Chemical pathology V - Plasma lipid and lipoprotein

Question 1

6 plasma lipiprotein calsses?

Answer 1

HDL
LDL
IDL 
VLDL
Chylomicrons 
Lipoprotein A (LDL variant, pathogenic)

Question 2

Content and apolipoproteins in HDL?

Answer 2

Cholesteyl ester

A-I,A-II, C,E

Question 3

Content and apolipoproteins in LDL?

Answer 3

CE

B-100

Question 4

Content and apolipoproteins in IDL?

Answer 4

CE + TG

B-100, C, E

Question 5

Content and apolipoproteins in VLDL?

Answer 5

TG (liver)

B-100, C, E

Question 6

Content and apolipoproteins in Chylomicron?

Answer 6

TG (intestine)

B-48, C, E, A-I, A-II, A-IV

Question 7

Content and apolipoproteins in Lipoprotein A?

Answer 7

CE
B-100
Lipoprotein A

Question 8

Morphological classification of serum lipid disorders?

Answer 8

Fredrickson classification

Question 9

Frederickson phenotype: Type I
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?

Answer 9

Creamy top layer

Chylomicron

Lipoprotein lipase deficiency, apolipoprotein C-II deficiency

Question 10

Frederickson phenotype: Type IIa
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?

Answer 10

Clear

LDL

Familial hypercholesterolemia, polygenic hypercholesterolemia, nephrosis, hypothyroidism, familial combined hyperlipidemia

Question 11

Frederickson phenotype: Type IIb
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?

Answer 11

Clear

LDL, VLDL

Familial combined hyperlipidemia

Question 12

Frederickson phenotype: Type III
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?

Answer 12

Turbid

IDL

Dysbetalipoproteinemia

Question 13

Frederickson phenotype: Type IV
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?

Answer 13

Turbid

VLDL

Familial hypertriglyceridemia, familial combined hyperlipidemia, sporadic hypertriglyceridemia, diabetes

Question 14

Frederickson phenotype: Type V
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?

Answer 14

Creamy top, turbid bottom

Chylomicrons, VLDL

Diabetes

Question 15

Patient:

• 2/m
• Healthy
• Achilles Xanthoma, elbow xanthoma, bilateral
• No family history, except maternal grandmother stroke from hyperlipidemia
• High LDL, High total cholesterol, Clear serum

Dx?

Answer 15

Clear serum: type IIa or IIb
Most often type IIa

Familial hypercholesterolemia

Question 16

Treatment of Familial combined hyperlipidemia

Answer 16

Low cholesterol diet

Cholestyramine

Question 17

Which phenotypes in Fredrickson classification of hyperlipidemia have high atherogenicity?

Answer 17

Major: IIa, IIb, III

Minor: IV, V

Not atherogenicity: I

Question 18

Which phenotype in Fredrickson classification of hyperlipidemia has normal Plasma TG level?

Answer 18

IIa

Only one**

Question 19

3 mutations that cause familial hypercholestrolemia?

Answer 19

LDLR gene mutation *** (90%)
APOB (Apolipoprotein B) (10%)
PCSK9 (gain of function) (<5%)

Question 20

3 mutations for autosomal recessive hypercholesterolemia

Answer 20

1) LDLR-AP1 reduced expression
2) ABCG5, ABCG8 deficiency > Sitosterolemia
3) CYP7A1 deficiency (decrease bile acid synthesis, high intrahepatic cholesterol)

Question 21

3 main causes of inherited high cholesterol

Answer 21

Familial hypercholestrolemia
Familial combined hyperlipidemia
Cerebrotendinous xanthomatosis

Question 22

D/dx cerebrotendinous xanthomatosis with familial hypercholestrolemia causing xanthoma formation

Answer 22

Both cause xanthoma

Cerebrotendinous xanthomatosis affects cognitive function, cause paraplegia and dementia, but NOT hypercholestrolemia

Question 23

4 criteria for clinical Dx of Familial hypercholestrolemia

Answer 23

1) Positive family history + high LDL
2) Tendon xanthoma + high LDL
3) Very high LDL (>6.2, under 20 years old)
4) DNA test for mutation (85% accurate only, not gold standard)

Question 24

Patient with familial hypercholesterolemia
2 heterozygous mutations in LDLR gene
- One missense (in mother)
- One duplication error (not found in parents)

2 possible cause of duplication error?

Answer 24

Germline mosaicism in one parent

De novo mutation

Question 25

What factors affect the phenotype of heterozygous familial hypercholestrolemia? What factors affect the phenotype of homozygous familial hypercholestrolemia?

Answer 25

Heterozygous: phenotype increase by Western lifestyle and diet: > 90% penetrance of LDLR with markedly high LDL All homozygous = severely affected

Question 26

Common complication of homozygous familial hypercholesterolemia?

Answer 26

Sever coronary heart disease Onset at mid-20s

Question 27

Treatment of heterozygous and homozygous familial hypercholesterolemia?

Answer 27

Heterozygous: Statin + Bile acid-binding resin drugs Homozygous: - LDL apheresis to reduce plasma LDL every 1-4 weeks ****1st line, preferred**** - Liver transplant to replace defective hepatic LDLR before coronary heart disease

Question 28

Describe transport of cholesteryl ester in LDL into cells? Defective transport consequence?

Answer 28

CE in LDL is shielded by hydrophilic coating (phospholipid, apoB-100, Unesterified cholesterol) Receptor - mediated endocytosis of LDL by LDLR takes CE into cells Defective LDLR on liver cells = accumulation of LDL in plasma

Question 29

MoA of HMG- COA reductase inhibitor and bile acid-binding resin?

Answer 29

Bile acid binding resin = stop enterohepatic recycling of bile acid = more excretion of cholesterol into intestines + More LDL intake in hepatocytes to form bile acid (upregulate LDLR) HMG-CoA reductase inhibitor = stop production of cholesterol in liver = Upregulation of LDLR to uptake plasma LDL to make bile acid for excretion through intestines

Question 30

4 components of blood phytosterol profile test

Answer 30

Cholestanol Campesterol Stigmasterol Beta-stiosterol

Question 31

Sitosterolemia. - Mutation - Effect on metabolism of plant sterols? - Disease?

Answer 31

ATP-Binding-Cassette: ABC-G5, ABC-G8 mutation Increase GI absorption and decrease biliary excretion of plant sterols autosomal recessive hypercholesterolemia

Question 32

Clinical presentation of sitosterolemia?

Answer 32

``` Xanthoma Premature atherosclerosis Hemolytic anemia Large platelets Increase plasma concentration of plant sterols: sitosterol, campesterol, stigmasterol ```

Question 33

Treatment of Sitosterolemia? | Genetic counselling of family?

Answer 33

Low plant sterol diet Ezetimibe: inhibit cholesterol and plant sterol uptake by NPC1L1 transporter No response to statin Offsprings are obligate carrier: plasma conc. of plant sterols is normal in carrier

Question 34

3 d/dx of xanthoma formation

Answer 34

Familial hypercholestrolemia Sitosterolemia Cerebrotendinous xanthomatosis

Question 35

``` Patient: 50/M Chronic achilles tendon xanthoma Serum clear High Campesterol (10x) ``` Dx?

Answer 35

Sitosterolemia autosomal recessive hypercholesterolemia ABCG5 and ABCG8 mutations Increase GI absorption and decrease biliary excretion of plant sterols

Question 36

``` Patient: 58/M Spastic tetraparesis unknown cause Wheelchair bound Achilles xanthoma Clear serum with normal lipid profile, high Cholestanol (3X) ``` Dx?

Answer 36

Cerebrotendinous xanthomatosis Autosomal recessive lipid storage disease

Question 37

Cerebrotendinous xanthomatosis - Inheritance pattern, mutation? - Effect of mutation? - Clinical manifestation (5)

Answer 37

Autosomal recessive lipid storage disease: CYP27A1 mutation Cholesterol cannot be converted into bile acid >> convert to cholestenol and bile alcohol - Tendon xanthoma - Progressive neurologic dysfunction (dementia, cerebellar, seizures...etc) - Chronic diarrhea - premature cataract - Early onset osteoporosis

Question 38

Treatment for cerebretendinous xanthomatosis?

Answer 38

Bile acid replacement therapy (chenodeoxycholic acid, Ursodeoxycholic acid) >> restart bile acid negative feedback mechanism