Lipoproteins & Abetalipoproteinemia Discussion
Lipoproteins are lipid transport molecules that transport lipids in the blood. Lipoproteins are risk factors for cardiovascular disease and other metabolic illnesses.1 They have a central core of triglycerides and cholesterol esters. Fatty acids derived from triglycerides can be employed for energy storage or production, while cholesterol is required for steroid synthesis, cellular membrane construction, and the creation of bile acids.1 This core is surrounded by a mixture of phospholipids, free cholesterol, and apolipoproteins (apo). Apolipoproteins are particularly significant because they play a role in categorizing lipoproteins into one of five major classes: chylomicrons, intermediate-density lipoprotein (IDL), very-low-density lipoprotein (VLDL), high-density lipoprotein (HDL), and low-density lipoprotein (LDL).1 Lipoprotein disorders are caused by both hereditary and environmental factors.1
Familial hypercholesterolemia is a series of inherited genetic abnormalities that cause substantial elevations in blood cholesterol levels. Familial hypercholesterolemia is clinically defined by a high blood level of low-density lipoprotein (LDL) cholesterol, which significantly increases the risk of cardiovascular disease (CVD), and genetically classified into two subgroups: (1) autosomal dominant (AD), and (2) codominant transmission.2 Familial hypercholesterolemia (FH) is caused by genetic abnormalities such as autosomal dominant hypercholesterolemia (ADH), polygenic hypercholesterolemia, and other uncommon syndromes such as autosomal recessive hypercholesterolemia (ARH).3 FH’s genetic architecture is more complicated than previously thought, and it is currently thought to be related with at least nine distinct genes, each with thousands of variations.3 The phrase “autosomal dominant hypercholesterolemia” refers to persons with dominantly inherited severe hypercholesterolemia – LDL-cholesterol (LDL-C) levels more than 190 mg/dL – who are likely to have mutations in genes that regulate serum LDL levels.3 Historically, the more prevalent causes of ADH include “classic” FH, a codominant condition involving abnormalities in the LDL receptor (LDLR), and other codominant types of “nonclassical” FH, which involve deficiencies in two additional genes that regulate plasma clearance of LDL.3 Apolipoprotein B (APOB) produces the primary protein of LDL (a ligand for the LDLR) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) produces a low abundance circulatory protein that shortens the LDLR’s life span.3 The LDLR is a cell surface glycoprotein of 893 amino acids that binds to and internalizes LDL particles, particularly in the liver.3 Nearly 90% of clinical ADH cases are caused by LDLR mutations. Over 2000 LDLR mutations, including deletions, insertions, missense, copy number variations, and nonsense mutations, have been found. FH patients might be homozygous, meaning they have mutations in both alleles encoding for LDLR, or heterozygous, meaning they have mutations in just one allele.3
Patients might have a homozygous or heterozygous abnormality, which determines the severity of the disease and the age at which symptoms of cardiovascular disease (CVD) appear. 2 Homozygous Familial Hypercholesterolemia is characterized by symptoms of ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis.2 Tendonitis or arthralgia may be present, as well as a history of unusual skin lesions. 2 Patients with Heterozygous Familial Hypercholesterolemia have severe hypercholesterolemia since childhood. Ischemic heart disease symptoms are widespread, especially when additional cardiovascular risk factors are present. 2 There may be symptoms of recurring Achilles’ tendinitis or arthritic problems. 2 Typically, abnormal physical tests are associated with cholesterol depositions in the eye or skin. 2 With homozygous familial hypercholesterolemia, it can occur at a young age. Tendon xanthomas, which appear as thickening of the tendons owing to cholesterol accumulated among macrophages in connective tissue, are pathognomonic for familial hypercholesterolemia (lipid-laden histiocytes) .2
Because all people with severe hypercholesterolemia are at high risk of CVD, treatment focuses on dietary and lifestyle changes, as well as the early implementation of lipid-lowering medication.3 Treatment should begin with statins, but most patients will require additional drugs such as ezetimibe and PCSK9 inhibiting monoclonal antibodies.3 Patients with excessive and unresponsive LDL-C increases will require more aggressive therapy such as lipoprotein apheresis and medicines for the treatment of severe hypercholesterolemia such as MTP inhibitors and evinacumab.3
1. Lent-Schochet D, Jialal I. Biochemistry, Lipoprotein Metabolism. [Updated 2021 Jan 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK553193/
2. Vaezi Z, Amini A. Familial Hypercholesterolemia. [Updated 2021 Oct 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK556009/
3. Warden BA, Fazio S, Shapiro MD. Familial Hypercholesterolemia: Genes and Beyond. [Updated 2021 Oct 23]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK343488/
Abetalipoproteinemia is a rare inherited disorder that results in the inability to absorb fat. It is characterized by low or absent levels of B containing lipoproteins. The B containing lipoproteins include chylomicrons, low-density lipoproteins (LDL), and very-low-density lipoproteins (VLDL). Betalipoproteins are essential in absorbing and transporting fats from the intestines into the circulatory system. Biallelic mutations in the microsomal triglyceride transfer protein (MTTP) gene result in abetalipoproteinemia. It is inherited in an autosomal recessive pattern. The clinical features of this disease can vary. The gastrointestinal tract, the nervous system, the eyes, and the blood are most commonly affected.
The microsomal triglyceride transfer protein (MTTP) is a vital component in lipid transfer. It is a heterodimer. In abetalipoproteinemia, mutations in the MTTP gene lead to a non-functional protein with an absent large microsomal triglyceride transfer protein (MTTP) subunit.1 MTTP is essential for the synthesis and secretion of chylomicrons and VLDL. Lack of MTTP leads to an impaired assembly of lipoproteins in hepatocytes and intestinal cells.2 This impairment leads to abnormal excretion of fats. More than 60 MTTP pathogenic variants have been identified to cause abetalipoproteinemia.3 These variants may be passed down in an autosomal recessive pattern.
Clinical features of the disease typically present in infancy. Problems beginning in infancy include vomiting, malabsorption, steatorrhea, and failure to thrive. Gastrointestinal symptoms often present first as a result of improper fat absorption.3 Many vitamins require B containing lipoproteins for their proper absorption and transport. Many patients with abetalipoproteinemia are deficient in fat-soluble vitamins E, A, D, and K. The vitamin deficiencies cause many complications. Lack of vitamin E can lead to cardiomyopathy and demyelination of spinocerebellar axons, which causes peripheral neuropathy and myopathy.3 Ophthalmic symptoms may appear gradually, including loss of night vision, loss of color vision, and alterations in visual acuity.3 Retinitis pigmentosa is often present in adolescents due to vitamin A and E deficiencies. Fatty liver is a common complication resulting from insufficient secretion of VLDL. Liver complications need to be closely monitored for further complications such as liver cirrhosis. The abnormal composition and distribution of lipids can result in various hematology problems. Acanthocytosis is one of the hallmarks of this disease. This abnormal red blood cell presentation occurs in more than 90 % of patients.1 Anemia and abnormal bleeding are also common due to vitamin deficiencies.
There is currently no cure for abetalipoproteinemia, but treatment focuses on targeting the symptoms. Restriction of fat intake is often advised to reduce steatorrhea. Fat malabsorption can lead to malabsorption of other macronutrients, so it is important to limit fat intake and consume an adequate number of calories to avoid malnutrition.3 Since many of the complications associated with the disease result from vitamin deficiency, it is recommended to supplement vitamins A and E in high doses orally.
Abetalipoproteinemia can be fatal if not diagnosed and treated early on. It is essential to be aware of the signs and symptoms and begin supplementation as soon as detected. Patients can live a long, healthy life when caught before significant damage is done. Unfortunately, the rareness of this disease causes delayed diagnosis, and proper treatment may not be established until permanent damage such as developmental delays, blindness, or neurological impairment has already set in. More studies are needed to understand the effects of this disease better.
1. Koulij N. A lipid metabolism disorder: Abetalipoproteinemia. 2021.
2. Rosenthal MD, Glew RH. Medical biochemistry human metabolism in health and disease. Hoboken, N. J: Wiley; 2009.
3. Takahashi M, Okazaki H, Ohashi K, et al. Current Diagnosis and Management of Abetalipoproteinemia. Journal of atherosclerosis and thrombosis. 2021;28(10):1009-1019. doi:10.5551/jat.RV17056