Lipid disorders

Lipid disorders encompass a broad spectrum of metabolic conditions that affect blood lipid levels. They can be characterized by elevated levels of cholesterol, triglycerides, and/or lipoproteins in the blood (hyperlipoproteinemias), which are often associated with an increased risk of (or current) cardiovascular disease. Hyperlipoproteinemias are most commonly caused by lifestyle factors (diet, lack of activity, alcohol consumption) but can also be congenital, e.g., familial hypertriglyceridemia, which is associated with extremely high levels of triglycerides that significantly increase the risk of pancreatitis, and familial hypercholesterolemia, which results in early atherosclerotic complications. Abetalipoproteinemia is a congenital lipid disorder that is characterized by a deficiency of apolipoproteins (hypolipoproteinemia), which leads to impaired intestinal absorption of fats and fat-soluble vitamins. Symptoms mainly consist of failure to thrive, steatorrhea, and signs of vitamin E deficiency. Lipid disorders are usually detected during routine laboratory testing, such as cardiovascular risk factor screening. The blood lipid profile includes total cholesterol, LDL, HDL, and triglycerides. To confirm the diagnosis, a fasting lipid profile must show pathological values on two different occasions. Dyslipidemia is diagnosed if LDL levels are > 130 mg/dL and/or HDL levels are < 40 mg/dL. The management of hyperlipoproteinemia involves lifestyle modifications and lipid-lowering agents (primarily statins). The treatment of abetalipoproteinemia includes supplementation of vitamin E.

• Dyslipidemia: abnormal concentration of lipids in the blood (e.g., high LDL, low HDL)
• Hyperlipidemia: elevated blood lipid levels (total cholesterol, LDL, triglycerides)
• Hypercholesterolemia: total cholesterol > 200 mg/dL
• Hypertriglyceridemia: triglyceride levels > 150 mg/dL
• Hyperlipoproteinemia: elevated levels of certain lipoproteins

• In the US, the prevalence of lipid disorders is estimated as follows:
  • Hypercholesterolemia: ∼ 50% ^[1]
  • Hypertriglyceridemia: ∼ 35% in men and ∼ 25% in women ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Acquired (more common)
  • Obesity
  • Diabetes mellitus
  • Physical inactivity
  • Heavy consumption of alcohol
  • Hypothyroidism
  • Nephrotic syndrome
  • Cholestatic liver disease
  • Cushing disease
  • Drugs: antipsychotics, beta blockers (e.g., metoprolol), oral contraceptive pill, high-dose diuretic use
• Inherited (less common): See “Frederickson classification of inherited hyperlipidemias” below.

• Elevated LDL and reduced HDL → promote atherosclerosis → increased risk of cardiovascular events
• See “Pathogenesis of atherosclerosis.”

Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease.

Typically no specific signs or symptoms

Skin manifestations

Xanthomas

• Description: nodular lipid deposits in the skin and tendons
• Pathophysiology: Extremely high levels of triglycerides and/or LDL result in extravasation of plasma lipoproteins and their deposition in tissue.
• Types

:

Xanthelasmas

• Description: typically bilateral, yellow, flat plaques on the upper eyelids (nasal side)
• Etiology
  • Idiopathic
  • Increased incidence in
    • Patients with diabetes mellitus
    • Patients with increased lipoproteins in plasma
    • Usually affects postmenopausal women
• Associated conditions: hypercholesterolemia (e.g., primary biliary cholangitis), hyperapobetalipoproteinemia, ↑ LDL levels

Eye manifestations

• Lipemia retinalis
  • Description: opaque, white appearance of the retinal vessels, visible on fundoscopic exam
  • Associated condition: hyperlipoproteinemia type I, III, and IV
• Arcus lipoides corneae
  • Associated with hyperlipoproteinemia type II
  • Not pathological in advanced age

Gastrointestinal manifestations

• Fatty liver (hepatic steatosis): associated conditions include abetalipoproteinemia, metabolic syndrome, heavy consumption of alcohol
• Pancreatitis in severe hypertriglyceridemia (typically > 1,000 mg/dL): associated conditions include hyperlipoproteinemia type I and IV, hypertriglyceridemia

Premature atherosclerosis

• Associated conditions: hyperlipoproteinemia type II, III, and IV
• Manifests with secondary diseases such as:
  • Coronary heart disease
  • Myocardial infarction
  • Stroke
  • Peripheral arterial disease
  • Carotid artery stenosis
  • Cholesterol embolization syndrome

• Laboratory analysis ^[11]
  • Fasting lipid profile : Total cholesterol, HDL, and triglycerides are measured.
    • The LDL level can be measured directly using assays or estimated using the Friedewald formula (LDL = total cholesterol – HDL – (triglycerides/5) ).
    • Pathological values on two different occasions are required to confirm the diagnosis.
    • Dyslipidemia is diagnosed if LDL > 130 mg/dL. and/or if HDL levels < 40 mg/dL.
  • Identify the underlying cause.
    • Fasting blood glucose level or HbA1c
    • TSH level
    • Liver function tests
    • Urine analysis

• Further workup: required in patients with confirmed dyslipidemia
  • Assess for cardiovascular disease (CVD).
    • Myocardial infarction
    • Stroke
    • Symptomatic carotid artery stenosis
    • Peripheral artery disease
    • Abdominal aortic aneurysm
    • CVD risk equivalents: diabetes mellitus, chronic kidney disease
  • Assess for other major risk factors of CVD.
    • Smoking
    • Hypertension
    • Elevated total cholesterol, LDL, and/or low HDL ^[13]
    • Family history of coronary heart disease (first degree relative ♂ < 55 years and ♀ < 65 years)
    • Age: ♂ ≥ 45 years and ♀ ≥ 55 years

General

• Goal: improve serum lipid levels to reduce the risk of cardiovascular disease
• Nonpharmacological measures: lifestyle modifications
  • Dietary changes
    • Reduce saturated fat and cholesterol intake.
    • Reduce or eliminate consumption of alcohol. ^[14]
  • Maintaining a healthy weight
  • Physical activity
• Medical therapy
  • Statins
  • Second-line lipid-lowering agents if there is a poor response to statins
• Treatment of xanthomas and xanthelasmas
  • Not required in most cases
  • Surgical removal for cosmetic reasons is possible but is associated with a high rate of recurrence
• Management of familial disorders
  • Lifestyle modifications and lipid-lowering agents (high-dose statin therapy and ezetimibe for hypercholesterolemia, fibrates for hypertriglyceridemia)
  • LDL apheresis may be required in severe cases

ACC/AHA guidelines on the management of blood cholesterol (2018) ^[15][16][17]

• Initiate moderate-intensity or high-intensity statin therapy.

National Heart, Lung, and Blood Institute pediatric guidelines (2011) ^[18]

• The decision to screen for hyperlipidemia primarily depends on the patient's overall risk of cardiovascular disease.
• Screening of high-risk individuals (i.e., with other risk factors for cardiovascular disease): ♂ > 20–25 years; ♀ > 30–35 years
• Screening of low-risk individuals: ♂ > 35 years; ♀ > 45 years

• Etiology
  • Deficiency of apolipoproteins (ApoB-48, ApoB-100)
  • Due to a mutation in the microsomal triglyceride transfer protein (MTTP) gene
• Pathophysiology
  • Autosomal recessive disease
  • Deficiency of chylomicrons, VLDL, and LDL (hypolipoproteinemia)
• Clinical features
  • Early
    • Steatorrhea
    • Failure to thrive
    • Fat malabsorption → fat-soluble vitamin deficiency
    • Acanthocytosis
  • Late
    • Developmental delay
    • Retinitis pigmentosa
    • Myopathy
    • Progressive ataxia
    • Spinocerebellar degeneration as a result of vitamin E deficiency
• Diagnostics
  • Extremely low levels of plasma cholesterol (< 50 mg/dL)
  • Acanthocytes in the blood
  • Other tests performed include complete blood count with differential, stool studies, and fasting lipid profile.
  • Confirmatory test: genetic testing to detect mutations in the MTTP gene
  • Intestinal biopsy: Histology may reveal lipid-laden enterocytes.
• Treatment
  • Vitamin E supplementation (high doses)
  • Reduced long-chain fatty acids intake