This document summarizes disorders of lipoprotein metabolism. It discusses the characteristic skin lesions seen in various disorders like familial dysbetalipoproteinemia and familial chylomicronemia. It also describes the structure and function of various lipoproteins like chylomicrons, VLDL, LDL, HDL and their receptors. The pathways of lipoprotein metabolism including exogenous and endogenous pathways are outlined. Various disorders affecting these pathways are explained like familial hypercholesterolemia, sitosterolemia, abetalipoprotenemia, Tangier's disease, familial LCAT deficiency. Diagnosis and management of severe hypertriglyceridemia and hypercholesterolemia is also covered

1. Disorders of Lipoprotein
Metabolism
Dr Sravan Kumar G
Assistant Professor
MRIMS

2. • Tuboeruptive & Palmar Xanthomas are seen in
1) Familial Dysbetalipoprotinemia (FDBL)
2) Familial Chylomicronemia
3) Familial hypercholesterolemia
4) Tangier disease

3. • Eruptive Xanthomas are seen in
1) Familial Dysbetalipoprotinemia (FDBL)
2) Familial Chylomicronemia
3) Familial hypercholesterolemia
4) Tangier disease

4. • Tendon Xanthomas are seen in
1) Familial Dysbetalipoprotinemia (FDBL)
2) Familial Chylomicronemia
3) Familial Hypercholesterolemia
4) Tangier disease

5. Lipoprotein structure

6. Density and size distribution of lipoprotein particles

7. • ApoB-48 - Chylomicrons
• ApoB-100 – VLDL, IDL, LDL
• ApoA-I – HDL
• Apo E – Chylomicron remnants, IDL
Receptors on liver:
SR-B1 - Scavenger receptor class B type 1 - for HDL
LDL Receptor - ApoB 100
LDL Receptor – Apo E (Chylomicron remnants)

9. Reverse cholesterol transport

10. INTESTINE
CHYLOMICRONS
THORACIC DUCT
SYSTEMIC CIRCULATION
LIPOPROTEIN LIPASE(HEART, ADIPOSE TISSUE, MUSCLE)
CHYLOMICRON REMNANTS
UPTAKE BY LIVER
LIVER
VLDL
SYSTEMIC CIRCULATION
LIPOPROTEIN LIPASE(HEART, ADIPOSE TISSUE, MUSCLE)
IDL
HEPATIC LIPASE
LDL
UPTAKE BY LIVER LDL R
PERIPHERAL TISSUES CHOLESTEROL
HDL
SR B1
UPTAKE BY LIVER
CHYLOMOCRON VLDL
CETP CETP
1 EXCESSIVE SECRETION VLDL
2 IMPAIRED LIPOLYIS
3DECREASED UPTAKE OF Apo B
Exogenous Endogenous

11. 1) Assembly and secretion of TG-rich VLDLs by the liver
2) Lipolysis of TG-rich lipoproteins by LPL
Familial chylomicronemia (lipoprotein lipase deficiency)
Familial hypertriglyceridemia
3) Receptor-mediated uptake of apoB-containing lipoproteins
by the liver
familial hypercholesterolemia(LDL Receptor mutation)
4) Very low HDL
Apo A-I Deficiency
Tangier Disease ( ABCA1 Deficiency)
Familial LCAT Deficiency
Familial hypoalphalipoprotenemia

12. EXCESSIVE SECRETION OF VLDL
• SECONDARY(high
TG/low HDL)
– High carbohydrate diet
– Obesity & Insulin
resistance
– Nephrotic syndrome
– Cushing syndrome
– Alcohol (high TG/high
HDL)
• PRIMARY (1 in 100)
• Familial combined
hyperlipidemia
– TG-200 – 600 mg/dL
– Total cholesterol – 200 –
400 mg/dL
– HDL-C < 40 in men, <50
in women
– Family h/o dyslipidemia
or premature CAD

13. Familial chylomicronemia
TG > 750 mg/dL, Acute pancreatitis
No increased incidence of ASCVD

14. Familial hypercholesterolemia
LDL C > 190 mg/dL
Increased incidence of ASCVD

15. Sitosterolemia/phytosterolemia
Hypercholesterolemia + Hemolysis & Splenomegaly
anisocytosis and poikilocytosis of erythrocytes and megathrombocytes
due to the incorporation of plant sterols into cell membrane
ABCG5
ABCG8

16. Abetalipoprotenemia
• Microsomal TG transfer protein (MTP; gene name MTTP)
• Fat malabsorption
• Ataxia, peripheral neuropathy
• Retinitis pigmentosa
• Star-shaped red blood cells (acanthocytosis)
• Plasma levels of cholesterol
and TGare extremely low.
chylomicrons, VLDLs, LDLs,
and apoB are undetectable
in plasma

17. Tangiers disease
• ABCA1 (ATP-binding cassette transporter A1)
• ABCA1 mediates the efflux of cholesterol and
phospholipids to lipid poor apolipoproteins (apo
A1 & apo E)
• Low HDL-C, low Apo-A1
• Hypertriglyceridemia
• Orange/yellow tonsils
• Hepatosplenomegaly
• Corneal clouding

18. Familial LCAT deficiency
• enzyme is activated by apoA-I and mediates
the esterification of cholesterol to form
cholesteryl esters
• Partial LCAT (alph LCAT) deficiency
– Fish eye disease (corneal clouding)
• Complete LCAT deficiency
– Corneal clouding + Hemolytic anemia +
hepatosplenomegaly + renal failure

19. • Fasting lipid profile after 12 hours fast
• Friedewald formula:
LDL-C = Total cholesterol – (TG/5) – HDL-C
– Invalid if TG > 400 mg/dL

20. Management of Severe Triglyceridemia
prevent pancreatitis
• Treat if TG > 500 mg/dL
– Avoid alcohol
– Exercise
– Reduce dietary fat
– Fibrates – fenofibrate 145 mg(T. Stanlip)
• Gallstones
• Myopathy (along with statins)
– Omega 3 fatty acids
• 3 to 4 gm/day

21. Management of cholesterol
prevent ASCVD
• HMG-CoA Reductase Inhibitors (Statins) if LDL-C >
190 mg/dL
• High intensity statin therapy (> 50 % reduction in
LDL-C) Target < 70 mg/dL
• Atorvastatin 40 mg & above
• Rosuvastatin 20 mg & above
• Moderate intensity statin therapy (30 – 50 %
reduction in LDL-C)
• Myopathy (Creatine Kinase)
• Tranasaminitis

22. Cholesterol Absorption Inhibitors
• Ezetimibe (10 mg)
• Binds inhibits NPC1L1 (Niemann-Pick C1-Like 1)
and blocks the intestinal absorption
of cholesterol
• Drug of choice
in sitosterolemia

23. Bile Acid Sequestrants (Resins)
• Reduce plasma LDL-C levels but can cause
an increase in plasma TGs
• Drug of choice in pregnancy
– Cholestyramine (Choltran 4 gm satchet)
– Colestipol
– colesevelam

24. PCSK9 Inhibitors (proprotein convertase subtilisin/kexin type 9)
Evolocumab(SC)
Alirocumab(SC)
Bococizumab(SC)
Subcutaneous injections

25. Apo B inhibitor - Mipomersen (200 mg SC weekly)
Antisense oligonucleotide against apo B

26. • MTP Inhibitor
– Lomitapide (5 mg daily orally)
• LDL Apheresis