Hypobetalipoproteinemia: Difference between revisions

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===Pathogenesis===
===Pathogenesis===
*Cholesterol and triglycerides are insolublei in the plasma, so they require a transport protien in the form of apolipoprotein B. These lipoproteins transport cholesterol and trigylcerides in spherical particles in which the cholesterol esters and triglyceride form the central core.
*Apolipoprotein B is the major carrier for triglycerides and cholesterol from the intestine and liver to the periphery.
*Apo B exits in two forms, Apo B48 and Apo B100.
{{Family tree/start}}
{{Family tree | | | | A01 | | | |A01= Apo B48 is produced in intestine and is critical in the formation and secretion of chylomicrons , Apo B100 is synthesized in liver and released into circulation as VLDL}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | B01 | | | |B01= MTP transfers triglycerides from cytsol onto nacent ApoB in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | C01 | | | |C01= In the periphery by the action of lipoprotein lipase in the endothelium of the capillaries and glycosylphosphatidylinositol-anchored high-density lipoprotein- binding protein 1 (GPIHBP1) triglycerides are hydrolysed to form free fatty acids and glycerol }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | D01 | | | |D01= This results in the formation of VLDL remnant( Intermediate density lipoprotein) and chylomicron remnants
The lipases are inhibited by Angiopoietin-like protein 3 (ANGPTL3) thereby decreasing the triglyceride and LDL C.}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | E01 | | | |E01= IDL on further removal of triglycerides forms a cholesterol ester rich LDL C}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | F01 | | | |F01=LDL C is removed from the circulation by binding to LDL receptors in the liver. The receptor degradation is enhanced by Proprotein convertase subtilisin kexin 9 (PCSK9), any mutation in the loss of function in the enzyme causes low LDL C levels}}
{{Family tree/end}}


===Genetics===
===Genetics===

Revision as of 16:52, 15 November 2016

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Synonyms and keywords: Familial hypobetalipoproteinemia, FHBL, normotriglyceridemic hypobetalipoproteinemia

Overview

It is a rare disease caused by mutation in the APOB gene or less commonly in the PCSK9 gene, characteristic findings include low plasma level of total cholesterol, low LDL C, and Apo B below the 5th percentile when compared to the normal population.

Historical Perspective

  • In 1960, Salt reported absence of betalipoprotein in the plasma of a patient associated with very low cholesterol levels in the parents. Low cholesterol levels in the parents differentiates it from abetalipoproteinemia[1].

Pathophysiology

Pathogenesis

  • Cholesterol and triglycerides are insolublei in the plasma, so they require a transport protien in the form of apolipoprotein B. These lipoproteins transport cholesterol and trigylcerides in spherical particles in which the cholesterol esters and triglyceride form the central core.
  • Apolipoprotein B is the major carrier for triglycerides and cholesterol from the intestine and liver to the periphery.
  • Apo B exits in two forms, Apo B48 and Apo B100.


 
 
 
Apo B48 is produced in intestine and is critical in the formation and secretion of chylomicrons , Apo B100 is synthesized in liver and released into circulation as VLDL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MTP transfers triglycerides from cytsol onto nacent ApoB in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the periphery by the action of lipoprotein lipase in the endothelium of the capillaries and glycosylphosphatidylinositol-anchored high-density lipoprotein- binding protein 1 (GPIHBP1) triglycerides are hydrolysed to form free fatty acids and glycerol
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This results in the formation of VLDL remnant( Intermediate density lipoprotein) and chylomicron remnants The lipases are inhibited by Angiopoietin-like protein 3 (ANGPTL3) thereby decreasing the triglyceride and LDL C.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IDL on further removal of triglycerides forms a cholesterol ester rich LDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDL C is removed from the circulation by binding to LDL receptors in the liver. The receptor degradation is enhanced by Proprotein convertase subtilisin kexin 9 (PCSK9), any mutation in the loss of function in the enzyme causes low LDL C levels
 
 
 

Genetics

  • Mutation in the APOB gene on chromosome 2p24 which codes for apolipoprotein B.
  • Mutation in the PCSK9 can also cause the disease but it is less common compared to the mutation in Apo B.
  • Familial hypobetalipoproteinemia-2 is caused by mutation in the ANGPTL3 gene (604774) on chromosome 1p31.

Natural History, complications and Prognosis

Diagnosis

History and Physical

Laboratory Results

Treatment=

Medical Therapy

Surgical Therapy

Prevention

Hypobetalipoproteinemia is a rare autosomal dominant genetic disorder causing abnormally low levels of LDL cholesterol and apolipoprotein B.[2] It is thought to be caused by a mutation in apolipoprotein B.[3] The patient can have low LDL level and simultaneously have high levels of HDL cholesterol. Typically in hypobtalipoproteinemia, plasma cholesterol levels will be around 80-120 mg/dL, LDL cholesterol will be around 50-80 mg/dL, and longevity can be expected with good nutrition. Affected individuals can be either homozygous or heterozygous, the latter being most commonly asymptomatic.[3]


Normotriglyceridemic hypobetalipoproteinemia, formally called normotriglyceridemic abetalipoproteinemia, is a condition characterized by absence of LDLs and apoB100 and normal triglyceride-rich lipoproteins.[4][5]


[6]


References

  1. SALT HB, WOLFF OH, LLOYD JK, FOSBROOKE AS, CAMERON AH, HUBBLE DV (1960). "On having no beta-lipoprotein. A syndrome comprising a-beta-lipoproteinaemia, acanthocytosis, and steatorrhoea". Lancet. 2 (7146): 325–9. PMID 13745738.
  2. Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C; et al. (2010). "Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia". N Engl J Med. 363 (23): 2220–7. doi:10.1056/NEJMoa1002926. PMC 3008575. PMID 20942659.
  3. 3.0 3.1 Schonfeld G, Lin X, Yue P (2005). "Familial hypobetalipoproteinemia: genetics and metabolism". Cell Mol Life Sci. 62 (12): 1372–8. doi:10.1007/s00018-005-4473-0. PMID 15818469.
  4. Harano Y, Kojima H, Nakano T, Harada M, Kashiwagi A, Nakajima Y; et al. (1989). "Homozygous hypobetalipoproteinemia with spared chylomicron formation". Metabolism. 38 (1): 1–7. PMID 2909827.
  5. Herbert PN, Hyams JS, Bernier DN, Berman MM, Saritelli AL, Lynch KM; et al. (1985). "Apolipoprotein B-100 deficiency. Intestinal steatosis despite apolipoprotein B-48 synthesis". J Clin Invest. 76 (2): 403–12. doi:10.1172/JCI111986. PMC 423826. PMID 4031057.
  6. Biemer JJ, McCammon RE (1975). "The genetic relationship of abetalipoproteinemia and hypobetalipoproteinemia: a report of the occurence of both diseases within the same family". J Lab Clin Med. 85 (4): 556–65. PMID 164511.

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