AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Dysbetalipoproteinemia is a rare lipid disorder characterized by high levels of blood cholesterol and triglycerides in adults. Cholesterol levels usually range from 300-600 mg/dL. Triglyceride concentrations usually are greater than 400 mg/dL and may exceed 1000 mg/dL. The disorder presents because of a decreased ability to convert very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) to low-density lipoprotein (LDL) particles in the blood and also decreased clearance of chylomicron remnants.

Affected individuals are at increased risk for atherosclerotic cardiovascular disease and peripheral vascular disease. The disease develops in approximately 1-2% of individuals who are homozygous for apolipoprotein E-2 (apoE-2) that is most often caused by a single amino acid substitution in the apolipoprotein E (apoE) gene. The disease responds well to treatment of the medical conditions that exacerbate this condition and to medications that reduce blood triglyceride concentrations.

Pathophysiology

VLDL is synthesized by the liver and is metabolized by lipoprotein lipase to IDL, also called VLDL remnants. Lipoprotein lipase hydrolyzes triglycerides releasing free fatty acids, which are taken up by myocytes and hepatocytes. Surface apolipoprotein Cs, and some phospholipids and apoEs are lost and triglycerides are transferred to high-density lipoprotein (HDL) cholesterol in exchange for cholesterol esters. IDL is, thus, cholesterol-enriched and triglyceride-poor compared to unmetabolized VLDL. The principal remaining apolipoproteins are apoEs and apoB-100, the structural or transmembrane apolipoprotein. As IDL is metabolized by hepatic lipase to LDL, the remaining surface apolipoproteins are lost. ApoEs are also present on chylomicrons and their remnants.  

ApoEs are ligands with greater affinity than apoB-100 for the LDL receptor, which should more accurately be designated the B/E receptor. ApoE also binds with high affinity to the LDL receptor-related protein, which uptakes chylomicron remnants, VLDL and IDL. ApoE also binds to cell-surface heparan sulfate proteoglycans (HSPG). 

The apolipoprotein E gene has been cloned, sequenced, and mapped to chromosome 19. Genetically altered apoE–deficient mice develop severe dyslipidemia with accelerated atherosclerosis, while transgenic mice overexpressing apoE appear to be protected from atherosclerosis. 

ApoE has 3 isoforms that are present in slightly varying proportions depending on race and geographic location. ApoE-3 is the most prevalent allele. Compared to apoE-3, apoE-2 has less affinity for the receptor, and apoE-4 has more. The alleles differ in 2 amino acid positions, 112 and 158. ApoE-2 is most commonly caused by cysteine substituted for arginine at position 158 in apoE-3. In apoE-4, an arginine is substituted for cysteine at position 112 in apoE-3. Other very rare genetic variants of apolipoprotein E exist, and several of these have been shown to have defective binding to the LDL receptor and LDL receptor-like protein. These variants act in a dominant fashion in that only one copy of apoE is necessary for susceptibility to development of type III hyperlipidemia.

While homology for apoE-2 or apoE-2 defect is necessary for the development of dysbetalipoproteinemia, an essential requirement is the presence of a metabolic abnormality that causes increases in VLDL. This may include obesity, diabetes mellitus, hypothyroidism, or another lipid disorder such as familial combined hyperlipidemia.

In addition to the apoE-2 homology or defect and metabolic condition, other genetic factors have been suggested that increase the likelihood of developing dysbetalipoproteinemia. Polymorphisms in the apoA-5, lipoprotein lipase and apoC-3 have all been mentioned as possible cofactors for the condition.

LDL cholesterol is usually low in individuals with dysbetalipoproteinemia and is thought to be caused by such mechanisms as upregulation of the LDL receptor in response to decreased cholesterol uptake from triglyceride-rich lipoproteins and enhanced clearance of LDL because of decreased competition from apoE-2 for binding of apoB-100 to the LDL receptor.

Frequency

International

The frequency of homozygosity for apolipoprotein E-2 is approximately 1%. But dysbetalipoproteinemia is rare, affecting only 0.1-0.2% of the population; therefore, of those homozygous for apoE-2, approximately 10% will develop the condition. A second medical condition that causes overproduction of VLDL cholesterol must be present to cause dysbetalipoproteinemia.

Mortality/Morbidity

• Patients are at increased risk for cardiovascular disease and peripheral vascular disease.
• Patients with triglyceride concentrations greater than 1000 mg/dL also may be at increased risk for pancreatitis.
• Normalizing blood lipids decreases the risk of developing atherosclerosis or pancreatitis.

Race

• The frequency of apolipoprotein E-2 varies somewhat by race, but the prevalence of dysbetalipoproteinemia appears to be similar among races.

Sex

• It is more common in men than in women.
• It is very rare in premenopausal women.
• Estrogen improves the clearance of VLDL remnants, and estrogen treatment appears to improve dysbetalipoproteinemia in some postmenopausal women.

Age

• It is primarily a disease of adults and rare in children and premenopausal women.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Patients usually have elevated levels of both cholesterol and triglycerides.
• They frequently present with skin lesions known as palmar xanthomas and tuberoeruptive or tuberous xanthomas.
• Patients may have premature coronary artery disease or peripheral vascular disease.
• Some other metabolic or lipid disorder will be present, including diabetes mellitus, glucose intolerance, obesity, or hypothyroidism.
• Frequently, a family history of dyslipidemia is present.
• The family history of premature cardiovascular disease may include (1) atherosclerotic cardiovascular disease in male first-degree relatives younger than 55 years and (2) atherosclerotic cardiovascular disease in female first-degree relatives younger than 65 years.

Physical

• Examination may reveal palmar xanthomas on hands.
• • Orange-yellow discoloration of the palmar creases is present, and these creases may be raised in more severe cases.

  • Tuberoeruptive xanthomas may be present on the elbows and buttocks. These are nonpainful, raised, erythematous, nodular lesions approximately 0.5 cm in diameter.

  • The tuberoeruptive xanthomas may coalesce into larger tuberous xanthomas, which are raised, moderately firm, nontender lesions that present predominantly on the elbows.

• Recognition of these skin lesions will alert clinicians to the likely diagnosis. However, many patients have no physical findings.
• Obesity or signs of hypothyroidism may be noted.

Causes

• More than 90% of affected individuals are homozygous for apoE-2.



• Genetic predisposition is present in approximately 1% of the population, but only 1-2% of individuals with apoE-2 actually develop dysbetalipoproteinemia.



• A secondary cause of hyperlipidemia must be present for the disease to develop. Secondary causes can include obesity, diabetes mellitus, or hypothyroidism. In addition, the patient may be taking drugs, such as protease inhibitors, that exacerbate hyperlipidemia.



• Extremely rare forms are associated with other genetic mutations in the apolipoprotein E gene or the complete absence of apolipoprotein E.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hypertriglyceridemia with elevations of VLDL with or without chylomicronemia
Mixed hyperlipidemia (type IIb hyperlipidemia) with elevations of both LDL and VLDL

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Fasting lipid profile (total cholesterol, high-density lipoprotein [HDL] cholesterol, and triglyceride)
  
  
  • The total cholesterol and triglyceride levels are both elevated.
  
  
  
  • Total cholesterol levels are approximately 300-600 mg/dL and the triglyceride levels are about 400-800 mg/dL.
  
  
  
  • With these elevations and given the rarity of dysbetalipoproteinemia, a mixed hyperlipidemia, type IIb with elevations of both LDL and VLDL, is the most likely diagnosis. 
  
  
  
  • Moderately elevated total cholesterol and triglyceride levels accompanied by the presence of palmar crease xanthomas confirm the diagnosis dysbetalipoproteinemia. Further laboratory workup may not be necessary. 
  
  
  
  • Even with no definitive diagnosis, treatment of presumed dysbetalipoproteinemia may proceed because other lipid disorders, such as type IIb hyperlipidemia produce similar elevations in cholesterol and triglyceride levels and will respond to the same medical interventions.

• A standard lipid profile using the Friedewald equation to calculate the LDL cholesterol is not useful if the triglyceride level is more than 400-500 mg/dL.

• The excess cholesterol present in beta-VLDL is included in the LDL cholesterol value.



• The Friedewald calculation is invalid when serum or plasma triglycerides are greater than 400-500 mg/dL.



• However, if the triglycerides are not higher than 500 mg/dL and the LDL cholesterol level is determined directly by enzymatic analysis, a comparison can be made with the calculated LDL cholesterol. If the calculated LDL cholesterol is significantly higher than the value determined by direct analysis, the diagnosis of dysbetalipoproteinemia is probable. Furthermore, if the cholesterol-to-triglyceride ratio in isolated VLDL is greater than 0.3, dysbetalipoproteinemia is likely (normal ratio 0.2).

• Lipoprotein electrophoresis can be used to demonstrate the broad beta-band that denotes beta-VLDL. Density-gradient ultracentrifugation also can isolate and measure VLDL and IDL. A relatively new test using nuclear magnetic resonance spectroscopy also can measure VLDL and IDL. These tests are reliable in helping diagnose dysbetalipoproteinemia, but they may be available only at lipid specialty laboratories.



• Apolipoprotein E genotyping or phenotyping can be used to determine if the patient is homozygous for apolipoprotein E-2, but this finding is not sufficient for the diagnosis of dysbetalipoproteinemia without clinical or lipid abnormalities consistent with the disorder.



• Measure thyroid-stimulating hormone (TSH) to screen for hypothyroidism.



• Obtain a fasting or random glucose measurement to screen for diabetes.



• Perform a urinalysis to screen for nephrotic syndrome.

Imaging Studies

• Imaging studies are not useful.

Procedures

• It usually is unnecessary, but a biopsy of cutaneous lesions suspected to be either planar or tuberous xanthomas reveals cholesterol deposition.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Patients first should be treated for the metabolic condition that is causing or exacerbating their hyperlipidemia.
  
  
  • If diabetes is present, glucose levels and glycosylated hemoglobin (HbA1c) should be normalized if possible.
  
  
  
  • If hypothyroidism is diagnosed, TSH should be normalized.
  
  
  
  • Obesity and inactivity should be addressed appropriately.
     

• A careful history should be obtained to find other modifiable risk factors for atherosclerosis, such as smoking and hypertension, that can be addressed.

• First-degree relatives should be screened for hyperlipidemia and the risks of cardiovascular disease.

Surgical Care

• Surgical care is not indicated.

Consultations

• A specialist in lipid disorders may be helpful in treating the hyperlipidemia that develops in these patients, which can be very severe and difficult to treat, often requiring multiple lipid-lowering agents.



• Patients should receive nutrition counseling and should be advised to restrict calories if overweight. They also should reduce saturated and trans fats and cholesterol intake.

Diet

• A dietitian or knowledgeable physician should counsel the patient.



• Encourage the following behaviors:
   
  • Consume less than 20% of calories as fat.
  
  
  
  • Consume less than 7% of calories from saturated fat and 0% trans fats.
  
  
  
  • Consume less than 200 mg of cholesterol per day.
  
  
  
  • Restrict refined carbohydrates, particularly sugar and liquid calories.
  
  
  
  • Increase fiber intake.
  
  
  
  • Abstain or severely limit alcohol consumption. Consuming more than 1 standard alcoholic drink per day may worsen hypertriglyceridemia.
  
  
  
  • Attain and maintain a desirable weight, and caution that rapidly regaining weight may cause severe hypertriglyceridemia.

Activity

• If patients have no known cardiovascular disease, they should be encouraged to begin an exercise program of graduated aerobics and toning.



• Encourage no less than 30 minutes of brisk aerobic activity 4 days per week.



• Frequent and sustained exercise lowers elevated triglyceride levels and may raise HDL cholesterol levels.



• Before beginning an exercise program, consider giving a stress test to older patients and patients with multiple risk factors for coronary artery disease. These patients are at increased risk for cardiovascular disease.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The drugs of choice for severe hypertriglyceridemia include fibric acid derivatives (gemfibrozil or fenofibrate) and niacin in patients who do not have diabetes or in patients with very well-controlled diabetes. While HMG CoA reductase inhibitors (statins) are not the drugs of choice to treat dysbetalipoproteinemia, they may be beneficial in combination lipid therapy if the patient is carefully monitored for symptomatic myositis. The use of bile acid sequestrants should be avoided because they usually increase triglycerides. Patients with diabetes mellitus should be treated aggressively to normalize blood glucose levels and to reduce the HbA1c level to less than 7%.

Drug Category: Antilipemic agents

Can reduce triglyceride levels in blood.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Not necessary unless the patient develops acute pancreatitis

Further Outpatient Care

• Follow up on diet and lipid-lowering therapy.
• Blood cholesterol, triglyceride, and lipoprotein levels should be monitored periodically.
• If patients are taking lipid-lowering medications, they should have periodic liver function tests.
• Patients should be advised to report unexplained generalized muscle pain, tenderness, or weakness if taking fibric acid derivatives or statins. Perform creatinine kinase determinations in these individuals.
• In patients with diabetes, aggressive glucose control should be pursued with diet, oral hypoglycemic agents, or insulin.

In/Out Patient Meds

• The preferred medications are fibric acid derivatives (gemfibrozil or fenofibrate) or niacin.

Transfer

• Not necessary

Deterrence/Prevention

• To decrease the risk of cardiovascular disease, patients should avoid smoking, obesity, and sedentary lifestyles.



• Aggressive treatment of hypertension and diabetes should be pursued.

Complications

• Patients are at extremely high risk of developing premature coronary artery disease (30%) or peripheral vascular disease (50%).
• Acute pancreatitis is associated with triglyceride elevations greater than 1000 mg/dL.

Prognosis

• Prognosis is poor if the disease is inadequately managed, especially if other cardiovascular risk factors are present.
• If the patient complies with lipid-lowering therapy, dietary modification, and lifestyle modification and if therapy is successful, outcome is improved significantly.

Patient Education

• A trained dietitian should provide thorough diet instructions.



• Instructions should be provided on the use of medications.



• Exercise counseling or monitoring may be helpful to treat the dyslipidemia and reduce the risk of symptomatic cardiovascular disease.



• Patients with diabetes should receive comprehensive diabetes education.



• For excellent patient education resources, visit eMedicine's patient education articles High Cholesterol, Understanding Your Cholesterol level, Lifestyle Cholesterol Management, and Understanding Cholesterol-Lowering Medications.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Patients treated with lipid-lowering medications should be carefully monitored for the development of myositis or liver disease.



• Patients with triglyceride concentrations greater than 1000 mg/dL should receive diet and drug therapy and be closely monitored to prevent pancreatitis.



• If possible, patients with diabetes mellitus should receive treatment that meets or exceeds the guidelines of the American Diabetes Association.

Special Concerns

• The use of lipid-lowering drugs in pregnant patients and pediatric patients has not been thoroughly investigated.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Blom DJ, O'Neill FH, Marais AD. Screening for dysbetalipoproteinemia by plasma cholesterol and apolipoprotein B concentrations. Clin Chem. May 2005;51(5):904-7. [Medline].
• Brummer D, Evans D, Berg D. Expression of type III hyperlipoproteinemia in patients homozygous for apolipoprotein E-2 is modulated by lipoprotein lipase and postprandial hyperinsulinemia. J Mol Med. Apr 1998;76(5):355-64. [Medline].
• Civeira F, Cenarro A, Ferrando J. Comparison of the hypolipidemic effect of gemfibrozil versus simvastatin in patients with type III hyperlipoproteinemia. Am Heart J. Jul 1999;138(1 Pt 1):156-62. [Medline].
• Civeira F, Pocovi M, Cenarro A. Apo E variants in patients with type III hyperlipoproteinemia. Atherosclerosis. Dec 20 1996;127(2):273-82. [Medline].
• Devaraj S, Vega G, Lange R. Remnant-like particle cholesterol levels in patients with dysbetalipoproteinemia or coronary artery disease. Am J Med. May 1998;104(5):445-50. [Medline].
• Evans D, Seedorf U, Beil FU. Polymorphisms in the apolipoprotein A5 (APOA5) gene and type III hyperlipidemia. Clin Genet. Oct 2005;68(4):369-72. [Medline].
• Feussner G, Kurth B, Lohrmann J. Comparative effects of bezafibrate and micronised fenofibrate in patients with type III hyperlipoproteinemia. Eur J Med Res. Apr 21 1997;2(4):165-8. [Medline].
• Feussner G, Piesch S, Dobmeyer J. Genetics of type III hyperlipoproteinemia. Genet Epidemiol. 1997;14(3):283-97. [Medline].
• Mahley RW, Huang Y, Rall SC Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res. Nov 1999;40(11):1933-49. [Medline].
• Mahley RW, Rall SC Jr. Type III hyperlipoproteinemia (dysbetalipoproteinemia): The role of apolipoprotein E in normal and abnormal metabolism, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Edited by Scriver CR, Beaudet AR, Sly WS, Valle D. New York, McGraw-Hill. 2001, pp 2835–2862.
• Smelt AH, de Beer F. Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects. Semin Vasc Med. Aug 2004;4(3):249-57. [Medline].
• Wang T, Nakajima K, Leary ET. Ratio of remnant-like particle-cholesterol to serum total triglycerides is an effective alternative to ultracentrifugal and electrophoretic methods in the diagnosis of familial type III hyperlipoproteinemia. Clin Chem. Nov 1999;45(11):1981-7. [Medline].

Article Last Updated: Oct 9, 2006