Low LDL Cholesterol (Hypobetalipoproteinemia)

Updated: Dec 16, 2014
  • Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI; Chief Editor: George T Griffing, MD  more...
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Overview

Background

Abetalipoproteinemia (ABL) and familial hypobetalipoproteinemia (FHBL) are relatively uncommon inherited disorders of lipoprotein metabolism that cause low cholesterol levels. [1] 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), [2] 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. [3]

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.

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Pathophysiology

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.

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Beta apolipoproteins

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. [9] 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.

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Abetalipoproteinemia

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). [12] 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. [13]

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. [11]

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Familial hypobetalipoproteinemia

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. [5]

Secondary causes

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.

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Epidemiology

Frequency

United States

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.

International

Frequency is similar to that reported in the United States.

Mortality/Morbidity

Abetalipoproteinemia (ABL)

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.

Race

No race predilection for abetalipoproteinemia or familial hypobetalipoproteinemia has been described. Cases have been reported from every continent.

Sex

No sex predilection for abetalipoproteinemia or familial hypobetalipoproteinemia has been noted. Both disorders are caused by a mutation on an autosomal chromosome.

Age

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.
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