Dyslipidemia - Symptoms, Causes, Risk Factors, Diagnosis, and Treatment

Dyslipidemia definition

Dyslipidemia refers to abnormal or impaired levels of lipids in the bloodstream. It is defined as increased levels of total cholesterol, low-density lipoprotein (LDL), and triglycerides (TG) with decreased levels of high-density lipoprotein (HDL) in the bloodstream. 

It is the most important modifiable risk factor for cardiovascular disease (CVD) which is the leading cause of death worldwide.

The intestine absorbs lipids such as cholesterol or triglycerides and via lipoproteins, they are carried throughout the body for the purpose of energy, steroid production, or bile acid formation. Cholesterol, low-density lipoproteins, triglycerides, and high-density lipoproteins are important factors for the pathway. Any disturbance in the pathway or imbalance to any of the factors, whatever may be the reason may lead to dyslipidemia. 

Early screening and effective lipid profile management may reduce the risk of cardiovascular disease. Lifestyle modifications, improving dietary interventions and drug therapies are the three major ways to treat dyslipidemia. Dyslipidemia can be successfully managed by an endocrinologist or a lipidologist.

Dyslipidemia meaning

In medical terms, "dys" means impaired or abnormal or difficult, "lipid" refers to lipids and "emia" means in blood so collectively dyslipidemia means abnormal or impaired levels of lipids in blood.

Prevalence of dyslipidemia

Dyslipidemia is a global public health problem affecting lakhs of people worldwide and increasing the risk of cardiovascular disease which is the leading cause of death worldwide. As per systematic protocol in adults, the global prevalence of dyslipidemia is estimated to range from 20 to 80 percent. 

Many studies have estimated that dyslipidemia is responsible for 44 lakh deaths around the world. Different studies have suggested that the prevention and treatment of dyslipidemia can reduce morbidity and mortality related to atherosclerosis and ischemic heart disease.

Prevalence of dyslipidemia in India

The prevalence of dyslipidemia is very high in India, therefore there is an urgent need for lifestyle intervention strategies to manage dyslipidemia as this is an important cardiovascular risk factor. 

Population-based studies indicate increasing mean total cholesterol levels. Studies reported that high cholesterol is present in 25 to 30 percent of urban areas and 15 to 20 percent in rural areas.

Dyslipidemia is usually asymptomatic, and it often coexists with other factors like hypertension, diabetes, obesity, and smoking habits. Various trials showed that lowering low-density lipoprotein (LDL) cholesterol by 1 mmol/L reduces the major vascular events by 20 percent. 

In children and adolescents, the prevalence of dyslipidemia is increasing due to factors like obesity, sedentary lifestyles, and unhealthy diets. Childhood dyslipidemia can persist into adulthood increasing the risk of premature cardiovascular disorder. 

Types of dyslipidemia

Dyslipidemia is classified as primary dyslipidemia and secondary dyslipidemia. Primary dyslipidemias are heterogeneous groups of diseases that are inherited and are caused by genetic mutations, and mono or polygenic etiology. 

Secondary dyslipidemia is acquired and is caused by various external factors and lifestyle factors. Primary dyslipidemia affects lipid metabolism whereas secondary dyslipidemia alters lipid metabolism. 

Primary dyslipidemia is further classified into: 

• Familial combined hyperlipidemia: It is characterized by increased plasma cholesterol and triglyceride levels affecting at least two members of the family. It is a prevalent hereditary lipid disorder.

• Familial hypercholesterolemia: It is defined as a group of inherited genetic defects characterized by severe elevations of serum cholesterol levels. It is diagnosed clinically as high serum levels of low-density lipoprotein (LDL) and genetically it is characterized into two groups. One is autosomal dominant and the other is codominant transmission. 

• Familial hyperbetalipoproteinemia: It is characterized by elevated levels of lipids (hyperlipidemia) due to the accumulation of remnants of triglyceride, triglyceride-rich proteins, very low-density lipoproteins (VLDL), chylomicrons (CM). This occurs in response to dysfunctional genetic variants of apolipoprotein E or the absence of apo E. 

• Familial hypertriglyceridemia: It is also known as type IV familial dyslipidemia. It is characterized by increased levels of triglycerides in blood, these elevations in triglycerides are due to increased production and decreased clearance of very low-density lipoprotein (VLDL). 

Following are some forms of dyslipidemia:

• High LDL (Low density lipoprotein) cholesterol, also called bad cholesterol, forms plaques in the arteries reducing blood flow. 

• Low HDL (High density lipoprotein) cholesterol removes low LDL (low-density lipoprotein) protecting against atherosclerosis. This form of dyslipidemia is also known as good cholesterol. 

• Triglycerides are reserved in fat cells and are released in the form of energy when required. These triglycerides may also contribute to the formation of plaque and inflammation in arteries. 

• High total cholesterol, which is the sum of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and half of the triglyceride level indicates an increased risk of heart disease and stroke.
  

Dyslipidemia symptoms

Individuals with dyslipidemia may have no symptoms, but some patients with severe dyslipidemia develop few signs and symptoms linked to atherosclerosis. Some of the common signs and symptoms of dyslipidemia are described below.

Clinical symptoms of dyslipidemia

Common dyslipidemia symptoms are as follows:

• Xanthomas, which are yellowish deposits of fats appearing on the skin of eyelids, palms, tendons, or others indicating high serum levels of cholesterol or triglycerides.

• Arcus senilis, which is common in elderly people, may occur in young patients appearing as grey or white rings around the eye cornea due to cholesterol depositing in the corneal margin indicating high cholesterol levels.

• Lipemia retinalis is a rare condition causing a milky appearance in retinal vessels and blurred vision indicating severe hypertriglyceridemia.

• Lower limb ischemia indicates high levels of low-density lipoproteins (LDL) cholesterol and triglycerides.

• Angina is described as chest pain occurring due to a lack of oxygen-rich blood reaching the heart. It is a symptom of coronary artery disease caused by thickening or narrowing of blood vessels. 

• Transient ischemic attacks and strokes: Due to the narrowing of blood vessels, there is a sudden interruption blockage of blood flow to the brain. This blockage of blood supply to the brain is a stroke, transient ischemic attack is a temporary blockage of blood flow to the brain, often referred to as mini stroke.

Dyslipidemia causes

Dyslipidemia has varied etiologies influenced by genetic, environmental, and lifestyle factors. It is categorized into primary and secondary based on etiology:

Primary causes of dyslipidemia

Primary dyslipidemia is caused by genetic mutations, it can be inherited as an autosomal dominant, autosomal recessive or X-linked. 

• Examples of primary dyslipidemia are familial hypercholesterolemia, familial hypertriglyceridemia, familial combined hyperlipidemia, and familial dysbetalipoproteinemia.

• The dyslipidemia mechanism involves defects in the synthesis, transport, or degradation of lipoproteins which result in the accumulation or deficiency of lipids and lipoproteins which ultimately increase the risk of atherosclerosis and cardiovascular disease. 

• Mutations in the low-density lipoproteins (LDL) receptor gene cause familial hypercholesterolemia that impairs low-density lipoprotein (LDL) cholesterol uptake from blood resulting in high LDL cholesterol levels and atherosclerosis. 

• Mutations in the low-density lipoprotein (LDL) gene or apo C II gene cause familial hypertriglyceridemia impairing the hydrolysis of triglycerides in chylomicrons resulting in high triglyceride levels and pancreatitis. 

• Overproduction of apo B containing lipoproteins such as very low-density lipoproteins and low-density lipoproteins causes familial combined hyperlipidemia leading to high triglyceride and cholesterol levels and resistance to insulin.

• Mutations in the apo E gene cause familial dysbetalipoproteinemia impairing clearance of chylomicrons and very low-density lipoprotein (VLDL) from blood resulting in high cholesterol, triglyceride levels, and xanthomas. 

Secondary causes of dyslipidemia

Secondary dyslipidemia is caused by certain medications and some lifestyle factors that alter lipid levels in the blood. By addressing the underlying cause, secondary dyslipidemia can be reversed or modified. 

Risk factors include physical inactivity, obesity, diabetes, hypothyroidism, chronic kidney disease, liver disease, smoking, etc. 

Recent studies in the United States (US) revealed that 28 percent of patients had one or more potential causes of secondary dyslipidemia, with excessive alcohol intake (10 percent) and uncontrolled diabetes mellitus (8 percent) as the most prevalent. 

• Obesity is usually associated with increased production of very low-density lipoproteins and decreased liver clearance of chylomicrons which leads to high triglyceride and low high-density lipoprotein cholesterol levels. 

• Diabetes mellitus is associated with insulin resistance and hyperglycemia which impairs triglyceride lipolysis and also the uptake of low-density lipoproteins (LDL) cholesterol ultimately leading to high triglyceride and low-density lipoprotein cholesterol levels and low high-density lipoprotein (HDL) cholesterol levels. 

• Chronic kidney disease (CKD) is generally allied with impaired catabolism of apo B-containing lipoproteins and decreased function of lipoprotein lipase and hepatic lipase, that impair the clearance of both triglycerides and cholesterol from the blood, resulting in high triglyceride and low-density lipoprotein cholesterol (LDL) levels and low high-density lipoprotein cholesterol levels (HDL).

• Excessive consumption of alcohol is allied with increased synthesis of very low-density lipoproteins (VLDL) and decreased oxidation of fatty acids by the liver, leading to high triglyceride levels.

• Smoking leads to increased oxidative stress and inflammation, impairing the function and synthesis of high-density lipoprotein (HDL) cholesterol, leading to low high-density lipoprotein cholesterol levels (HDL). 
  

Dyslipidemia risk factors

Identifying risk factors of dyslipidemia can guide appropriate interventions and the progression of the disease to reduce the risk of cardiovascular diseases associated with dyslipidemia. The following are the risk factors associated with dyslipidemia: 

• Obesity
• Lack of exercise
• Excessive alcohol consumption
• Excessive smoking
• Type II diabetes mellitus 
• Hypothyroidism
• Chronic kidney disease
• Age 
• Family history of dyslipidemia
• Female gender, as women tend to experience higher low-density lipoprotein (LDL) levels after menopause.
• Liver conditions that nonalcoholic fatty liver disease
  

Atherosclerotic risk score for diabetic dyslipidemia

• For initial cardiovascular risk assessment, the 2018 Multi Society Cholesterol Management Guidelines as well as the 2019 American Heart Association Primary Prevention of Cardiovascular Disease Guideline recommended Pooled Cohort Risk Estimator Plus. 

• Four US Cohorts comprising more than 30000 individuals developed this scoring algorithm with 10 years of follow-up for cardiovascular disease. This scoring algorithm predicts 10-year (for those individuals aged 40 to 79) and lifetime (20 to 59) atherosclerotic cardiovascular disease (ASCVD) risk.

• Statin therapy is definitely recommended when the patient is identified with a 10-year atherosclerotic cardiovascular disease (ASCVD) risk of more than or equal to 20 percent. Patients identified with 5 to 20 percent are given consideration for statin therapy. 

• Like other risk scores, it depends on a set of risk factors such as age, sex, systolic blood pressure, total high-density lipoprotein cholesterol, diabetes, smoking, etc. 

• The ten-year risk of atherosclerotic cardiovascular disease (ASCVD) is classified into low (less than 5 percent), borderline (5 to less than 7 percent), intermediate (7.5 to less than 20 percent), and high (greater than or equal to 20 percent). 

• Diabetes mellitus is treated as a binary factor as it is included in pooled cohort equations (PCE) and factors like duration and hemoglobin levels are not included. Diabetes Mellitus (DM) is not necessarily a congenital heart disease (CHD) risk equivalent, validating the consideration of diabetes specific risk score. 
  

Dyslipidemia as a macrovascular risk factor in diabetes

In type II diabetes mellitus (DM) patients even in good glycemic control there are abnormalities in lipid levels. Many studies estimated that about 30 to 60 percent of diabetic patients have dyslipidemia. 

Serum has increased levels of triglycerides, very low-density lipoproteins, and decreased high-density levels. An increase in serum triglycerides is emphasized and an increase in lipids may increase the risk of atherosclerotic cardiovascular disease.

Dyslipidemia complications

Cardiovascular disease is the most common complication of dyslipidemia. Complications includes sudden cardiac death, myocardial infarction, or stroke. Multiple studies have indicated that with statin therapy, there is a reduced risk of all mortality and other cardiovascular events. 

The complications associated with dyslipidemia include:

• Atherosclerosis (build-up of fats and cholesterol in arteries)
• Coronary artery disease (a disease characterized by narrowing of arteries carrying blood to the heart)
• Peripheral arterial disease (narrowing of peripheral arteries causing blockage of blood supply to legs)
• Stroke (sudden blockage of blood supply to the brain)
• Heart failure
  

Dyslipidemia diagnosis

General physicians gather the complete medical history of the patient including family history as an initial approach to diagnose dyslipidemia. Routine lipid screening, especially in high-risk patients, is necessary for early detection and effective management of rising dyslipidemia. Clinicians need to consider family history and risk factors to guide appropriate interventions.

A detailed family history is taken to consider and identify cardiovascular conditions like angina, acute myocardial infarction, coronary artery bypass graft, angioplasty, peripheral arterial disease, and stroke (if it occurs in females less than 65 years of age or males aged less than 55 years). 

Dyslipidemia being a major risk factor for cardiovascular diseases, comprehensive diagnostic approaches have been necessitated for accurate assessment. 

There is a debate on the age at which screening must be performed. Following are the screening guidelines given:

• The National Cholesterol Education Program provides guidelines that recommend a fasting lipid panel every 5 years for adults aged 20 years and above.

• The US Preventive Services Task Force recommends lipid screening in men aged 35 and older, in women 45 years and older. Only the younger adults who have cardiovascular risk factors are advised to get screening otherwise fasting lipid panel are suggested for individuals aged between 20 to 78 for every 5 years if no atherosclerotic disease is present.

• Screening for dyslipidemia in children and adolescents of age 9 to 11 years and 17 to 21 is recommended by American Academy of Pediatrics regardless of risk factors whereas selective screening is suggested for patients aged 2 to 6 years and 12 to 16 years having family history of dyslipidemia or cardiovascular diseases (CVD) or with risk factors like obesity, hypertension, diabetes or smoking. 

• Apart from screening the first phase of dyslipidemia approach is cardiovascular risk stratification (increased, moderate, or high-risk cardiovascular development in 10 years). In children high-risk conditions are uncommon, but their identification and assessment are very crucial. 

A fasting lipid panel comprising total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides is the primary evaluation for dyslipidemia.

Following are the lipid levels

Total Cholesterol 

• Desirable: less than 200 mg/dl
• Borderline: 200 mg/dl to 239 mg/dl
• High: greater than or equal to 240mg/dl

Low Density Lipoprotein Cholesterol 

• Optimal: less than 100mg/dl
• Near optimal: 100mg/dL to 129 mg/dL
• Borderline high: 130mg/dL to 159mg/dL
• High: 160mg/dL to 189mg/dL
• Very high: greater than or equal to 190mg/dL

High – Density Lipoprotein Cholesterol

• Low: Less than 40mg/dL in men and less than 50 mg/dL in women
• High: Greater than equal to 60 mg/dL

Triglycerides

• Normal: Less than 150 mg/dL
• Borderline: 150 mg/dL to 199 mg/dL
• High: 200 mg/dL to 499 mg/Dl
• Very high: More than or equal to 500 mg/dL
  

Dyslipidemia differential diagnosis

A spectrum of presentation coincides between different entities. Primary dyslipidemia is considered with the following 

• Presence of family history of dyslipidemia, xanthomas, or premature cardiovascular disease
• Personal or family history of pancreatitis
• Presence of any cutaneous xanthomas or tendons
• Plasma levels of low-density lipoprotein (LDL) greater than 500 mg/dL or triglyceride levels greater than 1000 mg/dL.

Inherited metabolic diseases without inducing lipid profiles led to intracellular accumulation of cholesterol. 

• Increased bile acid metabolism with defects in bile acid synthesis intermediates with cholestenol.
• Lysosomal diseases like Niemann–Pick disease type C or cholesterol ester deposit disease and Wolman disease (lysosomal acid lipase deficiency). 

Impaired lipoprotein values due to inborn metabolism errors are suggested by the following:

• Pseudo hypertriglyceridemia in glycerol kinase deficiency
• Hypertriglyceridemia in glycogenosis I
• Combined dyslipidemia which is severe in lipodystrophies
  

Dyslipidemia treatment

The criteria for the treatment of dyslipidemia primarily depend on the levels of low-density lipoproteins (LDL) with an aim to reduce the risk of cardiovascular disease in the future. 

Dietary Interventions and Lifestyle Changes: 

• The treatment is focused on diet. Dietary modifications must include a reduction in intake of saturated and trans-fat, cholesterol, and refined carbohydrates. Increase the uptake of unsaturated fats, fiber, plant sterols, and antioxidants. Increased intake of fruits and vegetables compared to the percentage of ingested fat (lipids by 25 percent, carbohydrates by 55 percent, and proteins by 15 to 20 percent. 

Physical Activity: 

• Physical activity can improve the lipid profile, reduce blood pressure, improve the sensitivity of insulin, and promote weight loss. Cardiovascular risk can be prevented or reduced by improving endothelial function, reducing inflammation, and by preventing thrombosis. 

• Moderate aerobic exercise for about 150 min or 75 min of vigorous-intensity aerobic exercise per week or a combination of both should be aimed by adults as recommended by the American Heart Association (AHA). 

Weight management and smoking cessation: 

• Dyslipidemia patients who are obese should aim for a gradual weight loss up to 5 to 10 percent of their initial body weight for 6 to 12 months which can be achieved by restricting calorie intake and with regular exercise. 

• Smoking can affect lipid profile by enhancing the levels of low-density lipoproteins (LDL), and triglycerides, it also increases the risk of cardiovascular diseases by damaging endothelial lining causing inflammation and promoting oxidation of low-density lipoproteins (LDL) which in turn causes vasoconstriction due to aggregation of platelets. 

• Smoking cessation can reverse these effects, enhance the lipid profile, and decrease the risk of cardiovascular disorder. 

Pharmacological Intervention: 

• Pharmacological treatment must consider cardiovascular risk stratification, and the type of treatment depends on age, severity, and presence of familial cardiovascular risk factors. 

• Statins are the first line treatment for dyslipidemia which acts by inhibiting 3 – hydroxy 3methylglutaryl – coenzyme A reductase. High-intensity statins are prescribed for patients aged less than 75 years and with clinically significant atherosclerotic cardiovascular disease (ASCVD). Moderate-intensity statins are prescribed for patients with atherosclerotic cardiovascular disease aged 75 or more. 

• Patients aged between 40 to 75 with diabetic history and with low-density lipoprotein values varying between 70 to 189 mg/dL are prescribed high-intensity statins. Patients aged between 40 to 75 years and with 10-year atherosclerotic cardiovascular disease greater than or equal to 7.5 percent should be on a moderate-intensity statin. 

• With a moderate intensity, statin therapy should lower low-density lipoprotein levels by approximately 30 percent to less than 50 percent and greater than or equal to 50 percent with high-density statins for primary prevention. 

• For a coronary artery disease patient, the motto is to achieve low-density lipoprotein levels of less than 70 mg/dL after being prescribed a high-intensity statin for about 6 weeks. Combination therapy is recommended in addition to high-intensity statin when low-density lipoprotein levels are significantly greater than 70 mg/dL. 

• Statins as first-line treatment is recommended from 8 years of age, and these are contraindicated in pregnancy. 

• Bile acid scavengers act by binding to bile acids thereby reducing their absorption, increasing the hepatic synthesis, and decreasing cholesterol content of hepatocytes. These are prescribed in patients aged above 6 years as monotherapy or with statins. These are rarely prescribed as they limit the absorption of fat-soluble vitamins and are less effective compared to statins. 

• Cholesterol absorption inhibitors which act by inhibiting intestinal cholesterol absorption are usually prescribed to patients aged above 10 years, given as monotherapy or in combination with statins. Also prescribed to children or adolescents with familial hypercholesterolemia, to patients with high-risk factors for premature cardiovascular disease, or to patients who do not reach their therapeutic goal with statin dose. 

• Fibrates or fibric acid derivatives enhance lipolysis, reducing hepatic cholesterol synthesis thereby increasing clearance of very low-density lipoproteins (VLDL). Fibrates reduce triglyceride levels by 20 to 50 percent, low-density lipoproteins (LDL) by 15 percent, and increase high-density lipoproteins (HDL) by up to 20 percent. 
  

Mixed dyslipidemia treatment

• Patients with mixed or combined dyslipidemia require combination therapy to achieve lipid levels recommended by the US National Cholesterol Education Program Third Adult Treatment Panel (ATP III) as they are at high risk for developing cardiovascular events. 

• Monotherapy with statin proved to be effective and by combination therapy, an additional benefit can be obtained by a greater reduction in levels of both low-density lipoprotein (LDL), and triglycerides and elevated levels of high-density lipoprotein (HDL).

• For combination therapy, careful monitoring and evaluation of the risk-benefit ratio have to be done. Clinical trials are conducted to obtain an optimal treatment plan for patients with combined dyslipidemia. 

Treatment of dyslipidemia in pregnancy

• In pregnancy, treatment recommendations for dyslipidemia are limited as pregnant women are usually excluded from clinical trials. Omega 3 fatty acids which act by decreasing maternal triglycerides (TG) are used as monotherapy and are safe. 

• Nicotinic acid and fibrates decrease triglyceride levels and increase the levels of high-density lipoprotein (HDL) concentration. Neither Niacin nor fibrates are recommended for treating dyslipidemia as they are not well studied in pregnancy.

• Statins which are first line treatments for dyslipidemia showed conflicting reports of teratogenicity and congenital malformation therefore not recommended.

Diabetic dyslipidemia treatment 

• Patients with diabetic dyslipidemia are at higher risk of developing atherosclerotic cardiovascular disease (ASCVD). Statin therapy is the first-line treatment in the majority of cases. 

• Other lipid-lowering agents are recommended when individuals on statin therapy do not attain desired low-density lipoprotein (LDL) goals. Eicosapentaenoic acid (EPA) as adjuvant therapy is also recommended. 
  

Dyslipidemia prevention

Prevention is important to decrease the risk of cardiovascular complications and to enhance the quality of life. The following strategies are included to prevent dyslipidemia:

• Screening must be performed regularly for individuals having a family history or associated with any of the risk factors. The type of screening and frequency of screening depends on the patient's age, gender, etc. Usually, a lipid profile test is suggested every 4 to 6 years in adults and every 2 years in children. 

• Aiming for a healthy lifestyle with a proper balanced diet including fruits, vegetables, whole grains, and proteins, avoiding saturated and trans food, and reducing cholesterol, salt, and sugar in the diet. Restraining from smoking, limiting alcohol consumption, and maintaining a healthy body weight with regular exercise is recommended. American Heart Association (AHA) suggests 150 minutes of moderate-intensity exercise and also recommends that adults should perform muscle-strengthening exercises twice a week. 

• Lipid levels can be altered by comorbidities like diabetes, hypertension, hypothyroidism, and chronic kidney disease. These can in turn increase the risk for cardiovascular diseases therefore medications are to be taken regularly.

Difference between Dyslipidemia and Hyperlipidemia