Hypobetalipoproteinemia: Difference between revisions

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!Homozygous familial
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hypobetalipoproteinemia
hypobetalipoproteinemia(FHBL)
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hypobetalipoprotienemia
hypobetalipoprotienemia

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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

These are a set of diseases caused my mutations in genes involved in triglyceride(TG), cholesterol transport and metabolism. These diseases primarily cause low plasma LDL C and triglyceride levels less than 5th percentile. Patients present with symptoms resulting from fat soluble vitamin deficiencies. As vitamin E is primarily transported by LDL and VLDL, features of deficiency are seen early in the course of disease.

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.


 
 
 
APOB gene is responsible for the productoion of Apo B48 in intestine which is critical for the formation and secretion of chylomicrons[2] , and Apo B100 in the liver which is released into circulation as VLDL
 
Mutation in the APOB gene affects the translation of mRNA of Apo B. The severity depends whether the patient is homozygous or heterozygous for the mutation.[3].
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MTP transfers triglycerides from cytsol onto nacent ApoB in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons.Mutation in MTP causes abetalipoproteinemia[4].
 
In Apo B48 associated chylomicrons, transport of protiens from endoplasmic reticulum to golgi complex is dependent on coat protien complex 2(COP II), secretion-associated, Ras-related GTPase 1B (Sar1b) encoded by the gene SARA2 is a major part of the protein essential for this intra cellular transport[5]. Mutation in Sar1b causes chylomicron retention disease[6].
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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)[7], a transporter for lipoprotien lipase 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[8].[9]
 
Loss of function mutations or complete absence of ANGPTL3 gene cause familial combined hypolipidemia [10][11] .
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IDL on further removal of triglycerides forms a cholesterol ester rich LDL C, the chylomicron and VLDL remnants removal is Apo E dependent via the LDL receptors and LDL receptor related protiens[12]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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)[13].
 
Mutation causing loss of function of the enzyme causes low LDL C levels, and gain of function mutations are associated with familial hypercholesterolemia[14].
 
 

Genetics

Homozygous familial

hypobetalipoproteinemia(FHBL)

Heterozygous familial

hypobetalipoprotienemia

Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

Inheritance Autosomal Codominant Autosomal codominant Autosomal Recessive Autosomal Codominant
Defective Gene APOB gene on chromosome locus 2p23-24 APOB gene SAR1B gene ANGPTL3 gene on chromosome 1[15]
Pathophysiology Absence of Apo B

results in absent plasma

VLDL, TG and LDL C.

Truncated Apo B protiens are formed

which affect the lipidation and secretion of the Apo B particles.

These poorly lipidated particles are are rapidly catabolized.

Intracellular transport of chylomicrons is affected ,resulting in the accumalation of lipids intracellularly in the intestine and liver[16]. Loss of function mutation results in the failure of inhibition of Lipoprotien lipase, leading to low LDL, VLDL and HDL levels.

Causes

The following are the list of causes for primary hypobetalipoproteinemia.

  • Abetalipoproteinemia
  • Familial hypobetalipoproteinemia
  • Chylomicron Retention Disease
  • PCSK9 deficiency
  • Familial Combined Hypolipidemia

Natural History, complications and Prognosis

Homozygous Familial

Hypobetalipoproteinemia

Heterozygous Familial

Hypobetalipoproteinemia

Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

Disease Course Steatorrhea early in infancy and progression

to neurological symptoms which begin in the 1st or 2nd decade.

Usually benign, few patients may

present with steatorrhea.

Early onset of symptoms with

diarrhea and failure to thrive.

Benign
Complications Neurologic degeneration, Anemia, Blindness Liver Cirrhosis,Hepatocellular carcinoma[17] Neurological symptoms with areflexia in the 1st decade, more severe symptoms like ataxia, myopathy and sensory neuropathy are seen with advancing age.[18]

Retinopathy, poor bone mineralization.

None
Prognosis Early treatment has proven to show good prognosis. Without treatment it compromises the quality of life and shortens the life span[19]. Few patients present with vitamin deficiency features which respond well to treatment. Patients outcome is good with regular follow up and treatment. Good

Diagnosis

History and Physical

Homozygous Familial

Hypobetalipoproteinemia

Heterozygous Familial

Hypobetalipoproteinemia

Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

Age of Presentation Infancy Asymptomatic 2months to 1 year Asymptomatic
Clinical Presentation
  • Similar to abetalipoproteinemia.
  • Steatorrhea, Failure to Thrive.
  • Symptoms progress without treatment with vitamin E to reduced visual acuity, ataxia, dysarthria, loss of vibration and proprioception and areflexia as the posterior columns are affected.
  • Retinal Degeneration
  • Essential fatty acid deficiency
  • Patients are asymptomatic, malabsorption can occur in patients with short trucated apo B forming mutations[20].
  • Common feature is hepatic steatosis[21].
  • Diarrhea, steatorrhea, abdominal distention, and failure to thrive, neurological symptoms manifest if vitamin E supplementation is not initiated[22][23].
  • Essential fatty acid deficiency.


Laboratory Results

Homozygous Familial

Hypobetalipoproteinemia

Heterozygous Familial

Hypobetalipoproteinemia

Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

Lipid analysis
  • ApoB <5th percentile
  • LDL-C between 20- 50 mg/dL[25]
  • LDL C is one third of normal value and not 50% of expected for age and sex.
  • Due to decreased production and increased catabolism of VLDL apo B-100[26]. This causes decreased secretion of triglycerides and low LDL C levels[27].
  • LDL and HDL 50% of normal[28]
  • Normal TG levels is the characteristic laboratory finding.
  • Homozygotes and compound heterozygotes show panhypolipidemia with LDL low TG and reduced HDL C[29].
  • Heterozygotes  : Normal HDL, with LDL <25th percentile[24].
Other findings
  • Low liposoluble vitamin level.
  • Mild elevation of LFTs
  • Acanthocytosis
  • Mild elevation of LFTs
  • Failure of chylomicron secretion after a lipid rich meal.
  • Low liposoluble vitamin level.
  • Endoscopy shows a typical white stippling.
  • The enterocytes on biopsy show accumulations of large lipid droplets free in the cytoplasm as well as membrane-bound lipoprotein-sized structures.[30]
  • Mild elevation of liver transaminases.[31]
  • Elevated Creatine Kinase
  • None
  • Definitive gold standard for diagnosis is gene sequencing for APOB, MTTP, SAR1B, ANGPTL3 to see the exact mutation.

Treatment=

Medical Therapy

  • The main goals of management of FHBL include early diagnosis and early initiation of low fat diet and fat soluble vitamin supplementation in all symptomatic patients, with yearly follow up to assess the growth and nutritional status, diet compliance, neurological function, lipid panel.
  • FHBL heterozygous patients with elevates liver transaminases regular imaging is recommended to monitor for progression of fatty liver to cirrhosis or hepatocellular carcinoma[32].

Chylomicron Retention Disease Management

  • If the patient is diagnosed early in the course of the disease diet modification and oral supplementation of vitamins improved outcomes[23].
    • Low-fat diet
    • Vegetable oil enriched in essential fatty acids ± Enriched in medium-chain triglycerides.
    • Vitamin E (hydrosoluble form): 50 IU/kg/d
    • Vitamin A: 15,000 IU/d (adjust according to plasma levels)
    • Vitamin D: 800-1200 IU/kg/d or 100,000 IU/2 month if < 5 y old, and 600,000 IU/2 month if > 5 y old
    • Vitamin K: 15 mg/week (adjust according to INR and plasma levels)
  • If patient is diagnosed late and with neurological disease combined oral and parental supplementation of fatty acids-intralipid 20%2g/kg/month, vitamin E 4 to 6 mg/kg/month, vitamin A 500 IU/kg/month once a month is recommended.
Follow up
  • Annual follow up to 10years to assess the growth and nutritional status, diet compliance, neurological function, lipid panel.
  • Every 3year follow up to check bone mineral density, liver function with ultrasound, ophthalmologic exam for fundus, color vision, visual evoked potentials and electroretinography after the age of 10years.
  • Echocardiography in adulthood.

Surgical Therapy

  • No surgical options are available.

Prevention

Primary Prevention

  • As the set of the diseases are rare there are no primary preventive measures.

Secondary Prevention

  • Regular follow up to look for complications and strict adherence to therapy has shown to prevent progression of the disease.

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. ↑ Dash S, Xiao C, Morgantini C, Lewis GF (2015). "New Insights into the Regulation of Chylomicron Production". Annu Rev Nutr. 35: 265–94. doi:10.1146/annurev-nutr-071714-034338. PMID 25974693.
  3. ↑ Di Leo E, Eminoglu T, Magnolo L, Bolkent MG, Tümer L, Okur I; et al. (2015). "The Janus-faced manifestations of homozygous familial hypobetalipoproteinemia due to apolipoprotein B truncations". J Clin Lipidol. 9 (3): 400–5. doi:10.1016/j.jacl.2015.01.005. PMID 26073401.
  4. ↑ Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR (2000). "The role of the microsomal triglygeride transfer protein in abetalipoproteinemia". Annu Rev Nutr. 20: 663–97. doi:10.1146/annurev.nutr.20.1.663. PMID 10940349.
  5. ↑ Shoulders CC, Stephens DJ, Jones B (2004). "The intracellular transport of chylomicrons requires the small GTPase, Sar1b". Curr Opin Lipidol. 15 (2): 191–7. PMID 15017362.
  6. ↑ Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S; et al. (2003). "Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders". Nat Genet. 34 (1): 29–31. doi:10.1038/ng1145. PMID 12692552.
  7. ↑ Young SG, Davies BS, Voss CV, Gin P, Weinstein MM, Tontonoz P; et al. (2011). "GPIHBP1, an endothelial cell transporter for lipoprotein lipase". J Lipid Res. 52 (11): 1869–84. doi:10.1194/jlr.R018689. PMC 3196223. PMID 21844202.
  8. ↑ Shan L, Yu XC, Liu Z, Hu Y, Sturgis LT, Miranda ML; et al. (2009). "The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms". J Biol Chem. 284 (3): 1419–24. doi:10.1074/jbc.M808477200. PMC 3769808. PMID 19028676.
  9. ↑ Yoshida K, Shimizugawa T, Ono M, Furukawa H (2002). "Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase". J Lipid Res. 43 (11): 1770–2. PMID 12401877.
  10. ↑ Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH; et al. (2009). "Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans". J Clin Invest. 119 (1): 70–9. doi:10.1172/JCI37118. PMC 2613476. PMID 19075393.
  11. ↑ Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K; et al. (2013). "Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids". Arterioscler Thromb Vasc Biol. 33 (7): 1706–13. doi:10.1161/ATVBAHA.113.301397. PMID 23661675.
  12. ↑ Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK (2008). "LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies". Physiol Rev. 88 (3): 887–918. doi:10.1152/physrev.00033.2007. PMC 2744109. PMID 18626063.
  13. ↑ Garvie CW, Fraley CV, Elowe NH, Culyba EK, Lemke CT, Hubbard BK; et al. (2016). "Point mutations at the catalytic site of PCSK9 inhibit folding, autoprocessing, and interaction with the LDL receptor". Protein Sci. 25 (11): 2018–2027. doi:10.1002/pro.3019. PMC 5079255. PMID 27534510.
  14. ↑ Marais AD, Kim JB, Wasserman SM, Lambert G (2015). "PCSK9 inhibition in LDL cholesterol reduction: genetics and therapeutic implications of very low plasma lipoprotein levels". Pharmacol Ther. 145: 58–66. doi:10.1016/j.pharmthera.2014.07.004. PMID 25046268.
  15. ↑ Fazio S, Sidoli A, Vivenzio A, Maietta A, Giampaoli S, Menotti A; et al. (1991). "A form of familial hypobetalipoproteinaemia not due to a mutation in the apolipoprotein B gene". J Intern Med. 229 (1): 41–7. PMID 1995762.
  16. ↑ Charcosset M, Sassolas A, Peretti N, Roy CC, Deslandres C, Sinnett D; et al. (2008). "Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein". Mol Genet Metab. 93 (1): 74–84. doi:10.1016/j.ymgme.2007.08.120. PMID 17945526.
  17. ↑ Cefalù AB, Pirruccello JP, Noto D, Gabriel S, Valenti V, Gupta N; et al. (2013). "A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia". Arterioscler Thromb Vasc Biol. 33 (8): 2021–5. doi:10.1161/ATVBAHA.112.301101. PMC 3870266. PMID 23723369.
  18. ↑ Lacaille F, Bratos M, Bouma ME, Jos J, Schmitz J, Rey J (1989). "[Anderson's disease. Clinical and morphologic study of 7 cases]". Arch Fr Pediatr. 46 (7): 491–8. PMID 2596948.
  19. ↑ Zamel R, Khan R, Pollex RL, Hegele RA (2008). "Abetalipoproteinemia: two case reports and literature review". Orphanet J Rare Dis. 3: 19. doi:10.1186/1750-1172-3-19. PMC 2467409. PMID 18611256.
  20. ↑ Tarugi P, Lonardo A, Gabelli C, Sala F, Ballarini G, Cortella I; et al. (2001). "Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene". J Lipid Res. 42 (10): 1552–61. PMID 11590210.
  21. ↑ Tanoli T, Yue P, Yablonskiy D, Schonfeld G (2004). "Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity". J Lipid Res. 45 (5): 941–7. doi:10.1194/jlr.M300508-JLR200. PMID 14967820.
  22. ↑ Peretti N, Roy CC, Sassolas A, Deslandres C, Drouin E, Rasquin A; et al. (2009). "Chylomicron retention disease: a long term study of two cohorts". Mol Genet Metab. 97 (2): 136–42. doi:10.1016/j.ymgme.2009.02.003. PMID 19285442.
  23. ↑ 23.0 23.1 Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J; et al. (2010). "Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers". Orphanet J Rare Dis. 5: 24. doi:10.1186/1750-1172-5-24. PMC 2956717. PMID 20920215.
  24. ↑ 24.0 24.1 Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G; et al. (2012). "Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization". J Clin Endocrinol Metab. 97 (7): E1266–75. doi:10.1210/jc.2012-1298. PMID 22659251.
  25. ↑ Lee J, Hegele RA (2014). "Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management". J Inherit Metab Dis. 37 (3): 333–9. doi:10.1007/s10545-013-9665-4. PMID 24288038.
  26. ↑ Welty FK, Lichtenstein AH, Barrett PH, Dolnikowski GG, Ordovas JM, Schaefer EJ (1997). "Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes". Arterioscler Thromb Vasc Biol. 17 (5): 881–8. PMID 9157951.
  27. ↑ Elias N, Patterson BW, Schonfeld G (1999). "Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia". Arterioscler Thromb Vasc Biol. 19 (11): 2714–21. PMID 10559016.
  28. ↑ Georges A, Bonneau J, Bonnefont-Rousselot D, Champigneulle J, Rabès JP, Abifadel M; et al. (2011). "Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease)". Orphanet J Rare Dis. 6: 1. doi:10.1186/1750-1172-6-1. PMC 3029219. PMID 21235735.
  29. ↑ 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.
  30. ↑ Dannoura AH, Berriot-Varoqueaux N, Amati P, Abadie V, Verthier N, Schmitz J; et al. (1999). "Anderson's disease: exclusion of apolipoprotein and intracellular lipid transport genes". Arterioscler Thromb Vasc Biol. 19 (10): 2494–508. PMID 10521380.
  31. ↑ Gusarova V, Brodsky JL, Fisher EA (2003). "Apolipoprotein B100 exit from the endoplasmic reticulum (ER) is COPII-dependent, and its lipidation to very low density lipoprotein occurs post-ER". J Biol Chem. 278 (48): 48051–8. doi:10.1074/jbc.M306898200. PMID 12960170.
  32. ↑ Welty FK (2014). "Hypobetalipoproteinemia and abetalipoproteinemia". Curr Opin Lipidol. 25 (3): 161–8. doi:10.1097/MOL.0000000000000072. PMC 4465983. PMID 24751931.

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