Dysbetalipoproteinemia
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
For the main page about other hyperlipoproteinemias click here.
For the main page on all lipoprotein disorders click here.
Overview
Familial dysbetalipoproteinemia is an heritable, 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.
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
- Remnants of chylomicrons and VLDL are cleared from circulation by Apolipoprotein E
- Apolipoprotein E, serving as a ligand for the low-density lipoprotein receptor, mediates hepatic clearance of chylomicrons and VLDL remnants from circulation.
- The most common Apo E isoform is E 3/3, which contains cysteine at position 112 and arginine at position 158.
- 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
Prevalence
- 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
- The risk factors for dysbetalipoproteinemia are:[3][4]
- Family history (most important)
- Hypothyroidism
- Obesity
- Diabetes
- coronary artery disease
- Kidney disease
- Alcohol abuse
Screening
There are no known screening recommendations for dysbetalipoprotenemia
Natural History, Complication, Prognosis
Natural History
- If left untreated dysbetalipoprotenemia can lead to chronic pancreatitis, atherosclerosis, stroke and intermittent claudication
Complications
Dysbetalipoprtenemia can cause the following complications:- [7]
- Atherosclerotic complications like coronary artery disease
- Pancreatitis
- Stroke
- Peripheral vascular disease
- Intermittent claudication
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 the complications
Diagnosis
History and Symptoms
A detailed history along with a focused family history must be obtained
Symptoms of dysbetalipoprotenemia include:- [7][8][9]
Dermatological and musculoskeletal
- Yellow papules (Xanthomas) involving skin and tendons may be seen
Cardiac
- Chest pain can be the presenting compliant signifying cardiac involvement
Vascular
- Leg pain (due to peripheral vascular disease)
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 following findings:-[7]
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 rarely
Vascular
Laboratory Findings
The laboratory findings consistent with dysbetalipoprotenemia include the following:[10]
| Appearance | VLDL cholesterol | Cholesterol | Triglycerides | Isoelectric focusing |
|---|---|---|---|---|
| Floating
beta lipoproteins |
VLDL cholesterol/
VLDL triglyceride >0.35 |
Elevated | Elevated | ApoE2 homozygote |
Molecular Genetic Testing
- Diagnosis can be confirmed by presence of two apo e2 genes, in the presence of characteristic symptoms.[11]
Treatment
Treatment of dysbetalipoprotenemia include:- [12][13]
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
- Bile acid binding agents are an option if triglyceride levels are <200mg/dL
- Statins can be used if triglyceride levels are <500mg/dL
- Fibrates and Nicotinic acid can also be used
Prevention
- There is no way to prevent someone from inheriting this syndrome
- Genetic counseling is recommended for patients and family members as well[14]
Secondary prevention
The secondary prevention for dysbetalipoproteinemia includes:-
- Lifestyle modifications
- 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
- ↑ Culliton BJ (1987). "Fredrickson's bitter end at Hughes". Science. 236 (4807): 1417–8. PMID 3296193.
- ↑ 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.
- ↑ 3.0 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.
- ↑ 4.0 4.1 4.2 Template:Https://medlineplus.gov/ency/article/000402.html
- ↑ 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.
- ↑ Walden CC, Hegele RA (1994). "Apolipoprotein E in hyperlipidemia". Ann Intern Med. 120 (12): 1026–36. PMID 8185134.
- ↑ 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.
- ↑ 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.
- ↑ Eto M, Saito M (2013). "[Familial type III hyperlipoproteinemia]". Nihon Rinsho. 71 (9): 1590–4. PMID 24205719.
- ↑ Braunwald, Eugene. Heart Disease- Fourth Edition. Harvard Medical School: W. B. SAUNDERS COMPANY. p. 1137. ISBN 0-7216-3097-9.
- ↑ 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.
- ↑ 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.
- ↑ Hachem SB, Mooradian AD (2006). "Familial dyslipidaemias: an overview of genetics, pathophysiology and management". Drugs. 66 (15): 1949–69. PMID 17100406.
- ↑ 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.