Low LDL Cholesterol (Hypobetalipoproteinemia)
- Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI; Chief Editor: George T Griffing, MD more...
Abetalipoproteinemia (ABL) and familial hypobetalipoproteinemia (FHBL) are relatively uncommon inherited disorders of lipoprotein metabolism that cause low cholesterol levels. Although persons whose low-density lipoprotein (LDL) cholesterol levels are moderately low (ie, individuals with FHBL) exhibit an enhanced tendency to develop fatty liver disease (FLD), persons with a profound reduction of LDL cholesterol may have a decreased risk for heart disease.
ABL is a rare disease associated with a unique plasma lipoprotein profile in which LDL and very low-density lipoprotein (VLDL) are essentially absent. The disorder is characterized by fat malabsorption, spinocerebellar degeneration, acanthocytic red blood cells, and pigmented retinopathy. It is caused by a homozygous autosomal recessive mutation in the gene for microsomal triglyceride transfer protein (MTP). MTP mediates intracellular lipid transport in the intestine and liver and thus ensures the normal function of chylomicrons (CMs) in enterocytes and of VLDL in hepatocytes.
Affected infants may appear normal at birth, but by the first month of life, they develop steatorrhea, abdominal distention, and growth failure. Children develop retinitis pigmentosa and progressive ataxia, with death usually occurring by the third decade. Early diagnosis, high-dose vitamin E (tocopherol) therapy, and medium-chain fatty acid dietary supplementation may slow the progression of the neurologic abnormalities. Obligate heterozygotes (ie, parents of patients with ABL) have no symptoms and no evidence of reduced plasma lipid levels.
FHBL is also a rare disorder of apolipoprotein B (apoB) metabolism characterized by levels of plasma cholesterol and LDL cholesterol that are less than one-half normal in heterozygotes and are very low (< 50 mg/dL) in homozygotes. FHBL is caused by an autosomal, codominant mutation in the gene for apoB (APOB), which is carried on chromosome 2. This mutation results in a truncated form of apoB.[4, 5] Homozygotes present with fat malabsorption and low plasma cholesterol levels at a young age. They develop progressive neurologic degenerative disease, retinitis pigmentosa, and acanthocytosis, similar to patients with ABL. Although heterozygotes are usually asymptomatic, they exhibit decreased LDL cholesterol and apoB levels and possibly have a decreased risk of atherosclerosis.[6, 7, 8]
The nonfamilial forms of hypobetalipoproteinemia are secondary to a number of clinical states, such as occult malignancy, malnutrition, and chronic liver disease.
Cholesterol and triglycerides are transported from sites of synthesis to sites of utilization in the form of lipoproteins. These particles consist of a core of cholesterol esters and triglycerides surrounded by a monolayer of free cholesterol, phospholipids, and proteins (apolipoproteins). The 4 major lipoproteins are very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and chylomicrons (CMs). VLDL and CMs are assembled within the lumen of the endoplasmic reticulum of hepatocytes and enterocytes, respectively, transported to the Golgi complex, and then secreted into the circulation.
Each lipoprotein is characterized by its lipid composition and by the type and number of apolipoproteins it possesses. CMs, VLDL, and LDL carry apolipoproteins on their surface; these apolipoproteins have lipid-soluble segments, the beta apolipoproteins, which remain part of the lipoprotein throughout its metabolism. Other apolipoproteins (A, C, D, E, and their subtypes) are soluble and are exchanged between lipoproteins during metabolism.
Beta apolipoproteins are the largest of the apolipoproteins. They are critically important for the formation and secretion of CMs and VLDL; abnormalities that impede this process result in abetalipoproteinemia (ABL) and hypobetalipoproteinemia.
The 2 beta apolipoproteins are B-100 and B-48. ApoB-100 is carried on VLDL and the lipoproteins derived from its metabolism, including VLDL remnants or intermediate-density lipoprotein and LDL. ApoB-100, which is synthesized by the liver, is larger than apoB-48, being made up of 4536 amino acids. Unlike apoB-48, apoB-100 contains the binding site essential for LDL uptake by hepatocyte LDL receptors. ApoB-48 is carried on CMs, is derived from the same gene as apoB-100, and is approximately half its size, consisting of 2152 amino acids.
MTP gene mutation
Formation and exocytosis of CMs at the basolateral membrane of intestinal epithelial cells is necessary for the delivery of lipids to the systemic circulation. One of the proteins required for the assembly and secretion of CMs is MTP. The gene for this protein (MTP) is mutated in patients with ABL.[10, 11]
Several mutations in the MTP gene have been described. In most patients with ABL, the mutation involves a gene encoding the 97-kd subunit of MTP. Consequently, children with ABL develop fat malabsorption and, in particular, suffer the results of vitamin E deficiency (ie, retinopathy, spinocerebellar degeneration). Biochemical test results show low plasma levels of apoB, triglycerides, and cholesterol. Membrane lipid abnormalities also affect the erythrocytes, causing acanthocytosis (burr cells). Long-chain fatty acids are very poorly absorbed, and the intestinal epithelial cells become engorged with lipid droplets. Such children respond to a low-fat diet rich in medium-chain fatty acids, as well as to supplementation with high-dose, fat-soluble vitamins, especially vitamin E.
Role of vitamin E
Most of the clinical symptoms of ABL are the result of defects in the absorption and transport of vitamin E. Normally, vitamin E is transported from the intestine to the liver, where it is repackaged and incorporated into the assembling VLDL particle by the tocopherol-binding protein. In the circulation, VLDL is converted to LDL, and vitamin E is transported by LDL to peripheral tissues and delivered to cells via the LDL receptor. Patients with ABL are markedly deficient in vitamin E because of the deficient plasma transport of vitamin E, which requires hepatic secretion of apoB-containing lipoproteins. Most of the major clinical symptoms, especially those of the nervous system and retina, are primarily due to vitamin E deficiency. This hypothesis is supported by the fact that other disorders involving vitamin E deficiency are characterized by similar symptoms and pathologic changes.
APOB gene mutation
FHBL is a rare autosomal dominant disorder of apoB metabolism. Most cases of known origin result from mutations in the APOB gene, involving 1 or both alleles. More than 30 mutations have been described. Most often, a mutation involving a 4–base–pair deletion in the APOB gene prevents translation of a full-length apoB-100 molecule, leading to the formation of truncated apoB molecules (apoB-37, with 1728 amino acids; apoB-46, with 2057 amino acids; or apoB-31, with 1425 amino acids).[4, 5, 14, 15, 16]
Metabolic turnover studies indicate that in some persons, these APOB gene mutations result in impaired synthesis of apoB-containing lipoproteins, and that in other patients, they cause increased catabolism of these proteins. Overall, beta-lipoprotein levels remain low.
Heterozygotes may have LDL cholesterol levels less than or equal to 50 mg/dL, but they often remain asymptomatic and have normal life spans. In the homozygous state, the absence of apoB leads to significant impairment of intestinal CM formation, which in turn leads to impaired absorption of fats and fat-soluble vitamins. Cholesterol absorption may also be impaired. Subsequent vitamin E malabsorption results in low tissue stores of vitamin E and leads to the development of degenerative neurologic disease.
The secondary causes of hypobetalipoproteinemia include occult malignancy, as well as conditions such as malnutrition, liver disease, and chronic alcoholism. These conditions must be excluded before the diagnosis of FHBL can be made.
Abetalipoproteinemia (ABL) and familial hypobetalipoproteinemia (FHBL) are rare inborn errors of lipoprotein metabolism. ABL occurs in less than 1 in 1 million persons. FHBL occurs in approximately 1 in 500 heterozygotes and in about 1 in 1 million homozygotes. Approximately one third of ABL and FHBL cases result from consanguineous marriages.
Frequency is similar to that reported in the United States.
Infants exhibit failure to thrive, with fat malabsorption and abdominal distention occurring during the first month of life. Spinocerebellar degeneration and pigmented retinopathy develop during childhood. Death usually occurs by the third decade. Obligate heterozygotes are asymptomatic and have normal plasma lipid levels; their risk of developing cardiovascular disease is probably lower than average.
The most prominent and debilitating clinical manifestations of ABL in adults are neurologic in nature and usually manifest for the first time in the second decade of life. Severe ataxia and spasticity develop by the third or fourth decade. Progressive central nervous system involvement is the eventual cause of death in most patients and often occurs by the fifth decade. Moreover, ophthalmic symptoms begin with decreased night and color vision, with progression to virtual blindness by the fourth decade.
Familial hypobetalipoproteinemia (FHBL)
Homozygotes are identified at a young age because of fat malabsorption and through the detection of decreased plasma cholesterol levels. A deficiency of fat-soluble vitamins may lead to retinitis pigmentosa, acanthocytosis (or burr cells due to altered red blood cell membrane lipids), and progressive, degenerative neurologic disease. Heterozygotes are asymptomatic and are often diagnosed when routine lipid screening discloses abnormally low plasma cholesterol levels. Fat malabsorption is rarely noted. Neurologic examination may reveal diminished or absent deep tendon reflexes and, less frequently, deficits in proprioception and ataxia. The syndrome is associated with normal longevity. Compound heterozygotes (ie, patients with mutations of the APOB gene at 2 different sites) have a clinical presentation similar to that of homozygotes.
No race predilection for abetalipoproteinemia or familial hypobetalipoproteinemia has been described. Cases have been reported from every continent.
No sex predilection for abetalipoproteinemia or familial hypobetalipoproteinemia has been noted. Both disorders are caused by a mutation on an autosomal chromosome.
The homozygous disorders are identified during infancy or childhood.
Persons with homozygous abetalipoproteinemia (ABL) are detected in the first decade of life. Heterozygotes are asymptomatic throughout life.
Familial hypobetalipoproteinemia heterozygotes are carriers of the recessive gene that leads to ABL and are asymptomatic. Heterozygotes are usually identified in adulthood after routine blood work, lipid screening, or a workup for gastrointestinal (GI) or neurologic disorders.
Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol. 2014 Jun. 25(3):161-8. [Medline].
Sen D, Dagdelen S, Erbas T. Hepatosteatosis with hypobetalipoproteinemia. J Natl Med Assoc. 2007 Mar. 99(3):284-6. [Medline].
Hussain MM, Rava P, Pan X, et al. Microsomal triglyceride transfer protein in plasma and cellular lipid metabolism. Curr Opin Lipidol. 2008 Jun. 19(3):277-84. [Medline].
Young SG, Hubl ST, Smith RS, et al. Familial hypobetalipoproteinemia caused by a mutation in the apolipoprotein B gene that results in a truncated species of apolipoprotein B (B-31). A unique mutation that helps to define the portion of the apolipoprotein B molecule required for the format. J Clin Invest. 1990 Mar. 85(3):933-42. [Medline]. [Full Text].
Linton MF, Farese RV, Young SG. Familial hypobetalipoproteinemia. J Lipid Res. 1993 Apr. 34(4):521-41. [Medline].
Tarugi P, Averna M, Di Leo E, et al. Molecular diagnosis of hypobetalipoproteinemia: an ENID review. Atherosclerosis. 2007 Dec. 195(2):e19-27. [Medline].
Tarugi P, Averna M. Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum. Adv Clin Chem. 2011. 54:81-107. [Medline].
Gutierrez-Cirlos C, Ordonez-Sanchez ML, Tusie-Luna MT, Patterson BW, Schonfeld G, Aguilar-Salinas CA. Familial hypobetalipoproteinemia in a hospital survey: genetics, metabolism and non-alcoholic fatty liver disease. Ann Hepatol. 2011 Apr-Jun. 10(2):155-64. [Medline].
Di Leo E, Lancellotti S, Penacchioni JY, et al. Mutations in MTP gene in abeta- and hypobeta-lipoproteinemia. Atherosclerosis. 2005 Jun. 180(2):311-8. [Medline].
Rader DJ, Brewer HB Jr. Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease. JAMA. 1993. 270:865-9. [Medline].
Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, et al. The role of the microsomal triglyceride transfer protein in abetalipoproteinemia. Annu Rev Nutr. 2000. 20:663-97. [Medline].
Burnett JR, Zhong S, Jiang ZG, et al. Missense mutations in APOB within the betaalpha1 domain of human APOB-100 result in impaired secretion of ApoB and ApoB-containing lipoproteins in familial hypobetalipoproteinemia. J Biol Chem. 2007 Aug 17. 282(33):24270-83. [Medline]. [Full Text].
Young SG, Bertics SJ, Curtiss LK, et al. Genetic analysis of a kindred with familial hypobetalipoproteinemia. Evidence for two separate gene defects: one associated with an abnormal apoB species, apolipoprotein B-37; and a second associated with low plasma concentrations of apoB-100. J Clin Invest. 1987 Jun. 79(6):1842-51. [Medline]. [Full Text].
Martin-Morales R, Garcia-Diaz JD, Tarugi P, Gonzalez-Santos P, Saavedra-Vallejo P, Magnolo L, et al. Familial hypobetalipoproteinemia: analysis of three Spanish cases with two new mutations in the APOB gene. Gene. 2013 Nov 15. 531(1):92-6. [Medline].
Sankatsing RR, Fouchier SW, de Haan S, et al. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 2005 Sep. 25(9):1979-84. [Medline]. [Full Text].
Dieckert JP, White M, Christmann L, et al. Angioid streaks associated with abetalipoproteinemia. Ann Ophthalmol. 1989 May. 21(5):173-5, 179. [Medline].
Dannoura AH, Berriot-Varoqueaux N, Amati P, et al. Anderson's disease: exclusion of apolipoprotein and intracellular lipid transport genes. Arterioscler Thromb Vasc Biol. 1999 Oct. 19(10):2494-508. [Medline]. [Full Text].
Mehta NN, Desai HG. Persistent transaminase elevation due to heterozygous (familial) apolipoprotein B deficiency. Indian J Gastroenterol. 1997 Oct. 16(4):158-9. [Medline].
Roussell MA, Hill AM, Gaugler TL, West SG, Vanden Heuvel JP, Alaupovic P, et al. Beef in an Optimal Lean Diet study: effects on lipids, lipoproteins, and apolipoproteins. Am J Clin Nutr. 2011 Dec 14. [Medline].
Aguie GA, Rader DJ, Clavey V, et al. Lipoproteins containing apolipoprotein B isolated from patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia: identification and characterization. Atherosclerosis. 1995 Dec. 118(2):183-91. [Medline].
Glueck CJ, Kelley W, Gupta A. Prospective 10-year evaluation of hypobetalipoproteinemia in a cohort of 772 firefighters and cross-sectional evaluation of hypocholesterolemia in 1,479 men in the National Health and Nutrition Examination Survey I. Metabolism. 1997 Jun. 46(6):625-33. [Medline].
Goerg KJ, Borchard F, Luley C, et al. [Snow white small intestinal villi in hypobetalipoproteinemia]. Z Gastroenterol. 1996 Sep. 34(9):528-33. [Medline].
Granot E, Deckelbaum RJ. Familial hypobetalipoproteinemia--differences in lipoprotein structure and composition. Ann Nutr Metab. 1993. 37(5):253-61. [Medline].
Gregg RE, Wetterau JR. The molecular basis of abetalipoproteinemia. Curr Opin Lipidol. 1994 Apr. 5(2):81-6. [Medline].
Hardman DA, Pullinger CR, Hamilton RL, et al. Molecular and metabolic basis for the metabolic disorder normotriglyceridemic abetalipoproteinemia. J Clin Invest. 1991 Nov. 88(5):1722-9. [Medline]. [Full Text].
Humphries SE, Mailly F, Gudnason V, et al. The molecular genetics of pediatric lipid disorders: recent progress and future research directions. Pediatr Res. 1993 Oct. 34(4):403-15. [Medline].
Ikewaki K, Nishiwaki M, Sakamoto T, et al. Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency. J Clin Invest. 1995 Sep. 96(3):1573-81. [Medline]. [Full Text].
Kane JP, Havel RJ. Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. Scriver C, Beaudet A, Sly W, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001. 2717-52.
Malloy MJ, Kane JP. Hypolipidemia. Med Clin North Am. 1982 Mar. 66(2):469-84. [Medline].
Narchi H, Amr SS, Mathew PM, et al. Rickets as an unusual initial presentation of abetalipoproteinemia and hypobetalipoproteinemia. J Pediatr Endocrinol Metab. 2001 Mar. 14(3):329-33. [Medline].
Pessah M, Beucler I, Loux N, et al. Genetic exclusion of apo-B gene in recessive abetalipoproteinemia. Biochem Biophys Res Commun. 1993 Jan 15. 190(1):97-103. [Medline].
Raabe M, Kim E, Véniant M, et al. Using genetically engineered mice to understand apolipoprotein-B deficiency syndromes in humans. Proc Assoc Am Physicians. 1998 Nov-Dec. 110(6):521-30. [Medline].
Schonfeld G. The hypobetalipoproteinemias. Annu Rev Nutr. 1995. 15:23-34. [Medline].
Schonfeld G, Lin X, Yue P. Familial hypobetalipoproteinemia: genetics and metabolism. Cell Mol Life Sci. 2005 Jun. 62(12):1372-8. [Medline].
Shah SS, Desai HG. Apolipoprotein deficiency and chronic liver disease. J Assoc Physicians India. 2001 Feb. 49:274-8. [Medline].
Tarugi P, Lonardo A, Ballarini G, et al. A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (APO B-54.5). J Hepatol. 2000 Sep. 33(3):361-70. [Medline].
Tarugi P, Lonardo A, Ballarini G, et al. Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B. Gastroenterology. 1996 Oct. 111(4):1125-33. [Medline].
Young SG. Recent progress in understanding apolipoprotein B. Circulation. 1990 Nov. 82(5):1574-94. [Medline].