Dysbetalipoproteinemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]Vishal Devarkonda, M.B.B.S[3]

Synonyms and keywords: Broad beta disease; Broad beta hyperlipoproteinemia; Broad-beta hyperlipoproteinemia; Dysbetalipoproteinemia; Familial dysbetalipoproteinemia; Familial hypercholesterolemia with hyperlipemia; Type III hyperlipoproteinemia.

Overview

Familial dysbetalipoproteinemia is a autosomal recessive disorder passed down through families in which there are high amounts of cholesterol and triglycerides in the blood. This form is due to high chylomicrons and IDL (intermediate density lipoprotein). Also known as broad beta disease or dysbetalipoproteinemia, the most common cause for this form is the presence of ApoE E2/E2 genotype. It is due to cholesterol-rich VLDL (β-VLDL). Prevalence is 1 in 5,000-10,000 people in the general population.

Historical perspective

Classification

  • There is no established classification system for dysbetalipoproteinemia.

Pathophysiology

  • Dysbetalipoproteinemia is an autosomal recessive disorder caused by mutations in Apo E gene:[2][3][4][5][6]
    • Apo E gene is located on the long arm of chromosome 19(19q13).

Pathogenesis

  • Remnants of chylomicrons and VLDL are cleared from circulation by Apolipoprotein E.
  • Apolipoprotein E serving as a ligand for the low-density lipoprotien receptor, mediates hepatic clearance of chylomicrons and VLDL remnants from circulation.
  • Most common Apo E isoform is E 3/3, containing cysteine at position 112 and arginine at position 158.
  • Homozygosity for the ApoE2 isoform , containing two cysteine residues, which has lower binding capacity for LDL receptor, is associated with majority of cases with Dysbetalipoproteinemia.
  • Besides Apo E2, naturally occurring Apo E mutations have also been describe to be associated with Dysbetalipoproteinemia. These are inherited in a dominant mode and expressed early in age.
  • VLDL and chylomicron remnants that contains Apo E2 on their surface are not cleared as efficiently from the plasma. Resulting in formation of dense VLDL particle known as beta-VLDL.
  • Accumulation of VLDL and chylomicrons results in atherosclerosis and dyslipidemia.

Causes

The cause of type 3 hyperlipidemia remains genetic.

Differential Diagnoses

Epidemiology and Demographics

  • Epidemiological and demographics of dysbetalipoproteinemia are discussed below:

Epidemiology

  • The disease has been described in all races.
  • The prevalence of dysbetalipoproteinemia is approximately 1 in 5,000-10,000 people in the general population.

Demographics

Age

  • Majority of cases occur during early adulthood. Rarely, cases have been described in children and the elderly.
  • Women are usually affected after menopause.

Gender

  • Males are more often affected then females.

Risk Factors

Screening

There are no known screening recommendations for dysbetalipoprotenemia.

Natural History, Complication, Prognosis

Natural History

If left untreated dysbetalipoprotenemia can lead to chronic pancreatitis which can permanently damage the pancreas, atherosclerosis, stroke and intermittent claudication.

Complications

Dysbetalipoprtenemia can cause the following complications [7]

Prognosis

Diagnosis

Diagnosis of dysbetalipoprotenemia is confirmed by the[8]

General Diagnosis

EKG

  • EKG is done to rule out cardiac involvement

Molecular and Genetic testing

History and Symptoms

A detailed history along with a focussed family history must be obtained. Symptoms of dysbetalipoprotenemia include [7][9][10]

Dermatological and musculoskeletal

  • Xanthomas involving skin and tendons may be seen

Cardiac

  • Chest pain can be the presenting compliant signifying cardiac involvement

Vascular

Physical Exam

A detailed physical exam is required for patients suspected to have dysbetalipoproteinemia. Physical examination in dysbetalipoproteinemia may range from being normal to the presence of these findings[7]

Dermatological

  • Xanthoma Striatum Palmare-consisting of yellow streaks in the palmar creases.

Musculoskeletal

Vascular

Laboratory Findings

The laboratory findings consistent with dysbetalipoprotenemia include the following:[11]

Appearance VLDL cholesterol Cholesterol Triglycerides Isoelectric focusing
Floating

beta lipoproteins

VLDL cholesterol/

VLDL triglyceride >0.35

Elevated Elevated ApoE2 homozygote

Treatment

Non-pharmacological therapy

  • Exercise and dietary therapy with low cholesterol and fat diet have been shown to be effective.
  • Avoiding other risk factors responsible for the complications, to decrease severity such as avoiding smoking.

Inappropriate or subnormal control with non pharmacological therapies requires pharmacological treatment.

Medical Therapy

Dysbetalipoprotenemia can be treated with the following options[12]

Lipid lowering therapies can help decrease the symptoms e.g xanthomas and the complications associated with dysbetalipoprotenemia [13]

Genetic counselling

Genetic Counselling can be used to help the patients with dysbetalipoproteinemia and their families.

Prevention

Primary Prevention

There are no guidelines for primary prevention of dysbetaliproteinemia.

Secondary prevention

The secondary prevention for dysbetalipoproteinemia includes

  • Lifestyle modifications
  • Genetic counselling
  • Screening the family members may lead to early detection and treatment.
  • Early treatment and avoiding other risk factors for vascular disease (such as smoking) are crucial to prevent complications.

References

  1. Culliton BJ (1987). "Fredrickson's bitter end at Hughes". Science. 236 (4807): 1417–8. PMID 3296193.
  2. Georgiadou D, Chroni A, Vezeridis A, Zannis VI, Stratikos E (2011). "Biophysical analysis of apolipoprotein E3 variants linked with development of type III hyperlipoproteinemia". PLoS One. 6 (11): e27037. doi:10.1371/journal.pone.0027037. PMC 3206067. PMID 22069485.
  3. 3.0 3.1 Zhao SP, Smelt AH, Leuven JA, Vroom TF, van der Laarse A, van 't Hooft FM (1994). "Changes of lipoprotein profile in familial dysbetalipoproteinemia with gemfibrozil". Am J Med. 96 (1): 49–56. PMID 8304363.
  4. 4.0 4.1 Template:Https://medlineplus.gov/ency/article/000402.html
  5. Mahley RW, Huang Y, Rall SC (1999). "Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes". J Lipid Res. 40 (11): 1933–49. PMID 10552997.
  6. Walden CC, Hegele RA (1994). "Apolipoprotein E in hyperlipidemia". Ann Intern Med. 120 (12): 1026–36. PMID 8185134.
  7. 7.0 7.1 7.2 Blom DJ, Byrnes P, Jones S, Marais AD (2002). "Dysbetalipoproteinaemia--clinical and pathophysiological features". S Afr Med J. 92 (11): 892–7. PMID 12506591.
  8. Rothschild M, Duhon G, Riaz R, Jetty V, Goldenberg N, Glueck CJ; et al. (2016). "Pathognomonic Palmar Crease Xanthomas of Apolipoprotein E2 Homozygosity-Familial Dysbetalipoproteinemia". JAMA Dermatol. doi:10.1001/jamadermatol.2016.2223. PMID 27603268.
  9. Cruz PD, East C, Bergstresser PR (1988). "Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders". J Am Acad Dermatol. 19 (1 Pt 1): 95–111. PMID 3042820.
  10. Eto M, Saito M (2013). "[Familial type III hyperlipoproteinemia]". Nihon Rinsho. 71 (9): 1590–4. PMID 24205719.
  11. Braunwald, Eugene. Heart Disease- Fourth Edition. Harvard Medical School: W. B. SAUNDERS COMPANY. p. 1137. ISBN 0-7216-3097-9.
  12. Hachem SB, Mooradian AD (2006). "Familial dyslipidaemias: an overview of genetics, pathophysiology and management". Drugs. 66 (15): 1949–69. PMID 17100406.
  13. Cho EJ, Min YJ, Oh MS, Kwon JE, Kim JE, Kim CJ (2011). "Disappearance of angina pectoris by lipid-lowering in type III hyperlipoproteinemia". Am J Cardiol. 107 (5): 793–6. doi:10.1016/j.amjcard.2010.10.063. PMID 21247547.


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