, and strict control and management are the keys to prevention of cardiovascular events.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Dyslipidemia: abnormal amounts of lipid in the blood 

  • Hyperlipidemia (HLD): elevated lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids in the blood (elevated cholesterol, triglycerides, and/or lipoproteins)
  • Hyperlipoproteinemia: elevated levels of LDL, VLDL
  • Hypercholesterolemia: elevated total cholesterol (> 200 mg/dL)
  • Hypertriglyceridemia: elevated triglyceride levels (> 150 mg/dL)

Epidemiology

  • Prevalence increases with age.
  • 50% of Americans have a high LDL count.
  • Only 35% of patients are adequately treated.
  • 54% of patients with HLD have a family history of atherosclerotic coronary artery disease (CAD).
  • Men > women
  • Whites > people of color

Pathophysiology

  • Familial causes of dyslipidemia usually result from mutations that result in:
    • Decreased uptake of lipoproteins (Lps) by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver (loss of receptor mediators) 
    • Reduced clearance of triglycerides from chylomicrons (loss of lipoprotein lipase (LPL))
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9, a serine protease) causes decreased LDL receptors on hepatocytes → decreased clearance of LDL by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver → hypercholesterolemia
  • Dyslipidemia is a major risk factor for CAD.
  • Chronic HLD (hypercholesterolemia) directly impairs endothelial function due to increased local free radical production.
  • Lp accumulation within the vascular (arterial, arteriolar) intima stimulates inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation through oxidized LDL and cholesterol crystals (foam cells).
  • Both of these processes are pathogenic steps in the development of atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis.

Etiology and Classification

Etiology

Causes of dyslipidemia can be divided into primary (familial) and secondary (acquired) causes.

Primary causes: 

  • Polygenic inheritance
  • 5 subtypes of dyslipidemias classified according to the Fredrickson phenotype

Secondary (acquired) causes:

  • Lifestyle:
    • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
    • Cigarette smoking
    • Heavy alcohol use
  • Systemic Illness:
    • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
      • HLD is associated with insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance.
      • Hypertriglyceridemia, low HDL, and high LDL
    • Cholestatic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
    • Nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome:
      • Decreased plasma oncotic pressure
      • Induced liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver production of Lps
      • Elevated total and LDL cholesterol  
    • Chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
    • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism 
    • Depression
    • Psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
  • Medications:
    • Thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics
    • Beta-blockers
    • Oral estrogens
    • Protease inhibitors

Fredrickson classification for inherited dyslipoproteinemia

Table: Fredrickson classification for inherited dyslipoproteinemia (DLP
Type Condition, mode of inheritance ( autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance (AD), autosomal recessive ( AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation)), lipid abnormality Pathology Notes
I Familial hyperchylomicronemia ( AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation)
Elevated chylomicrons
Deficiency in LPL or apolipoprotein C-II (ApoC-II)
  • Very high triglyceride levels (> 1,000 mg/dL)
  • No increased risk for atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis
IIa Familial hypercholesterolemia (FH) (AD)
Elevated LDL
Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in PCSK-9, defective LDL receptors or apolipoprotein B-100 (ApoB-100)
  • High total cholesterol
  • Normal triglyceride levels
  • Responsible for premature CAD
IIb Familial combined hypercholesterolemia (AD)
Elevated VLDL and LDL
  • Massively elevated total cholesterol
  • Responsible for premature CAD
III Familial hyperlipoproteinemia ( AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation)
Remnants of VLDL and chylomicrons
Defective ApoE
  • Elevated triglyceride and cholesterol levels
  • Responsible for premature CAD
IV Familial hypertriglyceridemia (AD)
Elevated VLDL
Excessive VLDL production by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
  • Massively increased triglyceride levels
  • Responsible for premature CAD
V Mixed HLD ( AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation)
Elevated chylomicrons and VLDL
Defective apolipoprotein A5 (ApoA5)
  • Massively elevated triglyceride levels
  • No increased risk for atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis

Clinical Presentation

  • Due to an increased risk of atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis, the majority of patients present with the following:
    • Peripheral artery disease Peripheral artery disease Peripheral artery disease (PAD) is obstruction of the arterial lumen resulting in decreased blood flow to the distal limbs. The disease can be a result of atherosclerosis or thrombosis. Patients may be asymptomatic or have progressive claudication, skin discoloration, ischemic ulcers, or gangrene. Peripheral Artery Disease (PAD)
    • CAD
    • MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction 
    • Stroke
  • High levels of triglycerides may also cause pancreatitis or fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver.
  • Clinical examination may reveal the following (usually indicative of an underlying primary cause):
    • Xanthomas: lipid deposits on skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
      • Tendon xanthomata: most commonly on the Achilles tendon and dorsum of hands 
      • Plantar xanthomas: occurs on palms and soles
    • Xanthelasmas: cholesterol plaques on the inner, upper eyelid
    • Arcus lipoides corneae: cholesterol deposition on cornea, resulting in yellow discoloration

Diagnosis and Management

Diagnosis

  • Indications for screening:
    • Everyone between 40 and 70 should receive yearly lipid blood work.
    • Patients of any age with a family history of premature CAD or FH should start annual screening with yearly lipid blood work starting 10 years before the earliest age of onset in a 1st-degree relative.
  • Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests:
    • Fasting lipid profile (preferred):
      • Total cholesterol
      • LDL cholesterol
      • HDL cholesterol
      • Triglycerides
    • Investigate for secondary causes in younger patients (HbA1c, thyroid-stimulating hormone (TSH), liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests, etc.)
    • Calculate Framingham risk score (risk for developing a cardiovascular event in the following 10 years)
    • Genetic testing may be done to confirm FH.
Table: Normal values of lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids in blood
Lipid Normal value
Total cholesterol < 200 mg/dL
HDL cholesterol > 60 mg/dL
LDL cholesterol < 100 mg/dL
Triglycerides < 150 mg/dL
Friedewald formula: LDL= total cholesterol – HDL – (triglycerides/5)

Management

The aim of management is to reduce the risk of cardiovascular diseases.

  • Encourage lifestyle modifications for all patients.
  • Lifestyle modifications include:
    • Diet management and weight loss
    • Smoking cessation
    • Decreased alcohol intake
    • Optimal physical activity 
    • Blood pressure management
      • Goal for the general population: < 140/90 mm Hg
      • Goal for individuals with risk >10%: < 130/80 mm Hg
  • Pharmacological approach:
    • Statins are the 1st line of therapy; the intensity varies based on LDL levels and Framingham risk.
    • Stain examples:
      • Atorvastatin (Lipitor)
      • Lovastatin (Altoprev)
      • Pitavastatin (Livalo, Zypitamag)
      • Pravastatin (Pravachol)
      • Rosuvastatin (Crestor, Ezallor)
      • Simvastatin (Zocor)

References

  1. Kaiser Permanente. (2020). Atherosclerotic Cardiovascular Disease Guidelines. https://wa.kaiserpermanente.org/static/pdf/public/guidelines/ascvd-primary.pdf
  2. Robertson, RS. (2021). Measurement of blood lipids and lipoproteins. UpToDate. Retrieved September 27, 2021, from https://www.uptodate.com/contents/measurement-of-blood-lipids-and-lipoproteins?search=cholesterol&topicRef=4565&source=see_link#H24361294
  3. Robertson, RS. (2021). Secondary causes of dyslipidemia. UpToDate. Retrieved September 27, 2021, from https://www.uptodate.com/contents/secondary-causes-of-dyslipidemia?search=dyslipidemia&source=search_result&selectedTitle=7~150&usage_type=default&display_rank=6#H2

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