Category: Disorder
Affected System: Circulatory System
| Synonyms and Related Keywords: |
alpha High Density Lipoprotein Deficiency Disease, Analphalipoproteinemia, Cholesterol thesaurismosis, Familial High Density Lipoprotein Deficiency Disease, Familial Hypoalphalipoproteinemia, HDL Lipoprotein Deficiency Disease, Lipoprotein Deficiency Disease, Tangier Disease Neuropathy, Familial HDL, Tangier Disease
| Introduction |
Definition:
A-alphalipoprotein Neuropathy or Tangier disease (TD) is a genetic disorder of cholesterol transport named for the secluded island of Tangier, located off the coast of Virginia. TD was first identified in a five-year-old inhabitant of the island who had characteristic orange tonsils, very low levels of high density lipoprotein (HDL) or 'good cholesterol', and an enlarged liver and spleen.TD is caused by mutations in the ABCA1 (ATP-binding cassette) gene on chromosome 9q31. ABCA1 codes for a protein that helps rid cells of excess cholesterol. This cholesterol is then picked up by HDL particles in the blood and carried to the liver, which processes the cholesterol to be reused in cells throughout the body. Individuals with TD are unable to eliminate cholesterol from cells, leading to its buildup in the tonsils and other organs.The discovery of this important cholesterol transport gene may lead to a better understanding of the inverse relationship between HDL levels and coronary artery disease, an important killer in the US. New drugs that regulate HDL levels may be developed and such drugs would not only help individuals with TD, but also people with more common disorders such as familial HDL deficiency. This is a good illustration of how research into rare diseases can sometimes help more common disorders.
Differential Diagnosis:
ApoA-I deficiency; ApoA-I/C-III deficiency; ApoA-I/C-III/A-IV deficiency; Familial lecithin:cholesteryl acyltransferase deficiency; Fish eye disease; Obstructive liver disease; Hepatic parenchymal diseases or tumors; Gaucher disease; Niemann-Pick, type C; Wolman disease; Acquired HDL deficiency states.
Diagnosis:
In patients with unexplained hepatic or splenic enlargement, neuropathy, or corneal deposits, examination of the oropharynx and quantification of plasma total cholesterol, HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglycerides are indicated. TD homozygotes have plasma levels of HDL-C and LDL-C that are typically <5%>ABCA1 gene through sequence analysis.
Signs and Symptoms:
People affected by this condition have slightly elevated amounts of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function (neuropathy). The tonsils are visibly affected by this disorder; they frequently appear orange or yellow and are extremely enlarged. Affected people often develop premature atherosclerosis, which is characterized by fatty deposits and scar-like tissue lining the arteries. Other signs of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the clear covering of the eye (cornea), and early-onset cardiovascular disease.
Inheritance:
This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.
Pathogenesis/Pathophysiology:
The ABC1 transporter was identified as the defect in Tangier disease by a combined strategy of gene expression microarray analysis, genetic mapping, and biochemical studies. Patients with Tangier disease have a defect in cellular cholesterol removal, which results in near zero plasma levels of HDL and in massive tissue deposition of cholesteryl esters. Blocking the expression or activity of ABC1 reduces apolipoprotein-mediated lipid efflux from cultured cells, and increasing expression of ABC1 enhances it. ABC1 expression is induced by cholesterol loading and cAMP treatment and is reduced upon subsequent cholesterol removal by apolipoproteins. The protein is incorporated into the plasma membrane in proportion to its level of expression. Different mutations were detected in the ABCA1 gene of 3 unrelated patients. Thus, ABC1 has the properties of a key protein in the cellular lipid removal pathway, as emphasized by the consequences of its defect in patients with Tangier disease.
Frequency/Epidemiology:
Tangier disease is a rare disorder with approximately 50 cases identified worldwide. This disorder was originally discovered on Tangier Island off the coast of Virginia, but has now been identified in people from many different countries.
Mortality/Morbidity:
Tangier disease is rare. Most patients died of the complication rather than of the disease itself.
Race:
Fewer than 100 cases of TD have been reported but exists in many different ethnic groups.
Age:
Age at diagnosis varied from 2 years to 67 years.
Sex:
Both genders.
| Clinical |
History:
The classic clinical signs of TD are hyperplastic orange-yellow tonsils, splenomegaly, and relapsing peripheral neuropathy, each resulting from cholesteryl ester deposition. A severely reduced HDL-C level in combination with hyperplastic orange-yellow tonsils is virtually pathognomonic for TD. Aside from these findings, the clinical expression of TD is variable, with some patients presenting with hepatomegaly, abnormal rectal mucosa, corneal opacities, anemia, lymphadenopathy, thrombocytopenia, and/or premature coronary heart disease.
Physical Assessment:
· Usually with extremely enlarged orange-yellow tonsils.
· Clouding of the clear covering of the eye (cornea)
· Peripheral neuropathy
· Discoloration of the rectal mucosa
Causes:
Massive tissue deposition of cholesteryl esters. See Pathogenesis/Pathophysiology.
| Test/Studies |
Lab Studies/Procedure:
A needle will be used to take a sample of blood from a vein, usually from the inside of the elbow or the back of the hand.
First, the area will be cleaned with a germ-killing product (antiseptic). An elastic band is placed around your upper arm to help the vein swell with blood, and the needle is inserted.
The needle is attached to an air-tight tube or syringe, which is used to collect the blood. During the procedure, the band is removed to restore circulation. Once the blood has been collected, the needle is removed, and the needle stick area is covered with a small bandage to stop any bleeding.
Preparations for the test:
Do not eat anything for 9 - 12 hours before the test.
Normal Values:
The normal value ranges may vary slightly among different laboratories.
In general, your risk for heart disease, including a heart attack, increases if your HDL cholesterol level is less than 40 mg/dL. More specifically, men are at particular risk if their HDL is below 37 mg/dL, and women are at particular risk if their HDL if their HDL is below 47 mg/dL.
An HDL 60 mg/dL or above helps protect against heart disease.
Women tend to have higher HDL cholesterol than men.
| Treatment/Management |
Independent Interventions:
Genetic Counseling
Medical Care:
No clear guidelines exist for treatment. Attempts to significantly raise plasma HDL-C levels have been unsuccessful. Other coronary disease risk factors should be treated, especially in patients with established coronary heart disease.
Consultation:
Individuals with severely reduced HDL levels (<20 mg/dL) may have a specific genetic etiology, such as LCAT deficiency, Tangier disease, or mutations in apo A-I. Ironically, these disorders are not commonly associated with an increased risk of atherosclerosis. Refer patients who may possibly have one of these diagnoses to a specialized lipid center for advanced management. Consultation with the following specialists may be required:
· Lipidologist
· Endocrinologist
· Cardiologist
· Vascular specialist
· Cardiovascular surgeon
· Dietitian
Diet:
Very low-fat diets are associated with low HDL-C levels. However, because no data are available that show reduction of the risk of CHD upon raising the HDL-C levels, no particular dietary interventions are needed for this specific purpose. In fact, increasing the fat content in the patient's diet is not recommended. Dietary management should follow the NCEP guidelines for lowering frequently associated LDL-C, which is the primary target in lipid management, and lowering of LDL levels has been demonstrated to reduce CHD morbidity and mortality in multiple randomized clinical trials.
· The NCEP has recommended a therapeutic lifestyle change diet, which should be incorporated in the treatment of all patients. The following are recommendations:
- Patients should reduce their intake of saturated fats to less than 7% of total calories (energy). Cholesterol intake should be reduced to less than 200 mg/d. Keep trans fatty acids (the HDL-lowering, LDL-raising fats) to a minimum. Polyunsaturated fats should constitute up to 10% of total energy intake and monounsaturated fats up to 20% of total energy intake. Total fat intake, therefore, should be in the range of 25-35% of total energy intake.
- Carbohydrates (complex carbohydrates from grains, whole grains, fruits, and vegetables) should constitute 50-60% of total energy intake.
- Patients should consume 20-30 g/d of fiber.
- The protein content should be approximately 15% of total energy intake.
- The total amount of energy consumed must be balanced in terms of energy intake and expenditure to maintain desirable body weight and to prevent weight gain.
Medication:
There are medications for Hypoalphalipoproteinemia and other underlying diseases associated with TD, however, it could not prevent or treat the genetic defect itself.
| Follow Up Treatment/Management |
Further Inpatient Care:
· Generally, patients with HA (Hypoalphalipoproteinemia) are discovered during routine lipid profile testing. Such patients are ambulatory and do not usually require hospitalization or inpatient care.
· Inpatient care is usually required for complications arising from accelerated atherosclerosis.
· In patients with secondary causes of HA, inpatient care may become necessary based on the primary pathology.
Further Outpatient Care:
· Provide outpatient care at regular intervals, especially clinical evaluation, lipid profile assessment, and follow-up evaluations for complications such as CHD.
· Monitor frequently for the effectiveness of medical therapy and possible complications of drugs. For example, monitor liver function tests and eye function when treating patients with lipid-lowering agents.
Transfer:
· Patients with TD rarely require transfer, and no specific recommendations are available for this purpose. In patients who are admitted to a health care facility, transfer depends mainly on the underlying condition or the complications of HA or premature atherosclerosis, such as MI, arrhythmia, or hypotension.
Deterrence/Prevention:
· Familial or genetically inheritable forms of HA are not amenable to prevention. Genetic counseling and screening may be applicable in rare cases.
Complications:
· Premature atherosclerosis
· Corneal opacification
Prognosis:
· If diagnosed early and monitored closely, the prognosis for patients with HA is generally reasonably good. The risk derives from the development of complications.
Patient Education:
· Pursue aggressive dietary modification.
· Discuss medications and their potential adverse effects, and monitor for adverse effects.
| Miscellaneous |
Medical/Legal Pitfalls:
· Patients presenting with TD must be evaluated and observed closely for the development of premature atherosclerosis. Screen such patients at frequent intervals through clinical assessment, stress test, or electron beam computed tomography. Missing the opportunity to diagnose premature atherosclerosis early may have legal implications.
· Siblings and first-degree relatives of patients with TD should be screened for HA and for the development of atherosclerosis.
· HA due to secondary causes must be treated by managing the underlying causes and by using pharmacologic agents to raise HDL levels. Failure to do so may have legal implications.
Special Concerns:
HDL will usually be done as part of an overall lipid profile, where "bad" cholesterol (LDL) and triglycerides will also be measured. The combined information gathered from all of these tests may help your risk of heart attack, stroke, and peripheral vascular disease.
Your health care provider will recommend therapy if your risk is found to be high. Regular exercise can increase HDL levels by several points.
| References |
Wikipedia
eMedicine
WrongDiagnosis.com
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