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Lipid Disorders (Clinical)

Lipid Disorders (Clinical)

An abnormal amount of lipids 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 atherosclerotic cardiovascular disease (ASCVD). Familial causes are classified according to the Fredrickson system, which looks into the pathology and the 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.

Last updated: Mar 4, 2024

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Contents

Overview

Definition[17]

Dyslipidemia: abnormal amounts of 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 

  • 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 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism, triglycerides Triglycerides Fatty Acids and Lipids, and/or lipoproteins Lipoproteins Lipid-protein complexes involved in the transportation and metabolism of lipids in the body. They are spherical particles consisting of a hydrophobic core of triglycerides and cholesterol esters surrounded by a layer of hydrophilic free cholesterol; phospholipids; and apolipoproteins. Lipoproteins are classified by their varying buoyant density and sizes. Lipid Metabolism)
  • Hyperlipoproteinemia: elevated levels of LDL, VLDL
  • Hypercholesterolemia Hypercholesterolemia A condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population. Lipid Disorders: elevated total cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism (> 200 mg/dL)
  • Hypertriglyceridemia Hypertriglyceridemia A condition of elevated levels of triglycerides in the blood. Lipid Disorders: elevated triglyceride levels (> 150 mg/dL)

Epidemiology[20]

  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency increases with age.
  • In the US, about 12% of adults (≥ 20 years of age) have total cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism > 240 mg/dL.
  • About 17% have low HDL levels (< 40 mg/dL), a risk factor for ASCVD.
  • 54% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with hyperlipidemia have a family history Family History Adult Health Maintenance of atherosclerotic coronary artery Coronary Artery Truncus Arteriosus disease (CAD).
  • Familial hypercholesterolemia Familial hypercholesterolemia Lipid Disorders is a common genetic disorder, affecting 1:250 individuals worldwide.
  • Men > women
  • Whites > people of color

Pathophysiology[17]

  • Familial causes of dyslipidemia usually result from mutations that result in:
    • Decreased uptake of lipoproteins Lipoproteins Lipid-protein complexes involved in the transportation and metabolism of lipids in the body. They are spherical particles consisting of a hydrophobic core of triglycerides and cholesterol esters surrounded by a layer of hydrophilic free cholesterol; phospholipids; and apolipoproteins. Lipoproteins are classified by their varying buoyant density and sizes. Lipid Metabolism (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: Anatomy (loss of receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors mediators) 
    • Reduced clearance of triglycerides Triglycerides Fatty Acids and Lipids from chylomicrons (loss of lipoprotein lipase Lipase An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. Malabsorption and Maldigestion (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 Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS) causes decreased LDL receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors on hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy → 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: Anatomy → hypercholesterolemia Hypercholesterolemia A condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population. Lipid Disorders
  • Dyslipidemia is a major risk factor for CAD.
  • Chronic hyperlipidemia ( hypercholesterolemia Hypercholesterolemia A condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population. Lipid Disorders) directly impairs endothelial function due to increased local free radical Free Radical Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Nitroimidazoles 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 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism crystals ( foam cells Foam cells Lipid-laden macrophages originating from monocytes or from smooth muscle cells. Atherosclerosis).
  • 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

Lipid disorders 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) disease. Lipid Disorders are due to a combination of diet and lifestyle habits coupled with a genetic predisposition.

Etiology[3,17]

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

Primary causes: 

  • Polygenic inheritance
  • 5 subtypes of dyslipidemias Dyslipidemias Abnormalities in the serum levels of lipids, including overproduction or deficiency. Abnormal serum lipid profiles may include high total cholesterol, high triglycerides, low high density lipoprotein cholesterol, and elevated low density lipoprotein cholesterol. Lipid Disorders classified according to the Fredrickson phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics

Secondary (acquired) causes:

  • Hyperlipidemia due to an underlying etiology separate from a primary disorder of lipid metabolism Lipid Metabolism Lipid metabolism is the processing of lipids for energy use, energy storage, and structural component production. Lipid metabolism uses fats from dietary sources or from fat stores in the body. A complex series of processes involving digestion, absorption, and transport are required for the proper metabolism of lipids. Lipid Metabolism in up to 28% of individuals[16]
  • 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 Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
    • Heavy alcohol use (10%)
  • Diseases:
    • Diabetes Diabetes 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 mellitus (8%):
      • Hyperlipidemia is associated with insulin resistance Insulin resistance Diminished effectiveness of insulin in lowering blood sugar levels: requiring the use of 200 units or more of insulin per day to prevent hyperglycemia or ketosis. Diabetes Mellitus.
      • Hypertriglyceridemia Hypertriglyceridemia A condition of elevated levels of triglycerides in the blood. Lipid Disorders, 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: Anatomy 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 Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products oncotic pressure Oncotic Pressure Edema
      • 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: Anatomy production of Lps
      • Elevated total and LDL cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism  
    • 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: Anatomy 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 Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication
    • Beta-blockers Beta-blockers Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. Class 2 Antiarrhythmic Drugs (Beta Blockers)
    • Oral estrogens
    • Protease inhibitors Protease Inhibitors Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). Anti-HIV Drugs
Table: Fredrickson classification for inherited dyslipoproteinemia[18,19]
Type Condition, mode of inheritance ( AD AD The term advance directive (AD) refers to treatment preferences and/or the designation of a surrogate decision-maker in the event that a person becomes unable to make medical decisions on their own behalf. Advance directives represent the ethical principle of autonomy and may take the form of a living will, health care proxy, durable power of attorney for health care, and/or a physician’s order for life-sustaining treatment. Advance Directives, 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 Familial Hyperchylomicronemia Lipid Disorders ( 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 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 Familial hypercholesterolemia Lipid Disorders(FH) ( AD AD The term advance directive (AD) refers to treatment preferences and/or the designation of a surrogate decision-maker in the event that a person becomes unable to make medical decisions on their own behalf. Advance directives represent the ethical principle of autonomy and may take the form of a living will, health care proxy, durable power of attorney for health care, and/or a physician’s order for life-sustaining treatment. Advance Directives)
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 Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors or ApoB-100
  • High total cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • Normal triglyceride levels
  • Responsible for premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis CAD
IIb Familial combined hypercholesterolemia Familial Combined hypercholesterolemia Lipid Disorders ( AD AD The term advance directive (AD) refers to treatment preferences and/or the designation of a surrogate decision-maker in the event that a person becomes unable to make medical decisions on their own behalf. Advance directives represent the ethical principle of autonomy and may take the form of a living will, health care proxy, durable power of attorney for health care, and/or a physician’s order for life-sustaining treatment. Advance Directives)
Elevated VLDL and LDL
  • Massively elevated total cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • Responsible for premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis CAD
III Familial hyperlipoproteinemia Familial hyperlipoproteinemia Lipid Disorders ( 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 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism levels
  • Responsible for premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis CAD
IV Familial hypertriglyceridemia Familial hypertriglyceridemia Lipid Disorders ( AD AD The term advance directive (AD) refers to treatment preferences and/or the designation of a surrogate decision-maker in the event that a person becomes unable to make medical decisions on their own behalf. Advance directives represent the ethical principle of autonomy and may take the form of a living will, health care proxy, durable power of attorney for health care, and/or a physician’s order for life-sustaining treatment. Advance Directives)
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: Anatomy
  • Massively increased triglyceride levels
  • Responsible for premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis CAD
V Mixed hyperlipidemia Mixed Hyperlipidemia Lipid Disorders ( 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 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
AD:autosomal dominant
AR: autosomal recessive
ApoC-I: apolipoprotein C-II
ApoB-100: apolipoprotein B-100
ApoA5: Defective apolipoprotein A5
Fredrickson classification type i and type iii

Schematic depiction of the Fredrickson classification types I and III
FFA: free fatty acid
ApoB-48: apolipoprotein-B-48
ApoC-II: apolipoprotein C-II
ApoE: apolipoprotein E
LPL: lipoprotein lipase

Image by Lecturio.
Schematic depiction of fredrickson classification type ii and type iv

Schematic depiction of Fredrickson classification types II and IV

Image by Lecturio.

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Clinical Presentation

Many individuals with hyperlipidemia and hypertriglyceridemia Hypertriglyceridemia A condition of elevated levels of triglycerides in the blood. Lipid Disorders are asymptomatic, without symptoms and signs (other than those listed below). The most common clinical manifestation of lipid disorders 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) disease. Lipid Disorders is ASCVD.[17,23]

  • People with homozygous familial hypercholesterolemia Familial hypercholesterolemia Lipid Disorders may present with consequences of premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis ASCVD while very young (< age 20).
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with heterozygous familial hyperlipidemia may present with:
    • 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 or angina
    • 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 or sudden cardiac death Sudden cardiac death Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest
    • Stroke
    • Coronary artery Coronary Artery Truncus Arteriosus calcification can be identified between ages 11 and 23.
  • High levels of triglycerides Triglycerides Fatty Acids and Lipids may also cause pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute 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: Anatomy.
  • Clinical examination may reveal the following (usually indicative of an underlying primary cause):
    • Xanthomas Xanthomas Lipid Disorders: 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. Skin: Structure and Functions
      • Tendon xanthomata: most commonly on the Achilles tendon and dorsum of hands 
      • Plantar xanthomas Xanthomas Lipid Disorders: occurs on palms and soles
    • Xanthelasmas Xanthelasmas Lipid Disorders: cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism plaques on the inner, upper eyelid
    • Corneal arcus Corneal arcus A corneal disease in which there is a deposition of phospholipid and cholesterol in the corneal stroma and anterior sclera. Cardiovascular Examination or arcus senilis Arcus senilis A corneal disease in which there is a deposition of phospholipid and cholesterol in the corneal stroma and anterior sclera. Lipid Disorders:
      • Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism deposition on cornea Cornea The transparent anterior portion of the fibrous coat of the eye consisting of five layers: stratified squamous corneal epithelium; bowman membrane; corneal stroma; descemet membrane; and mesenchymal corneal endothelium. It serves as the first refracting medium of the eye. Eye: Anatomy, resulting in yellow discoloration in younger individuals (< age 45) with familial hyperlipidemia
      • Associated with an increased risk of heart disease in people with familial hyperlipidemia
      • Not related to hyperlipidemia when seen in older adults (> age 45)
Xanthelasma

An elderly patient with yellow-tan deposits around the eyelids, most likely indicative of xanthelasma

Image: “Les différentes lésions jaunâtres au niveau des deux paupières en rapport avec le xanthélasma” by Elghazi, T. and Hafidi, Z. License: CC BY 2.0
Xanthomas

Multiple xanthomas on hands

Image: “Xanthomas” by Kumar, A.A. et al. License: CC BY 2.0
Corneal arcus

Four representative slides of corneal arcus:
Arcus deposits tend to start at 6 and 12 o’clock and fill in until becoming completely circumferential.

Image: “Corneal arcus” by Zech L.A. and Hoeg J.M. License: CC BY 2.0

Diagnosis

Dyslipidemia is defined as lipid values associated with an increased risk of and/or presence of disease for which the initiation of lipid-lowering therapy will be of benefit. There is controversy regarding the age at which to start screening Screening Preoperative Care, and guidelines for children and young adults vary. The recommendations listed below are based on the US Preventive Services Task Force (USPSTF) and the American Heart Association American Heart Association A voluntary organization concerned with the prevention and treatment of heart and vascular diseases. Heart Failure guidelines.

Lipid screening Screening Preoperative Care[8,13]

  • Screen individuals between 40 and 75 years of age.
  • No recommendations for or against screening Screening Preoperative Care for dyslipidemia in individuals < 35 years of age (USPSTF 2023 update in progress for individuals under 40)
  • Nonfasting screening Screening Preoperative Care for total cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism and HDL in men ≥ 35 and women ≥ 45
  • Screen and treat men ages 20–35 and women 20–45 if they have increased risk factors for cardiovascular disease:
    • Diabetes Diabetes 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
    • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Family history Family History Adult Health Maintenance of cardiovascular disease in 1st-degree male family members < age 50 and 1st-degree female family members < age 60
  • Baseline lipid testing in young adults is also recommended at initiation of care with an adult primary care provider.
    • Repeat screening Screening Preoperative Care is guided by the patient’s cardiovascular disease risk.
    • Assessment of cardiovascular disease risk and lipid levels are recommended to be repeated:
      • Generally, every 5 years 
      • Every 3 years if near the threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction for treatment

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[2,4,8,17]

  • Fasting lipid profile Lipid profile Lipid Disorders (preferred for screening Screening Preoperative Care):
  • Other lipid measurements:
    • Apolipoprotein B (apoB) and lipoprotein (a) (Lp(a)):
      • Can be considered risk-enhancing factors for ASCVD
      • Some studies show an association between apoB and ASCVD; others report correlation Correlation Determination of whether or not two variables are correlated. This means to study whether an increase or decrease in one variable corresponds to an increase or decrease in the other variable. Causality, Validity, and Reliability between apoB and non-HDL cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism.
      • Lp(a): modified form of LDL with atherogenic potential
    • ApoB levels: may be helpful for individuals with significant hypertriglyceridemia Hypertriglyceridemia A condition of elevated levels of triglycerides in the blood. Lipid Disorders
      • ApoB > 130 mg/dL corresponds to an LDL ≥ 160 mg/dL.
      • Expense and lack of reliability Reliability Reliability refers to the reproducibility of a test or research finding. Causality, Validity, and Reliability of testing makes this test nonstandard.
    • Lp(a) relative indications:
  • Investigate for secondary causes in younger patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship:
    • HbA1c
    • Thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones 
    • 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
  • Calculate 10-year ASCVD risk (risk for developing a cardiovascular event in the following 10 years): AHA/ACC calculator
  • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies 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 Desirable value
Total cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • < 200 mg/dL
  • Borderline high: 200‒239 mg/dL
  • High: ≥ 240 mg/dL
HDL cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • > 60 mg/dL
  • Low HDL: women < 50 mg/dL; men < 40 mg/dL
LDL cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • < Optimal: < 100 mg/dL
  • Borderline-high: 130‒159 mg/dL
  • High: 160‒189 mg/dL
  • Very high: ≥ 190 mg/dL
TGs
  • < 150 mg/dL
  • High: 200‒499 mg/dL
  • Very high: ≥ 500 mg/dL
Friedewald formula: LDL= total cholesterol – HDL – (triglycerides/5)
TGs: Triglycerides

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Hyperlipidemia: Diagnosis and Management

Management

The aim of management is to reduce the risk of cardiovascular disease including heart attack Heart attack 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 and stroke.[8]

  • Clinical trials show that lowering LDL reduces ASCVD risk:
    • Meta-analysis: ↓ LDL by 38.7 mg/dL → 21% reduction in ASCVD risk
    • Responses to statin therapy depend on baseline concentration.
  • Encourage lifestyle modifications for all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.

Diet management[9]

  • Ask about dietary habits in regular Regular Insulin medical visits: utilize evidence-based heart-healthy foods for improving cardiometabolic risk factors, dyslipidemia, and ASCVD risk.
  • Follow ACC/AHA diet recommendations for ASCVD prevention and lipid reduction:[5,22]
    • Limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation saturated fatty acids Saturated fatty acids Fatty Acids and Lipids and trans fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance.
    • Eat diet rich in fresh (unprocessed) fruits and vegetables.
    • Manage overweight/ 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 with calorie reduction and regular Regular Insulin exercise.
  • Include National Lipid Association (NLA) nutrition goals for optimizing LDL, non-HDL cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism, and TG Tg Thyroid Hormones levels.[8]
  • Dietary adjuncts:
    • Fiber supplements
    • Plant sterols Sterols Steroids with a hydroxyl group at c-3 and most of the skeleton of cholestane. Additional carbon atoms may be present in the side chain. Fatty Acids and Lipids (phytosterols) 

Other cardiovascular risk factor assessment and management[8]

  • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases 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
  • Screen for diabetes Diabetes 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 per guidelines:[10,24]
    • USPSTF: adults ages 35‒70 years with a BMI BMI An indicator of body density as determined by the relationship of body weight to body height. Bmi=weight (kg)/height squared (m2). Bmi correlates with body fat (adipose tissue). Their relationship varies with age and gender. For adults, bmi falls into these categories: below 18. 5 (underweight); 18. 5-24. 9 (normal); 25. 0-29. 9 (overweight); 30. 0 and above (obese). Obesity ≥ 25
    • American Diabetes Diabetes 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 Association ( ADA ADA An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism):
      • Screen all adults ≥ 35 years of age.
      • Consider screening Screening Preoperative Care adults of any age with overweight or 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 ( BMI BMI An indicator of body density as determined by the relationship of body weight to body height. Bmi=weight (kg)/height squared (m2). Bmi correlates with body fat (adipose tissue). Their relationship varies with age and gender. For adults, bmi falls into these categories: below 18. 5 (underweight); 18. 5-24. 9 (normal); 25. 0-29. 9 (overweight); 30. 0 and above (obese). Obesity ≥ 25 (≥ 23 in Asian Americans)) who have ≥ 1 risk factors (e.g., hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, HDL < 35 mg/dL).

Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins for primary prevention[1,5,8,14]

  • Calculate the patient’s ASCVD risk as a percentage based on:
    • Age
    • Systolic BP
    • Total cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism and HDL cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension on medications
    • Cigarette smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
    • Diabetes Diabetes 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
  • Risk calculators:
  • US: American Heart Association American Heart Association A voluntary organization concerned with the prevention and treatment of heart and vascular diseases. Heart Failure/American College of Cardiology (AHA/ACC) 2018 recommendations:[5,8]
    • In adults < 40 years of age:
      • Advised to estimate lifetime risk 
      • Statin therapy is recommended only for selected patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with moderately high LDL (≥ 160 mg/dL) or very high LDL (≥ 190 mg/dL). 
    • 3 high-risk categories for which statin therapy is recommended:
      • Severe hypercholesterolemia Hypercholesterolemia A condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population. Lipid Disorders LDL (≥ 190 mg/dL): no risk scoring required
      • Adults ages 40‒75 with diabetes Diabetes 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 mellitus
      • Adults ages 40‒75 with LDL ≥ 70 mg/dL and a 10-year ASCVD risk > 7.5%
  • UK: National Institute for Health and Care Excellence (NICE) recommendations:[14]
    • Adults ≤ 84 years with ≥ 10% 10-year ASCVD risk
    • Adults > 84 years may also benefit, but decision should consider:
      • Patient preference
      • Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids and frailty
      • Polypharmacy
      • Comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus
  • Check baseline 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: Anatomy transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids levels before starting statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins.

Lipid-lowering medications— statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins[8,21]

  • Choice depends on:
    • Degree of hyperlipidemia and ASCVD risk:
      • High-intensity therapy: lowers LDL by about ≥ 50%
      • Moderate-intensity: lowers LDL 30%–49% (start most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship here)
      • Low-intensity: lowers LDL by < 30%
      • Varies in clinical practice
    • Drug interactions
    • Comorbid CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease ( atorvastatin Atorvastatin A pyrrole and heptanoic acid derivative, hydroxymethylglutaryl-CoA reductase inhibitor (statin), and anticholesteremic agent that is used to reduce serum levels of ldl-cholesterol; apolipoprotein b; and triglycerides. It is used to increase serum levels of hdl-cholesterol in the treatment of hyperlipidemias, and for the prevention of cardiovascular diseases in patients with multiple risk factors. Statins or fluvastatin Fluvastatin An indole-heptanoic acid derivative that inhibits hmg CoA reductase and is used to treat hypercholesterolemia. In contrast to other statins, it does not appear to interact with other drugs that inhibit cyp3a4. Statins preferred; no dose adjustment needed)
    • Cost
  • Potential adverse effects of statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins:[6]
    • Myalgias Myalgias Painful sensation in the muscles. Tick-borne Encephalitis Virus: usually leg Leg The lower leg, or just “leg” in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg: Anatomy cramps Cramps Ion Channel Myopathy; not associated with an elevation in CK
      • Symptoms temporally related to status without known causality Causality Causality is a relationship between 2 events in which 1 event causes the other. Simply because relationships are observed between 2 variables (i.e., associations or correlations) does not imply that one variable actually caused the outcome. Demonstrating causality between an exposure and an outcome is the main objective of most published medical research. Causality, Validity, and Reliability (5%–25%)
      • Muscle symptoms due to pharmacologic properties of the statin (0.5%–4%)
    • Rare myonecrosis Myonecrosis A severe condition resulting from bacteria invading healthy muscle from adjacent traumatized muscle or soft tissue. The infection originates in a wound contaminated with bacteria of the genus Clostridium. C. perfringens accounts for the majority of cases (over eighty percent), while C. novyi, C. septicum, and C. histolyticum cause most of the other cases. Clostridia (0.5%) and rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis (< 0.1%) 
    • 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: Anatomy dysfunction
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship at increased risk of statin-associated myopathy Myopathy Dermatomyositis:
    • Acute or chronic renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
    • Obstructive 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: Anatomy disease
    • Neuromuscular disorders
    • Concurrent drug therapy with a cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury 3A4 ( CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers)) inhibitor
  • Common drug interactions with statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins:
    • Fibrates Fibrates Lipid Control Drugs: If combination therapy is needed, fenofibrate Fenofibrate An antilipemic agent which reduces both cholesterol and triglycerides in the blood. Lipid Control Drugs is preferred over gemfibrozil Gemfibrozil A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. Lipid Control Drugs.
    • Risk of muscle injury is higher when a statin metabolized by CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) ( lovastatin Lovastatin A fungal metabolite isolated from cultures of aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. Statins, simvastatin Simvastatin A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic ldl receptors, it increases breakdown of ldl cholesterol. Statins, atorvastatin Atorvastatin A pyrrole and heptanoic acid derivative, hydroxymethylglutaryl-CoA reductase inhibitor (statin), and anticholesteremic agent that is used to reduce serum levels of ldl-cholesterol; apolipoprotein b; and triglycerides. It is used to increase serum levels of hdl-cholesterol in the treatment of hyperlipidemias, and for the prevention of cardiovascular diseases in patients with multiple risk factors. Statins) is used with another substance that interferes with CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers). 
    • Inhibitors of CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers):
      • Clarithromycin Clarithromycin A semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50s ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. Macrolides and Ketolides
      • Grapefruit juice
      • Antifungals: ketoconazole Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Azoles and itraconazole Itraconazole A triazole antifungal agent that inhibits cytochrome p-450-dependent enzymes required for ergosterol synthesis. Azoles
      • Antiviral Antiviral Antivirals for Hepatitis B protease inhibitors Protease Inhibitors Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). Anti-HIV Drugs used for HIV HIV Anti-HIV Drugs infection (e.g., nelfinavir Nelfinavir A potent HIV protease inhibitor. It is used in combination with other antiviral drugs in the treatment of HIV in both adults and children. Anti-HIV Drugs, saquinavir Saquinavir An HIV protease inhibitor which acts as an analog of an HIV protease cleavage site. It is a highly specific inhibitor of HIV-1 and HIV-2 proteases, and also inhibits cytochrome p-450 cyp3a. Anti-HIV Drugs, ritonavir Ritonavir An HIV protease inhibitor that works by interfering with the reproductive cycle of HIV. It also inhibits cytochrome p-450 cyp3a. Anti-HIV Drugs)
    • Inducers of CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers):
      • Antiseizure drugs: phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs and carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs
      • Rifampin Rifampin A semisynthetic antibiotic produced from streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits dna-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. Epiglottitis
      • St. John’s wort
  • Contraindicated in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with heterozygous familial hyperlipidemia:
    • Start with high-intensity therapy.
    • Ezetimibe Ezetimibe An azetidine derivative and anticholesteremic agent that inhibits intestinal sterol absorption. It is used to reduce total cholesterol; ldl cholesterol, and apolipoproteins B in the treatment of hyperlipidemias. Lipid Control Drugs added to a moderate-intensity statin results in greater LDL reduction than monotherapy. 
    • LDL apheresis may be needed.
  • For statin-intolerant individuals:
    • Very high-risk (≥ 20% 10-year ASCVD risk and LDL > 160 mg/dL): Consider proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
    • All other patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship:
      • Nonstatin drugs are not routinely recommended for primary prevention (no prior ASCVD).
      • Continue lifestyle and diet modifications.
      • Consider antiplatelet therapy in higher-risk patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship (e.g., aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs))
Table: Statin medications and typical dosing[8]
Therapy intensity Typical medication choice and dose (adult)
High intensity
  • Atorvastatin Atorvastatin A pyrrole and heptanoic acid derivative, hydroxymethylglutaryl-CoA reductase inhibitor (statin), and anticholesteremic agent that is used to reduce serum levels of ldl-cholesterol; apolipoprotein b; and triglycerides. It is used to increase serum levels of hdl-cholesterol in the treatment of hyperlipidemias, and for the prevention of cardiovascular diseases in patients with multiple risk factors. Statins 40–80 mg
  • Rosuvastatin Rosuvastatin A hydroxymethylglutaryl-coa-reductase inhibitor, or statin, that reduces the plasma concentrations of ldl-cholesterol; apolipoprotein b, and triglycerides while increasing hdl-cholesterol levels in patients with hypercholesterolemia and those at risk for cardiovascular diseases. Statins 20–40 mg
Moderate intensity
  • Atorvastatin Atorvastatin A pyrrole and heptanoic acid derivative, hydroxymethylglutaryl-CoA reductase inhibitor (statin), and anticholesteremic agent that is used to reduce serum levels of ldl-cholesterol; apolipoprotein b; and triglycerides. It is used to increase serum levels of hdl-cholesterol in the treatment of hyperlipidemias, and for the prevention of cardiovascular diseases in patients with multiple risk factors. Statins 10–20 mg
  • Rosuvastatin Rosuvastatin A hydroxymethylglutaryl-coa-reductase inhibitor, or statin, that reduces the plasma concentrations of ldl-cholesterol; apolipoprotein b, and triglycerides while increasing hdl-cholesterol levels in patients with hypercholesterolemia and those at risk for cardiovascular diseases. Statins 5–10 mg
  • Pravastatin Pravastatin An antilipemic fungal metabolite isolated from cultures of nocardia autotrophica. It acts as a competitive inhibitor of hmg CoA reductase. Statins 40–80 mg
  • Simvastatin Simvastatin A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic ldl receptors, it increases breakdown of ldl cholesterol. Statins 20–40 mg
  • Lovastatin Lovastatin A fungal metabolite isolated from cultures of aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. Statins 40–80 mg
  • Fluvastatin Fluvastatin An indole-heptanoic acid derivative that inhibits hmg CoA reductase and is used to treat hypercholesterolemia. In contrast to other statins, it does not appear to interact with other drugs that inhibit cyp3a4. Statins XL 80 mg
  • Pitavastatin Pitavastatin Statins 1–4 mg
Low intensity
  • Pravastatin Pravastatin An antilipemic fungal metabolite isolated from cultures of nocardia autotrophica. It acts as a competitive inhibitor of hmg CoA reductase. Statins 10–20 mg
  • Lovastatin Lovastatin A fungal metabolite isolated from cultures of aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. Statins 20 mg
  • Fluvastatin Fluvastatin An indole-heptanoic acid derivative that inhibits hmg CoA reductase and is used to treat hypercholesterolemia. In contrast to other statins, it does not appear to interact with other drugs that inhibit cyp3a4. Statins 20–40 mg
All above statin drug doses are oral once-daily medications.

Lipid-lowering medications: others[7]

  • Ezetimibe Ezetimibe An azetidine derivative and anticholesteremic agent that inhibits intestinal sterol absorption. It is used to reduce total cholesterol; ldl cholesterol, and apolipoproteins B in the treatment of hyperlipidemias. Lipid Control Drugs:
    •  Inhibits cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy
    • 10 mg orally once daily
  • PCSK9 antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions: interfere with PCSK9, serine Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS that degrades LDL receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors, leading to ↑ LDL receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors on hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy
  • Bempedoic acid Bempedoic Acid Lipid Control Drugs:
    • Inhibits ATP-citrate lyase (enzyme in cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology)
    • Can be combined with a statin or ezetimibe Ezetimibe An azetidine derivative and anticholesteremic agent that inhibits intestinal sterol absorption. It is used to reduce total cholesterol; ldl cholesterol, and apolipoproteins B in the treatment of hyperlipidemias. Lipid Control Drugs
    • Can increase uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis
    • 180 mg orally once daily
  • Evinacumab:
  • Fibrates Fibrates Lipid Control Drugs:
    • Not recommended to reduce LDL (or increase HDL) in the absence of elevated TGs
    • Show no benefit in cardiovascular outcomes
    • Include:
      • Gemfibrozil Gemfibrozil A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. Lipid Control Drugs 600 mg orally twice a day
      •   Fenofibrate Fenofibrate An antilipemic agent which reduces both cholesterol and triglycerides in the blood. Lipid Control Drugs (dose varies by formulation)
  • Volanesorsen:
    • Inhibitor of apolipoprotein C-III (APOC3), reducing TGs
    • Approved for use in Europe but not in the US.

Subsequent monitoring and ASCVD risk assessment Risk assessment The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. Preoperative Care[8,14]

  • Monitoring:
    • Lipid:
      • 6 weeks after starting medication, evaluating the response to treatment
      • Assess adherence.
      • Ask about side effects.
    • 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: Anatomy transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
      • Obtain baseline level prior to initiating a statin.
      • Repeat within 3 months and 12 months, unless clinically indicated.
    • Creatine Creatine An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. Acute Kidney Injury kinase (CK):
      • Routine monitoring is not indicated. 
      • If patient reports generalized muscle pains, obtain CK prior to initiating statin.
      • Start statin at a lower dose if with increased CK but not 5x the upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal (ULN); do not give statin if levels are 5x the ULN.
  • Additional nonstatin lipid-lowering medication is not recommended for primary prevention in most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who are not at very high risk.
  • Reassess ASCVD risk periodically, especially when there is a change in clinical status.

Specialist referral[21]

  • Registered dietitian/nutritionist
  • Cardiology/lipid specialist:
  • UK:[14]
    • Total cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism > 9.0 mmol/L (SI units) or non‑HDL cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism > 7.5 mmol/L, even in the absence of a 1st‑degree family history Family History Adult Health Maintenance of premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis coronary heart disease Coronary heart disease Coronary heart disease (CHD), or ischemic heart disease, describes a situation in which an inadequate supply of blood to the myocardium exists due to a stenosis of the coronary arteries, typically from atherosclerosis. Coronary Heart Disease.
    • TG Tg Thyroid Hormones > 20 mmol/L unrelated to excess alcohol or poor glycemic control

References

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  11. US Preventive Services Task Force. (2022). Statin use for the primary prevention of cardiovascular disease in adults: US preventive services task force recommendation statement. JAMA, 328(8), 746–753. https://doi.org/10.1001/jama.2022.13044
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