Chemical pathology V - Plasma lipid and lipoprotein Flashcards
6 plasma lipiprotein calsses?
HDL LDL IDL VLDL Chylomicrons Lipoprotein A (LDL variant, pathogenic)
Content and apolipoproteins in HDL?
Cholesteyl ester
A-I,A-II, C,E
Content and apolipoproteins in LDL?
CE
B-100
Content and apolipoproteins in IDL?
CE + TG
B-100, C, E
Content and apolipoproteins in VLDL?
TG (liver)
B-100, C, E
Content and apolipoproteins in Chylomicron?
TG (intestine)
B-48, C, E, A-I, A-II, A-IV
Content and apolipoproteins in Lipoprotein A?
CE
B-100
Lipoprotein A
Morphological classification of serum lipid disorders?
Fredrickson classification
Frederickson phenotype: Type I
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?
Creamy top layer
Chylomicron
Lipoprotein lipase deficiency, apolipoprotein C-II deficiency
Frederickson phenotype: Type IIa
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?
Clear
LDL
Familial hypercholesterolemia, polygenic hypercholesterolemia, nephrosis, hypothyroidism, familial combined hyperlipidemia
Frederickson phenotype: Type IIb
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?
Clear
LDL, VLDL
Familial combined hyperlipidemia
Frederickson phenotype: Type III
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?
Turbid
IDL
Dysbetalipoproteinemia
Frederickson phenotype: Type IV
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?
Turbid
VLDL
Familial hypertriglyceridemia, familial combined hyperlipidemia, sporadic hypertriglyceridemia, diabetes
Frederickson phenotype: Type V
Clear or turbid?
Lipoprotein abnormality?
Associated disorders?
Creamy top, turbid bottom
Chylomicrons, VLDL
Diabetes
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?
Clear serum: type IIa or IIb
Most often type IIa
Familial hypercholesterolemia
Treatment of Familial combined hyperlipidemia
Low cholesterol diet
Cholestyramine
Which phenotypes in Fredrickson classification of hyperlipidemia have high atherogenicity?
Major: IIa, IIb, III
Minor: IV, V
Not atherogenicity: I
Which phenotype in Fredrickson classification of hyperlipidemia has normal Plasma TG level?
IIa
Only one**
3 mutations that cause familial hypercholestrolemia?
LDLR gene mutation *** (90%)
APOB (Apolipoprotein B) (10%)
PCSK9 (gain of function) (<5%)
3 mutations for autosomal recessive hypercholesterolemia
1) LDLR-AP1 reduced expression
2) ABCG5, ABCG8 deficiency > Sitosterolemia
3) CYP7A1 deficiency (decrease bile acid synthesis, high intrahepatic cholesterol)
3 main causes of inherited high cholesterol
Familial hypercholestrolemia
Familial combined hyperlipidemia
Cerebrotendinous xanthomatosis
D/dx cerebrotendinous xanthomatosis with familial hypercholestrolemia causing xanthoma formation
Both cause xanthoma
Cerebrotendinous xanthomatosis affects cognitive function, cause paraplegia and dementia, but NOT hypercholestrolemia
4 criteria for clinical Dx of Familial hypercholestrolemia
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)
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?
Germline mosaicism in one parent
De novo mutation
What factors affect the phenotype of heterozygous familial hypercholestrolemia?
What factors affect the phenotype of homozygous familial hypercholestrolemia?
Heterozygous: phenotype increase by Western lifestyle and diet:
> 90% penetrance of LDLR with markedly high LDL
All homozygous = severely affected
Common complication of homozygous familial hypercholesterolemia?
Sever coronary heart disease
Onset at mid-20s
Treatment of heterozygous and homozygous familial hypercholesterolemia?
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
Describe transport of cholesteryl ester in LDL into cells?
Defective transport consequence?
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
MoA of HMG- COA reductase inhibitor and bile acid-binding resin?
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
4 components of blood phytosterol profile test
Cholestanol
Campesterol
Stigmasterol
Beta-stiosterol
Sitosterolemia.
- Mutation
- Effect on metabolism of plant sterols?
- Disease?
ATP-Binding-Cassette: ABC-G5, ABC-G8 mutation
Increase GI absorption and decrease biliary excretion of plant sterols
autosomal recessive hypercholesterolemia
Clinical presentation of sitosterolemia?
Xanthoma Premature atherosclerosis Hemolytic anemia Large platelets Increase plasma concentration of plant sterols: sitosterol, campesterol, stigmasterol
Treatment of Sitosterolemia?
Genetic counselling of family?
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
3 d/dx of xanthoma formation
Familial hypercholestrolemia
Sitosterolemia
Cerebrotendinous xanthomatosis
Patient: 50/M Chronic achilles tendon xanthoma Serum clear High Campesterol (10x)
Dx?
Sitosterolemia
autosomal recessive hypercholesterolemia
ABCG5 and ABCG8 mutations
Increase GI absorption and decrease biliary excretion of plant sterols
Patient: 58/M Spastic tetraparesis unknown cause Wheelchair bound Achilles xanthoma Clear serum with normal lipid profile, high Cholestanol (3X)
Dx?
Cerebrotendinous xanthomatosis
Autosomal recessive lipid storage disease
Cerebrotendinous xanthomatosis
- Inheritance pattern, mutation?
- Effect of mutation?
- Clinical manifestation (5)
Autosomal recessive lipid storage disease: CYP27A1 mutation
Cholesterol cannot be converted into bile acid»_space; convert to cholestenol and bile alcohol
- Tendon xanthoma
- Progressive neurologic dysfunction (dementia, cerebellar, seizures…etc)
- Chronic diarrhea
- premature cataract
- Early onset osteoporosis
Treatment for cerebretendinous xanthomatosis?
Bile acid replacement therapy (chenodeoxycholic acid, Ursodeoxycholic acid)
> > restart bile acid negative feedback mechanism
