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LIPID DISORDERS AND MANAGEMENT (slide 1-22)

A. LIPID TRANSPORT
Klasifikasi lipids and lipoproteins (Pengangkutnya lipid):
Lipoprotein ada 2 :
-HDL = menangkut 80%
kolesterol

-Non HDL = LDL


(mengangkut 70%
kolesterol), VLDL, IDL

Characteristics of lipoproteins:
- Semakin kecil TG nya, kolesterol & pospolipid akan
semakin besar (kok gak sesuai ya sama tabel)

- Semakin banyak kompleks lipid, simplek lipid akan


semakin sedikit

Triglyceride-rich lipoproteins::
Chylomicrons : berasal dari usus + very high
TG content.
VLDL : berasal dari liver + cleaved by LPL jadi
IDL
Jika lipoproteins decrease in density, makaTG
content decreases, & cholesterol and
phospholipid content increases.
Overview of Cholesterol Metabolism: Absorption and Synthesis
PPT
Key Point:
Plasma cholesterol levels depend on the balance of
cholesterol production and intestinal absorption.

Additional Background Information:


Cholesterol production: 10% cholesterol disintesis
oleh liver The other 90% is synthesized by other cells
in the body.

Intestinal cholesterol sources: Intestinal cholesterol


is derived from bile (~75%) and diet (~25%).

Absorption of intestinal cholesterol: 50% intestinal


cholesterol diserap plasma.

After absorption from the intestine: Cholesterol is esterified and packaged dibawa chylomicrons ke sirlukasi
darah sampai nyampe liver.

Changes in intestinal cholesterol absorption affect blood cholesterol levels. Decreasing cholesterol
absorption provides a key target for lipid-lowering therapy, especially when combined with statin therapy, which
decreases hepatic cholesterol synthesis Lemak dimakan (TAG>>) diemulsi garam
empedu + phospholipids bentuk micelles di
Digestion and metabolism of dietary fat:
small intestine didiuresis o/ enzim
pankreas (amilase, lipase) bentuk
cholesterol, free fatty acids, and
monoglycerides masuk ke cairan
mukosa gabung dgn apoprotein, free
cholesterol, phospholipids bentuk
kilomikron ngangkut lipid ikut sirkulasi
o/ lipoprotein lipase dihidrolisis jd
kilomikron remnant ke jalur berikutnya
bentuk free beta HDL. Kilomikron remnant
(lipid yg aterogenic) disimpan di hati, jika
kilomikron remnant numpuk jd fatty liver
hepatoseluler karsinoma.

HDL metabolism and reverse cholesterol transport


Jadi lipid yg kita makan, di intestine, juga yg
disimpan di kilomikron remanant diubah jd
Free beta HLD ngikat kolesterol bebas dari
jaringan perifer (lemak, otot) + mengikat
apoA1 & apo A-II yg dikatalis oleh LCAT
bentuk HDL diikat di hati oleh reseptor Cla-
1/SR-B I lalu di ingested + catabolized
HDL mentransfer lipoprotein yg kaya TAG
ditransfer ke LDL Diserap di jaringan
perifer dikatabolisasi/ di metabolisme di
jaringan hati. Maka semakin banyak ada
HDL, non HDL akan menurun krn melakukan
transfer kolesterol (jd kolesterol akan nurun)
Cholesterol efflux and reverse cholesterol transport is modulated by two receptors

PPT:

ABCA-1 gene codes for the membrane-bound


transport protein cholesterol efflux regulatory
protein (CERP), yg memfasilitasi cholesterol
efflux dari cell cholesterol dilepas + mengikat
pre-b-HDL Cla-1/SR-BI (the HDL scavenger
receptor) mengikat HDL + memediasi CE uptake
ke cell (liver, adrenal gland, ovary) for catabolism
or steroidogenesis.

Structure of Lipoproteins Types of Lipoprotein Particles


1.Triglyceride-rich lipoproteins
o Chylomicrons
o Very low-density lipoprotein (VLDL)

2. Cholesterol-rich lipoproteins
o Low-density lipoprotein (LDL)
o High-density lipoprotein (HDL)

Chylomicrons and Very Low-density Lipoproteins


o Chylomicrons ukurannya lebih besar dari VLDL
o Chlylomicrons berisi >>> triglyceride per particle daripada VLDL [ krn diameternya >>>]
o Apolipoproteins pada permukaannya:
- B apolipoproteins (B100 VLDL; B48 chylomicrons):
- C apolipoproteins (CII and CIII)
- A apolipoproteins (A-I and A-II)
- apoE

LDL cholesterol:
o Increased risk atherosclerosis & CVD events
o Peningkatan 10% meningkatkan risiko CHD 20%
o Most of the cholesterol in plasma ditemukan dlm bentuk LDL particles
o Semakin kecil dense LDL artinya semakin atherogenic jadi smakin mudah masuk ke tunica intima
o Faktor risiko peningkatan LDL-C:
-low HDL-C [Tidak terjadi transfer lipoprotein yg kaya TAG]
- smoking
- hypertension
- diabetes

HDL cholesterol:
o HDL-C punya protective effect u/ mengurangi atherosclerosis & CHD
o Lower the HDL-C level, smakin tinggu risiko atherosclerosis & CHD
o low level (<40 mg/dL, 1 mmol/L) increases risk. [Laki normal: >40 ; Wanita: >50]
o HDL-C akan tetap low ketika triglycerides high
o HDL-C menurun akibat smoking, obesity and physical inactivity
o ApoA-I is the major apolipoprotein in HDL &peningkatan apoA-I menurunkan risiko CVD

Triglycerides
o increased risk of CHD events
o Peningkatan risiko CHD jika:
Direct effect bikin smaller TAG-rich lipoproteins atau
Berhubungan dengan:
low HDL levels Jika diperiksa:
highly atherogenic forms of LDL-C -LDL normal maka periksa Apo B (krn blm
hyperinsulinaemia/insulin resistance tentu non HDL yg lain sudah bagus)
procoagulation state
hypertension
abdominal obesity

Apolipoproteins
o Protein content dari lipoproteins (Protein yg mengikat lipoprotein)
o ApoB levels u/ estimasi jumlah LDL particle & meningkatkan risiko CVD
o ApoA-I - major apolipoprotein in HDL & menurunkan CVD risk
o Fungsi apolipoproteins:
facilitation of lipid transport
activation of three enzymes in lipid metabolism
lecithin cholesterol acyltransferase (LCAT)
lipoprotein lipase (LPL)
hepatic triglyceride lipase (HTGL)
binding to cell surface receptors

NCEP Guidelines

-Jika punya penyakit jantung, diabetes dll penurunan harus high intencity (dosis obat tingi +
golongan statin paling kuat) krn targetnya nurunin LDL 50% dari base line
- Jika very high risk target LDL <70 ----------------------- (+) diabetes& gangguan jantung
-Jika high risk target LDL < 100 ------------------------(+) diabetes / gangguan jantung
-Jika borderline risk target LDL < 120 ------------------ (+) 2 atau lebih risk
- Jika low risk target LDL < 160
B. LIPID DISORDERS
1. HYPERTRIGLYCERIDEMIA
Penyebabnya:
Primary
Deficiency LPL (Lipoprotein Lipase) /cofactornya shg pembentukan kilomikron &free beta HDL
tidak terjadi
Endogenous & mixed lipemias
Familial combined hyperlipidemia
Familial dysbetalipoproteinemia (Type III hyperlipoproteinemia)

Secondary Alcohol ingestion


DM [akan mengganggu LPL] Nonalcoholic steatohepatitis
Uremia Nephrosis
HIV infection Glycogen strorage disease
Corticosteroid exess Hypopituitarism & Acromegaly
Exogenous estrogens Hypothyroidism
Immunoglobulin-lipoprotein complex
disorders

2. HYPERCHOLESTEROLEMIA 3. HYPOLIPIDEMIA
Penyebabnya: Penyebabnya:
Primary Primary
Familial hypercholesterolemia Due to deficiency of HDL
Familial combined hyperlipidemia Tangier disease
LP (A) hyperlipoproteinemia Familial hypoalphalipoproteinemia
Familial ligand-defective apo B Deficiency of lecithin-cholesterol
Cholesterol 7a-hydroxylase deficiency acyltransferase
Due to deficiency of Apo B-containing
Secondary lipoproteins
Hypothyroidism Recessive abetalipoproteinemia
Nephrosis Familial hypobetalipoproteinemia
Immunoglobulin disorders Chylomicron retention disease
Anorexia nervosa Secondary
Cholestasis Diseases characterized by chronic
cachexia (eg. Advanced cancer)

Klasifikasi Dyslipidaemias: Fredrickson


(WHO)
Fig. Clinical manifestation of hyperlipidemia
A. Achiles tendon xanthoma; B. Tendon xanthomata on
dorsum of hand; C. Subperiosteal xanthomata; D.
Planar xanthoma in antecubital fossa; E. Striate palmar
xanthomata; F. Tuberoeruptive xanthomata on elbow
and extensor surface of arm; G. Milky plasma from
acute abdominal pain; H. Eruptive xanthomata on
extensor surface of forearm
A,B,C,D: heterozygote FHC; E,F: type III
hyperlipoproteinemia; G,H: severe hypertriglyceridemia

COMPLICATION OF DYSLIPIDEMIA
Kalau Hypertriglyceridemia:
Atherosclerosis
Pankreatitis: krn kan enzim pankreas ni
berperan penting dipaksa kerja bisa
inflamasi

Hypercholesterolemia
Atherosclerosis

Low HDL
Atherosclerosis

six stages of development of AS:


Grades I IV: accumulation of lipids, first
intracellularly, then extracellularly;

Grade V: fibrosis around the lipid core


forming an atherosclerotic plaque;

Grade VI: complicated plaque (rupture,


clot or bleed) leading to a clinical event.

Cholesterol: A Modifiable Risk Factor


In the USA, 51% (105 million) have elevated total cholesterol (>200 mg/dL, 5.2 mmol/L)1
In EUROASPIRE II, 58% of patients with established CHD had elevated total cholesterol (5 mmol/L, 190
mg/dL)2
10% reduction in total cholesterol results in:
o 15% reduction in CHD mortality (p<0.001)
o 11% reduction in total mortality (p<0.001)3
LDL-C is the primary target to prevent CHD

Kl misalnya high: kasi dulu statin baru ke fibrater gabole


langsung
Proposed Modifications to NCEP ATP III Guidelines 2004 UpdateHigh and Very High Risk
Patients:

Overall LDL-C goal remains <100 mg/dL, but for


Very high-risk patients - new therapeutic option of treating to <70 mg/dL
For the overall category of high-risk patients, the for drug therapy threshold is lowered to an LDL-C
of 100 mg/dL or higher and those high-risk patients whose LDL-C is 100 to 129 mg/dL should
receive therapy.

C. LIPID LOWERING DRUGS (STATIN BUAT NGATASIN LDL yaitu ngambat sintesis di hati, kl fibrate
nurunin TAG, ezetimibe ngambat kolestrol diet)

Main Pleiotropic Effects of Statins


Improving or restoring endothelial function
Enhancing the stability of atherosclerotic plaques
Decreasing oxidative stress
Decreasing vascular inflammation
The first major therapeutic action of activated
Anti-thrombotic effects
PPARa is the regulation of genes involved in
lipoprotein metabolism.
PPARs: regulation of lipoprotein metabolism by PPARa
1. Stimulation of apo A-I and A-II genes, which
results in increased synthesis of the
corresponding apoproteins, which leads to
increased formation of HDL particles;

2. Stimulation of LPL genes, thereby increasing


LPL production, which leads to increased
lipolysis of TG-rich particles;

3. Inhibition of apo C-III, which indirectly


decreases apo C-III transcription, which
leads to a decrease in TG-rich particles.

Niasin: u/ naikin HDL