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]

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Synonyms and Keywords: Broad beta disease; Broad beta hyperlipoproteinemia; Broad-beta hyperlipoproteinemia; Dysbetalipoproteinemia; Familial dysbetalipoproteinemia; Familial hypercholesterolemia with hyperlipemia; Type III hyperlipoproteinemia; Type 3 hyperlipoproteinemia

Overview

Familial dysbetalipoproteinemia is an inheritable, autosomal recessive disorder in which there are high amounts of cholesterol and triglycerides in the blood. This form of hyperlipoproteinemia, also known as broad beta disease or dysbetalipoproteinemia, occurs due to high levels of chylomicrons and IDL (intermediate density lipoprotein). The most common genetic cause of this disease is the presence of the ApoE E2/E2 genotype. It is due to cholesterol-rich VLDL (β-VLDL). The prevalence of familial dysbetalipoproteinemia is 1 in 5,000-10,000 people in the general population.

Historical perspective

In 1967, Fredrickson classified lipoprotein disorder using paper electrophoresis.[1]

Classification

There is no established classification system for dysbetalipoproteinemia. For a detailed classification of hyperlipoproteinemia click here.

Pathophysiology

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

Genetics

  • Homozygosity for the ApoE2 isoform, which contains two cysteine residues and has lower binding capacity for the LDL receptor, is associated with majority of cases with dysbetalipoproteinemia.
  • Besides Apo E2, naturally occurring Apo E mutations have also been found to be associated with dysbetalipoproteinemia. These are inherited in a dominant mode and expressed at an early age.

Pathogenesis

Causes

The cause of type 3 hyperlipidemia is genetic.

Differential Diagnosis

Dysbetalipoproteinemia must be differentiated from all other kinds of hyperlipidemias. On the basis of high triglyceride levels it can be differentiated from:

For a detailed differential diagnosis of hyperlipoproteinemia click here.

Epidemiology and Demographics

The prevalence of dysbetalipoproteinemia is approximately 1 in 5,000-10,000 people in the general population.[3][4]

Age

The majority of cases occur during early adulthood. Rarely, cases have been described in children and the elderly.

Gender

Males are more commonly affected than females.

Race

There is no racial predilection for familial dysbetalipoproteinemia.

Risk Factors

Common risk factors in the development of dysbetalipoproteinemia are:[3][4]

Screening

There are no established screening recommendations for dysbetalipoproteinemia.

Natural History, Complication, Prognosis

Natural History

If left untreated, dysbetalipoproteinemia can lead to chronic pancreatitis, atherosclerosis, stroke, and intermittent claudication.

Complications

Dysbetalipoproteinemia is associated with the following complications:[8] [9]

Prognosis

Patients with dysbetalipoproteinemia have an increased risk for coronary artery disease and peripheral vascular disease. With treatment, most people show a significant reduction in lipid levels and thus associated complications.

Diagnosis

Symptoms

A detailed history, complete with a focused family history, must be obtained in order to ensure an accurate diagnosis is made. Symptoms of dysbetalipoprotenemia include:[8][10][11]

Dermatological and musculoskeletal
Cardiac
  • Chest pain can be the presenting complaint 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 being remarkable for the following findings:[8]

Dermatological

  • Xanthoma Striatum palmare-consisting of yellow streaks in the palmar creases
  • Tuberoeruptive xanthomas on the elbow or tibial tuberosities
  • Cutaneous xanthomas

Musculoskeletal

  • Tendon xanthomas may also be seen in rare cases

Vascular

Laboratory Findings

The laboratory findings consistent with a diagnosis of dysbetalipoprotenemia include the following:[5][12]

Appearance Lipid Profile VLDL cholesterol Isoelectric focusing
Total Cholesterol Triglycerides LDL HDL
Floating

beta lipoproteins

Elevated Elevated Decreaesd Normal VLDL cholesterol/

VLDL triglyceride >0.35

ApoE2 homozygote

Molecular Genetic Testing

A diagnosis of dysbetalipoproteinemia can be confirmed by presence of two Apo E2 genes, in the presence of characteristic symptoms.[13]

Treatment

Options for the treatment of dysbetalipoprotenemia include both medical and non-medical approaches, as described below.[14][15]

Non-pharmacological Therapy

  • Exercise and dietary therapy involving a low-cholesterol and low-fat diet have been shown to be effective.
  • Patients may also be counseled to avoid other risk factors responsible for complications, such as smoking.
  • Inappropriate or subnormal control of the disease with the implementation of non-pharmacological therapies requires pharmacological treatment.

Medical Therapy

Prevention

Primary Prevention

Secondary Prevention

Measures for the secondary prevention for dysbetalipoproteinemia include:[15]

  • Lifestyle modifications
  • Screening family members to increase the likelihood of early detection and treatment
  • Early treatment and avoidance of other risk factors for vascular disease (e.g., smoking) to prevention of 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 3.2 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 4.2 Template:Https://medlineplus.gov/ency/article/000402.html
  5. 5.0 5.1 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. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH et al. (2014) National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin Lipidol 8 (5):473-88. DOI:10.1016/j.jacl.2014.07.007 PMID: 25234560
  8. 8.0 8.1 8.2 Blom DJ, Byrnes P, Jones S, Marais AD (2002). "Dysbetalipoproteinaemia--clinical and pathophysiological features". S Afr Med J. 92 (11): 892–7. PMID 12506591.
  9. 9.0 9.1 Marais AD, Solomon GA, Blom DJ (2014). "Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E." Crit Rev Clin Lab Sci. 51 (1): 46–62. doi:10.3109/10408363.2013.870526. PMID 24405372.
  10. 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.
  11. Eto M, Saito M (2013). "[Familial type III hyperlipoproteinemia]". Nihon Rinsho. 71 (9): 1590–4. PMID 24205719.
  12. Braunwald, Eugene. Heart Disease- Fourth Edition. Harvard Medical School: W. B. SAUNDERS COMPANY. p. 1137. ISBN 0-7216-3097-9.
  13. 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. 152 (11): 1275–1276. doi:10.1001/jamadermatol.2016.2223. PMID 27603268.
  14. The Measurement of Lipids, Lipoproteins, Apolipoproteins, Fatty Acids, and Sterols, and Next Generation Sequencing for the Diagnosis and Treatment of Lipid Disorders. Schaefer EJ, Tsunoda F, Diffenderfer M, Polisecki E, Thai N, Asztalos B.
  15. 15.0 15.1 Hachem SB, Mooradian AD (2006). "Familial dyslipidaemias: an overview of genetics, pathophysiology and management". Drugs. 66 (15): 1949–69. PMID 17100406.



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