abetalipoproteinemia final

CASE REPORT:ABETALIPOPROTEINEMIA

GROUP 3

COLOBONG, CARLOMAR

CONCEPCION, CHUCK

CORDERO, ALEXIS

CLEOFAS, JOAN

COMENDADOR, ABEGAIL

CONTACTO, MIKE

• 22y/o woman referred after a routine cholesterol screening

• Decreased plasma cholesterol concentration 0.45mmol/L (N 3.88-5.25mmol/L)

• Significant decrease in level of LDL 0.03mmol/L (N 1.3-3.4mmol/L)

• MODERATE decrease in HDL 0.39mmol/L (N 0.8-2.4mmol/L)

• Complaint of numbness in feet and difficulty in maintaining balance

• History was POSITIVE with 2 standing problems: malabsorption and decreased night vision

• Childhood history of malabsorption and was diagnosed with CELIAC DISEASE

• Decreased deep-tendon reflex

• Decreased Vibratory and proprioceptive senses in lower extremity

• Observed to have gait ataxia and positive for Rhomberg sign

• Found to have bilateral pigmented retinopathy

• Slightly prolonged prothrombin time and decreased haematocrit

• Numerous ACANTHOCYTES were seen in blood smear

• Increased reticulocyte count increased and erythrocyte sedimentation decreased

DIAGNOSIS:

• Abetalipoproteinemia cases are frequently misdiagnosed due to the rarity of the disease and amount of unrelated symptoms and laboratory abnormalities making it difficult to be recognized.

• Cholesterol screening programs critical for early detection of the irreversible neurological damage.

• Absence of poB is the biochemical defect in ABL. apoB is the principal protein of large lipoprotein particles (chylomicron, VLDL, LDL) fat malabsorption, which leads to fat soluble vitamin deficiencies (vitamin E)

• First symptom is malabsorption which is also misdiagnosed as celiac disease, Symptoms are alleviated by avoiding fatty foods.

• Fats such as cholesterol and fatty acids are readily absorbed but with the absence of apoB production, absorbed fats cannot be secreted into the lymphatics

• apoB is a major structural protein of cylomicrons acting as a detergent in maintaining solubility of proteins in plasma.

• Several years of malabsorption of fats in patients with ABL develop fat soluble vitamin deficiencies (A for decreased night vision, K abnormal coagulation tests coagulation factors II, IV, IX, X).

• The most affected tissue by vitamin E is neural tissues accounting for the neurologic abnormalities ABL.

• Pigment retinopathy is also a result of vitamin E deficiency, and will result to blindness if left untreated. Due to association of retinopathy with ataxia, is also misdiagnosed a Friedreich’s ataxia.

• Hematologic factors, presence of acanthocytes Due to decreased plasma cholesterol level in ABL the integrity of the cell membrane of RBC is altered accounting for the change in the cells appearance (star shape)

• Decreased sedimentation rate is also due to abnormal shape of RBC and decreased ability to self-aggregate (rouleaux) into the more rapidly sedimenting cell clusters.

LIPOPROTEINS

•Plasma lipoproteins are spherical •Macromolecular complexes of lipids & specific protein (apoproteins or apolipoproteins)•Includes Chylomicrons, VLDL, LDL, and HDL•Functions:

–To keep their component lipids soluble as they transport them in the plasma

–Provide an efficient mechanism for transporting their lipid content to the tissues.

COMPOSITION

Neutral lipid core (has triacylglycerol & cholesterol esters)

Surrounded by amphipathic apoproteins, phospholipid and nonesterified cholesterol

• Polar portions are exposed on the surface of the lipoprotein

• Soluble in aqueous solution

SIZE AND DENSITY• Chylomicrons – lowest in

density, largest in size, has the highest percentage of lipid, and lowest percentage of protein

• VLDL and LDL are denser, high ratios of protein to lipid

• VLDL and LDL – denser, higher ratios to protein

• HDL most denser

THE FOUR MAJOR GROUPS OF LIPOPROTEINS :

1. Chylomicrons – synthesized in the small intestines during fat absorption for transport of exogenous or dietary triacylglycerols and other lipids in the blood

2. Very low density lipoprotein (VLDL, pre-β-lipoprotein) – synthesized in the liver for transport of hepatic triacylglycerol in the blood

3. Low density triacylglycerol lipoprotein (LDL, β-lipoprotein) – transports endogenous cholesterol in the blood

4. Highly density lipoprotein (HDL, α-lipoprotein) – involved in the reverse cholesterol transport in the blood.

CHYLOMICRONS

Metabolism

1. Synthesis of apolipoproteins

2. Assembly of chylomicrons

3. Modification of nascent chylomicron particles

4. Degradation of triacylglycerol by lipoprotein lipase

5. Regulation of lipoprotein lipase activity

6. Formation of chylomicron remnants

METABOLISM OF VLDL

1. Release of VLDL

2. Modification of circulation VLDL

3. Production of LDL from VLDL in the plasma

METABOLISM OF LDL

1. Receptor mediates endocytosis

2. Effect of endocytosed cholesterol on cellular cholesterol homeostasis

3. Uptake of chemically modified LDL by macrophage scavenger receptors

METABOLISM OF HDL

1. HDL is a reservoir of apolipoprotiens

2. HDL uptake of unesterified cholesterol

3. Esterification of cholesterol

4. Reverse cholesterol transport

APOLIPOPROTEINS

•Functions:–Provides recognition sites for cell surface receptors–Serves as activators or coenzymes for enzymes involved

in lipoprotein metabolism•Five major classes

–Apo A–Apo B–Apo C–Apo D–Apo E

APO AI

• activates lecithin-cholesterol (LCAT) acyltransferase, which is responsible for cholesterol esterification in plasma.

APO B

• In humans, Apo B48 and Apo B100

• Apo B100 is the major physiological ligand for the LDL receptor

• synthesized in the liver and is required for the assembly of VLDL.

• It is found in IDL and LDL after the removal of the ApoA, E and C

APOB 48

• present in chylomicrons and their remnants

• essential for the intestinal absorption of dietary lipids

•  synthesized in the small intestine

• It comprises approximately half of the N-terminal region of ApoB100 and is the result of posttranscriptional mRNA editing by a stop codon in the intestine not found in the liver.

APO C

• ApoCI has been found to activate LCAT

• ApoCII activates lipoprotein lipase that hydrolyzes fatty acids from triacylglycerols in chylomicrons

• It may inhibit the activation of lipoprotein lipase by ApoCII.

APO E•  involved with triglyceride, phospholipid, cholesteryl ester,

and cholesterol transport in and out of cells and is a ligand for LDL receptors

VITAMINS A D E K (FAT SOLUBLE)

VITAMIN A METABOLISM

VITAMIN D METABOLISM

HOW VITAMIN D IS MADE IN THE BODY

VITAMIN E METABOLISM

VITAMIN K METABOLISM

ABETALIPOPROTEINEMIA

is a rare autosomal recessive disorder that interferes with the normal absorption of fat and fat-soluble vitamins from food. It is caused by a mutation in microsomal triglyceride transport protein (MTTP) resulting in deficiencies in the apolipoproteins B-48 and B-100, which are used in the synthesis and exportation of Chylomicrons and VLDL respectively.

CASE

• Low levels of the following:

• Plasma Cholesterol• Low Density Lipoprotein

MTTP INTEREFERENCE

VITAMIN A AND K

Vitamin A:

•Night vision (decreased)

Vitamin K:

•Coagulation factor is affected (factors II, VII, IX and X)

•Prolonged prothrombin time

VITAMIN E• Absorption of Vit. E is decreased

• Vit. E cannot be secreted because of defective chylomicrons in the intestine

• Vit. E delivered in the liver cannot be secreted due to defective VLDL

VITAMIN E

VITAMIN E

ATAXIA AND BILATERAL PIGMENTED RETINOPATHY

ACANTHOCYTOSIS

MANAGEMENT

• Key is early diagnosis

• Supplementation of fat-soluble vitamins

• Especially Vitamin E, given in large doses for supplementation

• Malabsorption can be treated by modifying the diet. Limit their fat intake.