1. HYPERLIPIDAEMIA
HA MWAKYOMA, MD.

2. INTRODUCTION:
Lipids are fats that are either absorbed from food or synthesized in the liver.
Triglycerides (TGs) and cholesterol contribute most to disease, although all lipids are physiologically important. The primary function is to store energy in adipocytes and muscle cells.

3. Introduction cont--
Cholesterol is an ubiquitous constituent of cell membranes, bile acids and signaling molecules.
All lipids are hydrophobic and mostly insoluble in blood, so that they require transport within hydrophobic spherical structures called lipoproteins which posses surface proteins (Apoproteins) that are cofactors and ligands for lipid-processing enzymes.

4. Introduction cont--
Lipoproteins are classified by size and density (defined as the ratio of lipid to protein) and are important because high levels of low-density lipoproteins (LDLs) and low levels of high-density lipoproteins (HDLs) are mojor risk factors for artherosclerotic heart disease.

5. Exogenous (dietary) lipid metabolism:-
Over 95% of dietary lipids are TGs, the rest are Phospholipids, Free fat acids (FFAs), Cholesterol (present in food as esterified cholesterol) and Fat-soluble vitamins.
Dietary TGs are digested in the stomach and duodenum into monoglycerides (MGs) and FFAs by gastric lipase, emulsification from vigorous stomach peristalsis, and pancreatic lipase.

6. Exogenous (Dietary)lipid metabolism
Dietary cholesterol esters are de-esterified into by these same mechanism.
MGs, FFAs and Free cholesterol are then solubilized in the intestine by bile acids micelles, which shuttle them in intestinal villi for absorption.

7. Exogenous (Dietary) lipid metabolism.
Once absorbed into enterocytes, they are reassembled into TGs and packed with cholesterol into chylomicrons, the largest lipoproteins.

8. CHYLOMICRONS:
These transport dietary TGs and Cholesterol from enterocytes through lymphatics into the circulation.
In capillaries of adipose and muscle tissue, apoprotein C-II (apo C-II) on the chylomicron activates endothelial lipoprotein lipase (LPL) to convert 90% of chylomicron TG to Fatty acids and glycerol which are taken up by adipocytes and muscle cells for energy use or storage

9. Chylomicrons cont--
Cholesterol-rich chylomicron remnants then circulate back to the liver, where they are cleared in a process mediated by apoprotein E (apo E).\

10. Endogenous Lipid Metabolism
Lipoproteins synthesized in the liver transport endogenous TGs and Cholesterol.
Lipoproteins circulate through the blood continuously until the TGs they contain are taken up by peripheral tissue or the lipoproteins themselves are cleared by the liver

11. Endogenous Lipid Metabolism
Lipoproteins become more cholesterol-rich as they lose factors that stimulate hepatic lipoprotein synthesis generally lead to elevated plasma cholesterol.

12. Very-low density lipoproteins (VLDLs):
Contain apoprotein B-100 (apo B)
Are synthesized in the liver, and they transport TGs and cholesterol to peripheral tissues.
VLDL is the way the liver exports excess TGs, derived from plasma FFA and chylomicron remnants.

13. VLDLs
VLDLs synthesis increase with increases in intrahepatic FFA such as occurs with high-fat diets and when excess adipose tissue releases FFA directly into the the circulation, obesity, uncontrolled diabetes mellitus.
ApoC-II on VLDL surface activates endothelial LPL to break down TGs into FFAs and Glycerol, which are taken up by cells.

14. Intermediate-density lipoproteins (IDLs):
Are the product of LPL processing of VLDLs and Chylomicrons.
They are cholesterol-rich VLDLs and Chylomicrons remnants that are either cleared by the liver or metabolized by lipoprotein lipase (LPL) into LDL, which retains apoB.

15. Low-density lipoproteins (LDLs):
The products of VLDL and IDL metabolism, are the most cholesterol-rich of all lipoproteins.
About 40 to 60% of all LDLs are cleared by the liver in a process mediated by apoB and hepatic receptors. The rest are taken up by either hepatic LDL or non-hepatic, non-LDL (Scavenger) receptors.

16. LDLs cont--
Hepatic LDL receptor are down regulated by delivery of cholesterol to the liver by chylomicrons and by increased dietary saturated fat; they can be up-regulated by decreased dietary fat and cholesterol.
Non-hepatic scavenger receptor, most notably on microphages, take up excess oxidized circulating LDLs not processed by hepatic receptors.

17. LDLs cont --
Oxidized-LDL-rich macrophages can then migrate into endothelium in response to endothelial inflammation or other stimuli and form foam cells within atherosclerotic plaques.
There are 2 forms of LDL:-
Large buoyant and small dense LDL-rich in cholesterol esters, associated with metabolic disturbances such as hypertriglycerimia and increased oxidation.

18. High-density lipoproteins (HDLs):
These are initially cholesterol-free lipoproteins that are synthesized in the enterocytes and the liver.
HDL’s overall role is to obtain cholesterol from peripheral tissues and other lipoproteins and transport it to where it is needed most-other cells, other lipoproteins (using cholesteryl ester transfer protein – CETP), and the liver (for clearance). Its overall effect is anti-atherogenic).

19. HDLs cont ---
Exflux of free cholesterol from cells is mediated by ATP-binding cassette transporter A1 (ABCA1) which combines with ApoA-1 to produce nascent HDL, producing mature HDL.

20. HYPERLIPIDAEMIA:-
Definition:- is the presence of elevated or abnormal levels of lipids and/or lipoproteins in the blood.
Lipid and lipoprotein abnormalities are extremely common in general population and are regarded as a highly modified risk factors for cardiovascular disease due to the influence of cholesterol, one of the most clinically relevant lipid substances, on the atherosclerosis.

21. Hyperlipidaemia cont--
An increase in chylomicrons or VLDL leads to increase in TGs, while an increase in LPL or IDL leads to an increase in cholesterol esters.

22. CLASSIFICATION: Primary hyperlipidaemia Secondary hyperlipidaemia
Primary hyperlipidaemias are classified according to the Fredrickson classification which is based on eletrophoresis or ultracentrifugation.

23. Primary hyperlipidaemia cont--
This classification was later adopted by World Health Organization (WHO).
It does not directly account for HDL and
It does not distinguish the different genes that may be partially responsible for some of these conditions.

24. Classification of hyperlipidaemia
HYPERLIPIDAEMIA TYPE 1.
(Hyperlipoproteinemia type 1)
Synonyms:
Familial hyperchylomicronemia
Primary hyperlipoproteinemia
Burger-Grunetz
HYPERLIPIDAEMIA TYPE 2.
(Hyperlipoproteinemia type 2).

25. Hyperlipidaemia type 2 cont---
Type 2a.
Synonyms:-
Familial hypercholesterolaemia
Polygenic hypercholesterolaemia
Type 2b.
Combined (mixed) hyperlipidaemia

26. Classification of hyperlipidaemias cont--
HYPERLIPIDAEMIA TYPE 3.
(Hyperlipoproteinemia type 3.)
Synonyms:-
Familial dysbetalipoproteinemia
HYPERLIPIDAEMIA TYPE 4.
(Hyperlipoproteinemia type 4.)
Endogenous hyperlipemia

27. Classification cont---
HYPERLIPIDAEMIA TYPE 5.
(Hyperlipoproteinemia type 5.)
Synonyms:-
Familial hypertriglyceridemia.

28. TYPE 1 HYPERLIPIDAEMIA: Problem:-
Apo-C2 deficiency (altered apolipoprotein C2)
Lipoprotein lipase (LPL) deficiency
Laboratory findings:-
Elevated chylomicrons, the particle that transfers fatty acids from the digestive tract to the liver. There is an increased triglyceride primarily in chylomicrons. (hyperchlomicronaemia).
The risk of atherosclerosis is thought to be slight.

29. Type 1 hyperlipidaemia cont--
Laboratory findings:-
Elevated chylomicrons, the particle that transfers fatty acids from the digestive tract to the liver. There is an increased triglyceride primarily in chylomicrons. (hyperchlomicronaemia).
The risk of atherosclerosis is thought to be slight.

30. Type 1 hyperlipidaemia Features: Recessive inheritance
Eruptive xanthomata
Lipaemia retinalis
Acute pancreatitis

31. TYPE 2 HYPERLIPIDAEMIA:
This is by far the most common type of hyperlipidaemias.
It is further classified into type 2a and type 2b, depending mainly on whether there is elevation of triglyceride level in addition to LDL cholesterol.

32. Type 2 hyperlipidaemia – classification.
Type 2a:
Is a familial hypercholesterolaemic syndrome.
Problem:
LDL receptor deficiency
The truly familial form results from a mutation either LDL receptor gene on chromosome 19 or the ApoB gene

33. Type 2a hyperlipidaemia cont---
Features:
Autosomal dorminant inheritance
Presentation is with early onset ischaemic heart disease
Tendon xanthoma are common
Laboratory findings:-
Elevated LDL only (High LDL levels).

34. Type 2b: hyperlipidaemia cont---
This is a combined (mixed) hyperlipidaemia.
Problem:
Decreased LDL receptor and
Increased ApoB

35. Type 2b hyperlipidaemia cont---
Laboratory findings:
Raised plasma cholesterol (raised LDL)
Raised triglycerides (raised VLDL).
The high VLDL levels are due to overproduction of substrates including triglycerides, acetyl CoA, and increase in Apo B-100 synthesis

36. Type 2b hyperlipidaemia cont---
VLDL may also be caused by the decreased clearance of LDL.
Features:
There is an increased risk of ischaemic heart disease.

37. TYPE 3 HYPERLIPIDAEMIA; (Type 3 Hyperlipiproteinemia)
This type of hyperlipidaemia is characterized high chylomicrons and IDL (Intermediate Density Lipoprotein – partially metabolized VLDL, collectively termed beta-VLDL or cholesterol-rich VLDL) in the circulation.

38. Type 3 hyperlipidaemia cont ---
Problem:
Defect in ApoE synthesis
There is decreased clearancer of VLDL and IDL at the ApoE (or hepatic remnant) receptor.
Laboratory findings:
Increased IDL (Beta-VLDL or Cholesterol-rich VLDL)

39. Type 3 hyperlipidaemia cont---
Association:
Type 3 hyperlipidaemia is associated with;
Accelerated atherosclerosis in the coronary, iliac, femoral, and tibial arteries
High incidence of intermittent claudication
Fasting levels of cholesterol and triglyceride are raised (generally cholesterol)

40. TYPE 4 HYPERLIPIDAEMIA: (Type 4 Hyperlipoproteinemia).
There is high triglyceride levels (= hypertriglyceridemia).
Autosomal dorminant inheritance
Problem:
Overproduction of VLDL and decreased elimination

41. Type 4 hyperlipidaemia cont--
Laboratory findings:
Increased triglyceride levels (increased VLDLs).
Normal or slightly raised plasma cholesterol.

42. TYPE 5 HYPERLIPIDAEMIA: ( Hyperlipoproteinemia).
This type is very similar to type 1 but with high VLDL in addition to chylomicrons.
Problem:
Lipolipase deficiency or
Apo-C2 deficiency, resulting in increased VLDL production or decreased LPL.

43. Laboratory findings:
Raised triglycerides (= increased VLDL + increased Chylomicrons).

44. Type 5 hyperlipidaemia cont---
Features:
Eruptive xanthoma, these are characteristic of severe hypertriglycermia, yellow papules on the extensor surfaces of back, arms, buttocks.
Hepatosplenomegally
Lipaemia retinalis – retinal arteries and veins appearing with fundoscopy.

45. Secondary hyperlipidaemia:
This type follows certain diseases or conditions
Some examples of conditions include;
Nephrotic syndrome – chol. ++, TG(+)
Hypothyroidism – chol. ++, TG +
Biliary obstruction – chol. +, TG(+)
Pregnancy – chol. +
Myeloma – chol. +

46. Secondary hyperlipidaemia cont--
Steroids – chol. +, TG +
Obesity – chol. +, TG +
Diabetes mellitus – chol.+, TG ++
Renal failure – TG +
Beta blockers – TG +
Oral contraceptive pill – TG +
Glycogen storage disease – TG +

47. RISK FACTORS FOR LIPID DISORDERS
A risk factor is something that increases chances of getting a disease or condition
Risk factors for lipid disorders include the following:

48. SPECIFIC LIFESTYLE FACTORS.
A diet high in saturated fat, trans fat, and cholesterol:
Eating food high in saturated fat, trans fat, and cholesterol, increases cholesterol levels

49. Specific lifestyle Risk factors cont---
Physical inactivity:
Moderate to intense exercise done on regular basis helps decrease LDL (bad) cholesterol, with increasing HDL (good) cholesterol, the type that helps helps prevent heart disease.

50. Specific lifestyle risk factors cont --
Smoking:
Smoking lowers the amount of HDL, the health type of cholesterol, in blood.
Acohol intake:
While the moderate amount of alcohol can raise the healthy type of cholesterol, alcohol can also raise unhealthy triglyceride levels.

51. Risk factors cont--- MEDICAL CONDITIONS. Overweight and obesity:
Being overweight causes cholesterol levels to rise.
Hypothyroidism:
An under-active thyroid can lead to increased TG and cholesterol levels.
Diabetes mellitus:
DM is associated with elevated TG levels.

52. Risk factors – medical conditions cont---
Liver disease:
Having liver disease can raise cholesterol levels.
Kidney disease:
Some kidney disease called nephrotic syndrome are associated with elevated cholesterol and TG levels.

53. Risk factors cont--- Certain medications:
Many medications, including some hypertensives, oral contraceptives, and steroids can raise cholesterol levels.

54. Other risk factors AGE:
Advancing age , cholesterol levels tend to increase with age due to a number of factors. In women, LDL levels often increase after menopause because of changing hormone levels.

55. Other risk factors cont---
GENETIC FACTORS:
Family history of lipid disorders: certain types of high cholesterol are inherited.