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Dyslipidemias . SCHEME FOR LIPID TRANSPORT. Production / Catabolism = Number.  Over- production Very common (? Cause).  Decreased Catabolism Defective Receptor in FH (RARE). Cell receptors. Endogenous transport. Lipoprotein lipase. Hepatic lipase. LDL receptor. VLDL.

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Presentation Transcript
slide2
SCHEME FOR LIPID TRANSPORT

Production / Catabolism

= Number

Over-

production

Very

common

(? Cause)

Decreased

Catabolism

Defective

Receptor

in FH

(RARE)

Cell receptors

Endogenous

transport

Lipoprotein

lipase

Hepatic

lipase

LDL

receptor

VLDL

IDL

LDL

Lipoprotein lipase

Exogenous

transport

chylomicrons

remnants

gut

Remnant

receptor

Free cholesterol + phospholipids + C-apolipoproteins

Nascent HDL

Mature HDL

Lecithin: cholesterol

acyltransferase

 [circulating LDL]

 risk for atherosclerosis

slide3
GENETIC

DYSLIPIDEMIAS

I ApoB:

II HDL

III Lipoprotein Modifying Enzymes

slide4
GENETIC/METABOLIC CLASSIFICATION

OF PRIMARY HYPERLIPIDAEMIAS

slide5
GENETIC/METABOLIC CAUSES

OF PRIMARY HYPERLIPIDAEMIAS

slide6
Chylo

↑ ↓ ↓

slide7
Familial Lipoprotein Lipase Deficiency

APO C-II

DEFICIENCY

LIPOPROTEIN LIPASE

DEFICIENCY

NORMAL

CHYLOMICRON

CHYLOMICRON

CHYLOMICRON

APO C-II

APO C-II

LIPOPROTEIN

LIPASE

LIPOPROTEIN

LIPASE

FFA

FFA

slide9
CLINICAL FINDINGS IN

Familial Lipoprotein

Lipase Deficiency

RECURRENT ACUTE PANCREATITIS

ERUPTIVE XANTHOMAS

RETINAL LIPEMIA

HEPATOSPLENOMEGALY

AUTOSOMAL RECESSIVE INHERITANCE

(CONSANGUINITY COMMON)

slide11
DISORDERS OF LDL

RECEPTORS: RARE

  • Familial hypercholesterolemia
    • (defective receptor)
  • Familial defective B100
    • (defective ligand)
slide12
FH

B Tg

B

Tg

VLDL

B

B

B

B

B

B

B

B

B

B

B

B

CE

CE

CE

CE

CE

CE

CE

CE

CE

CE

CE

CE

LDL

LDL

Clearance

slide13
IDL

IDL

Free Cholesterol

Free Cholesterol

HTGL

Lysis

Lysis

B-100

Receptor

LDL

LDL

B-100

Receptor

PERIPHERAL

CELLS

LIVER

slide19
→ →

↑ ↑ ↑

slide20
Familial

Combined

Hyperlipidemia/

HyperapoB

slide21
PRODUCTION

BREAKDOWN

slide22
Features of HyperapoB
  • Increased LDL particle number due
  • primarily to increased secretion of
  • hepatic B100 lipoprotein particles.
  • Often, but not always, many of the
  • LDL particles are smaller and denser
  • than normal.
slide23
HETEROGENEITY OF LDL

B

CE

NORMAL

FC

CE

Tg

FC

Tg

PL

B

FC

B

CE

FC

CE

Tg

FH

Tg

PL

B

B

CE

CE

FC

Tg

HYPERAPO B

Tg

FC

PL

PL

slide24
CII

FH

CI

CIII

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CE

CE

CE

CE

CE

CE

CE

CE

CE

CE

E

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CE

CE

CE

CE

CE

CE

CE

CE

CE

slide25
HyperapoB

CII

CII

CI

CI

CIII

CIII

Tg

Tg

Tg

Tg

Tg

Tg

CE

CE

CE

CE

CE

CE

E

E

E

E

Tg

CE

Tg

CE

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CE

CE

CE

CE

CE

CE

CE

CE

CE

slide26
Interaction of apoB and LDL size as

Determinants of CAD Risk

6.2

(p < 0.001)

apoB

Odds ratios for IHD

2.0

1.0

1.0

LDL peak particle diameter

slide27
HYPERAPO B IS
  • ASSOCIATED WITH:
  • SMOKING
  • MALE SEX
  • ABDOMINAL OBESITY
  • HYPERINSULINEMIA
  • OFFSPRING OF PARENTS WITH CAD
slide28
Principle I:

VLDL synthesis and secretion

is substrate

driven.

slide29
Effect of Fatty Acid on

Liver Cholesterol Synthesis

4HR

pmol/min/mg

slide30
Direct Correlation between Cholesterol Synthesis and

Hepatic Secretion of apoB 100 in Normolipidemic Subjects

15

10

5

Hepatic secretion ratio to

VLDL apoB (mg/kg/day)

0 2 4 6 8 10

Plasma mevalonate concentration (ng/ml)

slide31
Principle II:

What comes out

depends on what went in.

FA

CHO

slide32
HDL ←

↑ ↑

slide33
COMMON GENETIC CAUSES

OF HDL DEFICIENCY

SECONDARY:

1. Familial Hypertriglyceridemia with

Hypoalphalipoproteinemia (low apo A1)

2. Familial Combined Hyperlipidemia

(Hyperapo B) with Hypoalphalipoproteinemia

PRIMARY:

Familial Hypoalphalipoproteinemia

slide34
FUNCTIONS OF HDL

CHOLESTEROL

ESTERS

LCAT

LCAT

CHOLESTEROL

LIVER

PERIPHERAL

CELLS

NASCENT

VLDL

VLDL

NASCENT

CHYLOMICRON

CHYLOMICRON

HDL

VLDL

HDL

CHYLOMICRON

slide35
RARE GENETIC CAUSES

OF HDL DEFICIENCY

Name Premature CAD

Tangier disease +

Apo A1, Clll, AlV deficiency ++

Apo A1, Cll deficiency +++

Apo A1 deficiency UK

Apo A1 variants UK

LCAT deficiency +

slide36
SECONDARY CAUSES OF

DECREASED HDL

  • Hypertriglyceridemia
  • Obesity
  • Diabetes Mellitus
  • Cigarette smoking
  • Beta blockers
  • Liver cirrhosis
slide37
SECONDARY

DYSLIPIDEMIAS

AND

DRUG EFFECTS

ON LIPIDS

slide38
DISEASES CAUSING

SECONDARY HYPERLIPIDAEMIA

slide39
LIPID ABNORMALITIES

IN LIVER DISEASE

slide40
LIPID ABNORMALITIES

IN RENAL DISEASE

slide41
DRUGS THAT CAN CAUSE

SECONDARY HYPERLIPIDAEMIA

DIURETICS

BETA BLOCKERS

ESTROGENS

PROGESTERONE

RETINOIDS

CORTICOSTEROIDS

MICROSOMAL ENZYME INDUCERS

egPHENYTOIN

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