Hypolipoproteinemia pathophysiology

Lipid Disorders Main Page
Overview
Causes
Classification Abetalipoproteinemia Hypobetalipoproteinemia Familial hypoalphalipoproteinemia LCAT Deficiency Chylomicron retention disease Tangier disease Familial combined hypolipidemia
Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Overview

Multiple mechanisms have been described in different diseases and clinical conditions that are found to be associated with hypolipidemia. Secondary causes are far more common than primary causes and include anemia, hyperthyroidism, critical illness, malignancy, malabsorption, infection, Chronic liver disease, and Chronic inflammation.

Primary Lipoprotein Disorders

Shown below is a table summarizing the primary hypolipoproteinemia along with the involved gene and main lipoprotein.

Primary Hypolipoproteienmia	Gene	Main Lipoprotein Involved
Abetalipoproteienmia	Mirosomal triglyceride transfer protein (MTR)	LDL
Apolipoprotein 1 deficiency	Apolipoprotein AI	HDL
Chylomicron retention disease	SAR1B	Multiple
Familial combined hypolipidemia	ANGPTL3	Multiple
Hypobetalipoproteinemia	Apo B	LDL
LCAT deficiency	LCAT	HDL
Primary alphalipoproteinemia	Undetermined	HDL
PCSK9 deficiency	PCSK9	LDL
Tangier disease	ABCA1	HDL

• Abetalipoproteinemia (Bassen-Kornzweig syndrome): is a rare autosomal recessive disorder that interferes with the normal absorption of fat and fat-soluble vitamins from food. It is caused by a mutation in microsomal triglyceride transfer protein, resulting in deficiencies in the apolipoproteins B-48 and B-100, which are critical to chylomicron and very-low-density lipoprotein (VLDL) formation. Dietary fat cannot be absorbed, and lipoproteins in both metabolic pathways are virtually absent from serum, TC is typically < 45 mg/dL (< 1.16 mmol/L), TGs are < 20 mg/dL (< 0.23 mmol/L), and LDL is undetectable. The condition is often first noticed in infants with fat malabsorption, steatorrhea, and failure to thrive.

• Hypobetalipoproteinemia: is an autosomal dominant disorder, defined as below 5th percentile LDL-cholesterol or apolipoprotein (apo) B in the plasma. Subjects are generally heterozygous and asymptomatic except for TC < 120 mg/dL and LDL cholesterol < 80 mg/dL, TGs are normal. Homozygous patients have lower lipid levels (TC < 80 mg/dL, LDL cholesterol < 20 mg/dL), or absent apo B synthesis, leading to symptoms and signs of abetalipoproteinemia.

• Chylomicron retention disease: is a very rare autosomal recessive condition caused by an unknown mutation leading to deficient apo B secretion from enterocytes. Chylomicron synthesis is absent, but VLDL synthesis remains intact.

Secondary Lipoprotein Disorders

Hypolipedemia has been found in association with different clinical conditions.

• Anemia: Hypolipedemia has been identified in association with different types of anemia e.g.congenital dyserythropoietic anemia, congenital spherocytosis, sickle cell anemia, beta-thalassemia, aplastic anemia, and sideroblastic anemia. The exact etiology of hypolipidemia in anemic patients is not known, some studies outlined different mechanisms, another study suggest that hypolipidemia might be the cause rather than the consequence of anemia, which is explained by that cholesterol deficiency leads to rigidity of the erythrocytes, making them more prone to destruction.

• Hyperthyroidism: Thyroid hormone influence lipid metabolism and are common in dyslipidemic patients, and its dysfunction affect composition and transport of lipoproteins, hence the importance of Biochemical screening for thyroid dysfunction in all dyslipidemic patients.

• Critical illness: Cholesterol levels drop at the onset of acute illness, and normalize after recovery. This may predispose the critically ill patient to sepsis and adrenal failure, and early enteral nutrition and tight glycemic control recommended to accelerate the recovery of the cholesterol levels.

• Malignancy: Several epidemiological studies suggested an inverse relation between serum cholesterol level and cancer mortality.

• Malabsorption: Fat malabsorption can lead to hypolipidemia, as the dietary fats constitute the exogenous source of body lipids. Brar et al demonstrated that celiac disease is associated with hypocholesterolemia and a gluten-free diet will result in rising of total cholesterol and HDL.

• Infection: The chronic effect of proinflammatory cytokines on lipoprotein metabolism seen in acute and chronic, bacterial, viral, and parasitic infections all might induce hypocholesterolemia.

• Chronic liver disease: Hypolipidemia is frequently observed in severe chronic hepatic insufficiency, as the hepatocytes is the main site for lipid metabolism.

• Chronic inflammation: In the acute phase response to inflammation, reduction in plasma lipid levels is a well known phenomenon, it is explained by the chronic effect of proinflammatory cytokines on lipoprotein metabolism.