Primary Disorders of Lipoprotein Metabolism

Ashikh Seethy

Junior Resident

Maulana Azad Medical College

New Delhi-2

Overview

• Lipoproteins

• Transport of lipids

• Diseases due to abnormality of lipoproteins

• Molecular mechanisms

• Sites of action of drugs

Lipoprotein Electrophoresis Major

Chylomicrons Origin ApoB-48

Chylomicron remnants Slow pre-β ApoB-48

VLDL Pre-β ApoB-100

IDL Slow pre-β ApoB-100

LDL β ApoB-100

HDL α ApoA-I

Lp(a) Pre-β ApoB-100

Why is it that we have lipoproteins?

Apolipoprotein Primary Source Lipoprotein Association Function

ApoA-I Intestine, liver HDL, chylomicrons Structural protein for HDL Activates LCAT

ApoA-II Liver HDL, chylomicrons Structural protein for HDL

ApoA-IV Intestine HDL, chylomicrons Unknown

ApoA-V Liver VLDL, chylomicrons Promotes LPL-mediated triglyceride lipolysis

Apo(a) Liver Lp(a) Unknown

ApoB-48 Intestine Chylomicrons Structural protein for chylomicrons

ApoB-100 Liver VLDL, IDL, LDL, Lp(a) Structural protein for VLDL, LDL, IDL, Lp(a). Ligand for binding to LDL receptor

ApoC-I Liver Chylomicrons, VLDL, HDL Unknown

ApoC-II Liver Chylomicrons, VLDL, HDL Cofactor for LPL

ApoC-III Liver Chylomicrons, VLDL, HDL Inhibits lipoprotein binding to receptors

ApoE Liver Chylomicron remnants, IDL, HDL Ligand for binding to LDL receptor

ApoH Liver Chylomicrons, VLDL, LDL, HDL Platelet activation

ApoJ Liver HDL Unknown

ApoL Unknown HDL Unknown

ApoM Liver HDL Unknown

Transport of dietary lipids

Transport of endogenous lipids

Apo B-100 in VLDL and Apo B-48 in Chylomicron. How?

Cytidine deaminase

How?

Disorders of lipoprotein metabolism

Phenotype I IIa IIb III IV V

Lipoprotein, elevated

Chylomicrons LDL LDL and VLDL Chylomicron and VLDL remnants

VLDL Chylomicrons and VLDL

Triglycerides +++ N + ++ ++ +++

Cholesterol (total)

+ +++ ++ ++ N/+ ++

LDL-cholesterol - +++ ++ - - -

HDL-cholesterol - - - N/- - N - - - - -

Plasma appearance

Lactescent Clear Clear Turbid Turbid Lactescent

Xanthomas Eruptive Tendon, tuberous

None Palmar, tuberoeruptive

None Eruptive

Pancreatitis +++ 0 0 0 0 +++

Coronary atherosclerosis

0 +++ +++ +++ +/– +/–

Peripheral atherosclerosis

0 + + ++ +/– +/–

Molecular defects

LPL and ApoC-II LDL receptor, ApoB-100, PCSK9, LDLRAP, ABCG5 and ABCG8

ApoC-III ApoE ApoA-V ApoA-V and GPIHBP1

Genetic nomenclature

FCS FH, FDB, ADH, ARH, sitosterolemia

FCHL FDBL FHTG FHTG

Classification:• Primary Disorders of Elevated ApoB-Containing

Lipoproteins Lipid Disorders Associated with Elevated LDL-C and Normal

Triglycerides

Elevated Plasma Levels of Lipoprotein(a)

Lipid Disorders Associated with Elevated Triglycerides

• Inherited Causes of Low Levels of ApoB-Containing Lipoproteins

• Genetic Disorders of HDL Metabolism

Inherited Causes of Low Levels of HDL-C

Inherited Causes of High Levels of HDL-C

Secondary forms of hyperlipidemia

Primary Disorders of Elevated ApoBContaining Lipoproteins

Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides

1. Familial Hypercholesterolemia (FH)

2. Familial Defective ApoB-100 (FDB)

3. Autosomal Dominant Hypercholesterolemia Due to Mutations in PCSK9 (ADH-PCSK9 or ADH3)

4. Autosomal Recessive Hypercholesterolemia (ARH)

5. Sitosterolemia

6. Polygenic Hypercholesterolemia

Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides

LDL-C –apo B100LDL RECEPTORLDL-RAPCLATHRIN

Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides

Familial hypercholesterolemia

[Class IIa]

Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides-

Tendon Xanthoma

Tuberous Xanthoma

Why are statins not effective in receptor negative homozygous FH ?

Primary Disorders of Elevated ApoB-Containing Lipoproteins

Familial Defective ApoB-100 (FDB)

Primary Disorders of Elevated ApoB-Containing Lipoproteins

Autosomal Recessive Hypercholesterolemia (ARH)

Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides

• Autosomal Dominant Hypercholesterolemia Due to Mutations in PCSK9 (ADH-PCSK9)

Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides

• Sitosterolemia/ Phytosterolemia

• Misshapen RBCs

• Megathrombocytes

• Hemolysis

• Gas chromatography

• Ezetimibe

Primary Disorders of Elevated ApoBContaining Lipoproteins

Lipid Disorders Associated with Elevated Triglycerides

1. Familial Chylomicronemia Syndrome

2. Apo A-V Deficiency

3. GPIHBP1 Deficiency

4. Familial Hypertriglyceridemia (FHTG)

5. Familial Combined Hyperlipidemia (FCHL)

6. Hepatic Lipase Deficiency

7. Familial Dysbetalipoproteinemia

Lipid Disorders Associated with Elevated Triglycerides

Lipid Disorders Associated with Elevated Triglycerides

Familial Chylomicronemia Syndrome (Type I Hyperlipoproteinemia; Lipoprotein Lipase and Apoc-II Deficiency)

Clinical features

Lipemia Retinalis

Eruptive Xanthomas

Lipid Disorders Associated with Elevated Triglycerides

GPIHBP1 Deficiency ApoA-V Deficiency

Familial Hypertriglyceridemia (FHTG)•Type IV hyperlipoproteinemia•Type V hyperlipoproteinemia

Lipid Disorders Associated with Elevated Triglycerides

Hepatic Lipase Deficiency

Familial Dysbetalipoproteinemia(Type III Hyperlipoproteinemia)

Paradoxes in Familial Dysbetalipoproteinemia(Type III Hyperlipoproteinemia)

• Increased remnants

• High TAG

• Reduced LDL-C

• Increased CADVL

Lipid Disorders Associated with Elevated Triglycerides

Familial Combined Hyperlipidemia (FCHL) [Type IIb]

Inherited Causes of Low Levels of ApoBContaining Lipoproteins

1. Abetalipoproteinemia

2. PCSK9 Deficiency

3. Familial Hypobetalipoproteinemia (FHB)

Inherited Causes of Low Levels of ApoB Containing Lipoproteins

ApoB-48 Intestine Chylomicrons Structural protein for chylomicrons

ApoB-100 Liver VLDL, IDL, LDL, Lp(a)

Structural protein for VLDL, LDL, IDL, Lp(a). Ligand for binding to LDL receptor

Familial Hypobetalipoproteinemia(FHB)

Abetalipoproteinemia[Bassen-Kornzweigsyndrome]

Abetalipoproteinemia [Bassen-Kornzweig syndrome]

Acanthocytes

Genetic Disorders of HDL Metabolism

Inherited Causes of Low Levels of HDL-C

1. Gene Deletions in the Apoav-AI-CIII-AIV Locus and Coding Mutations in ApoA-I

2. Tangier Disease (ABCA1 Deficiency)

3. LCAT Deficiency

4. Primary Hypoalphalipoproteinemia

Inherited Causes of High Levels of HDL-C

1. CETP Deficiency

2. Familial Hyperalphalipoproteinemia

Genetic Disorders of HDL Metabolism

Inherited Causes of Low Levels of HDL-C

• Gene Deletions in theApoAV-AI-CIII-AIV Locus& Coding Mutations inApoA-I

• LCAT def.

• Corneal opacity

• CKD

• Hemolytic anemia

Inherited Causes of Low Levels of HDL-C

Diagnosis?? Tangier Disease

Inherited Causes of High Levels of HDL-C

CETP Deficiency

Familial Hyperalphalipoproteinemia

Lp(a)

Management

• Investigations

• Treatment

Summary:

• Role of lipoproteins

• Elevated ApoB-Containing Lipoproteins

• Low Levels of ApoB-Containing Lipoproteins

• Disorders of HDL Metabolism

• Cardiovascular diseases

• Management

THANK YOU