Disorders of lipid metabolism

Question 1

Normal lipid serum values

Answer 1

Total cholesterol: 3.6-5.2 mmol/L
LDL cholesterol: <3.4 mmol/L
HDL cholesterol: male > 1.0 mmol/L, female: > 1.3 mmol/L, total triglycerol: 0.8-1.7 mmol/L

Question 2

Key enzymes and cofactors in lipid metabolism

Answer 2

HMG-CoA reductase; rate-limiting step in cholesterol synthesis
LPL (lipoprotein lipase): digests the Triacylglycerol core of chylomicrons and VLDL
HL (hepatic lipase): conversion of IDL to LDL
CETP: transfers cholesteryl esters from HDL to other lipoproteins in exchange for triacylglyerides
LCAT: conversion of cholesterol to cholesterol esters
Apolipoprotein A: major protein of HDL
Apolipoprotein B: major structural protein of VLDL, IDL and LDL
Apolipoprotein CII and apolipoprotein E: obtained from HDL to CMC and VLDL for activation of LPL and receptor recognition

Question 3

Dyslipidemia

Answer 3

fatty oxidation disorders or lipid storage disorder. Inborn errors of metabolism, enzyme defects which affect the ability to oxidize FFA in order to produce energy within muscles, liver etc.

Question 4

Significance of cholesterol and oxidized LDL

Answer 4

Cholesterol is a major risk factor for coronary heart disease.
Oxidized LDL is unable to bind to hepatic receptors and rather bind to scavenger receptor on macrophages, thus forming Foam cells.

Question 5

Types of dyslipidemia

Answer 5

Type I: Famlilial hyperchylomicronemia (low LDL, altered CII)
Type IIa: Familial hypercholesterolemia (decreased LDL-R)
Type IIb: Familial combined hypercholesterolemia (decreased LDL-R and increased Apo-B)
Type III: Familial dysbetalipoproteinemia (ApoE2 synthesis defect)
Type IV: Familial hyperlipidemia (Increased VLDL prod, decreased VLDL elimination)
Type V: Familial hypertriglyceridemia (Increased VLDL prod, decreased LPL)

Question 6

Type I

Answer 6

Serum abnormality: Increased Chylomicron.
Clinical features: pancreatitis, lipemia, retinalis, skin eruptions, Xanthoma, hepatosplenomegaly.
Treatment: Diet.

Question 7

Type IIa

Answer 7

Serum abnormality: Increased LDL
Clinical features: Xanthelasma, arcus senilis, tendon xanthomas.
Treatment: Cholestyramine or Cholesterol, Statins, Niacin

Question 8

Type IIb

Answer 8

Serum abnormality: increased LDL and VLDL.

Treatment: Statins, niacin, fibrate

Question 9

Type III

Answer 9

Serum abnormality: increased IDL.
Clinical features: Turbo-eruptive xanthomas, palmar xanthoma.
Treatment: Fibrate, statins

Question 10

Type IV

Answer 10

Serum abnormality: Increased VLDL

Treatment: Statins, Niacin, Fibrate

Question 11

Type V

Answer 11

Serum abnormality: Increased VLDL and decreased LPL

Treatment: Niacin and Fibrate

Question 12

Diagnosis

Answer 12

Lipemic serum
High serum TG (TG above 10 mmol/L) with normal or moderately increased serum cholesterol
Fredewald equation: LDL-C= Chol-HDL-C - (TG/2.2) (mmol/L) can be used if TG is less than 4.5 mmol/L
Direct determination of LDL-C (immunological determination)

Question 13

Adult treatment panel III (NCEP)

Answer 13

Repeat once every 5 years.
If non-fasting sample is obtained and HDL is lower or Cholesterol is higher: fasting profile is recommended. If no significant change in HDL and cholesterol, rescreen in 5 years.

Question 14

Treatment

Answer 14

Diet with lipid restriction
Moderate length-chain triacylglycerides (MCT)
Substitution of ApoCII with FFP
Statins - HMG-CoA reductase inhibitors
Fibrates - increases LPL activity
Resins: binds colic acids - decreases serum LDL-C
Nicotinic acid - decreased lipolysis and VLDL synthesis
Ezetimibe - selective inhibitor of cholesterol uptake in the small intestine
Fish oil - promotes intracellular breakdown of ApoB-100

Question 15

Secondary dyslipidemia

Answer 15

Very common. Hyperlipidemia which develops in normolipidemic patients due to other diseases.

Question 16

Diseases causing secondary dyslipidemia

Answer 16

Type 1 DM: VLDL incr, LDL incr, HDL decr
Type 2 DM: VLDL incr, LDL incr, HDL decr
Hypothyroidism: VLDL incr, LDL incr, HDL incr
Obesity: VLDL incr, LDL incr, HDL decr
Alcoholism: VLDL incr, LDL incr, HDL incr
Nephrosis: VLDL incr, LDL incr, HDL decr
Chronic kidney disease: VLDL incr, LDL incr, HDL decr
Cholestasis: VLDL - , LDL incr, HDL decr
Hepatocellular diseases: IDL incr, LDL -, HDL decr
Hyperuricemia: VLDL incr, LDL - , HDL decr
Pregnancy: VLDL incr, LDL incr, HDL incr

Question 17

Metabolic syndrome

Answer 17

Coexistence of at least 3 of the following factors:

• Central obesity, waist circumference > 102cm (men), >88cm (women)
• Fasting glucose >6.1 mmol/L
• Hypertension
• Serum triglycerides increased >1.7 mmol/L
• HDL cholesterol: Men <1.0mmol/L, women <1.3mmol/L

Question 18

Diagnosis

Answer 18

Blood test: cholesterol, triglycerides, HDL, glucose, electrolytes

Question 19

Treatment for metabolic syndrome

Answer 19

Lifestyle changes, diet, regular physical activity, medical treatment for each risk factor

Question 20

Congenital enzyme defects

Answer 20

Lipid storage disorders:
Autosomal recessive or X-linked recessive - leads to accumulation of lipids within cells and leads to permanent damage to cells and tissue damage over time (especially brain, PNS, Liver, spleen, bone marrow). They are collectively a part of the lysosomal storage diseases.

Question 21

Lysosomal storage diseases

Answer 21

GM1 & GM2 gangliosidoses (GM2 is also called Tay-Sachs)
Gaucher disease - deficiency of glucocerebrosidase
Niemann-Pick
Metachromatic leukopathy
Krabbe disease
Wolman disease

Question 22

Treatments of lysosomal storage diseases

Answer 22

Enzyme replacement

Bone marrow replacement - Last resort

Question 23

Malabsorption

Answer 23

Whipple disease
- Systemic tissue damage due to macrophages loaded with Tropheryma Whippelii organisms
Abetalipoproteinemia
- Also known as Bassen-Kornzweig syndrome. Rare
- Autosomal recessive deficiency of apolipoprotein B-48 and B-100, leads to malabsorption as there is defective Chylomicron formation