Hyperlipidemia, hyperlipoproteinemia:involves

abnormally elevated levels of any or

all lipidsand/or lipoproteins in the blood

lipid include biologically important materials such as

1-sterols as cholesterol

2-glycerides as triglyceride (TG) and phospholipid.

these lipid transported within the body by

incorporating lipids within lipoproteins. Plasma

cholesterol and TG are clinically important because

they are major treatable risk factors for cardiovascular

disease also severe hypertriglyceridaemia can

predisposes to acute pancreatitis.

Lipoproteins are larger and less dense when the fat to protein

ratio is increased. Lipoproteins may be classified as follows,

listed from larger and less dense to smaller and denser.

1- Chylomicrons :carry triglycerides (fat) from the intestines to

the liver, to skeletal muscle, and to adipose tissue.

2-(VLDL) carry (newly synthesised) triglycerides from the liver

to adipose tissue.

3-(IDL): transports a variety of triglyceride and cholesterol

4-(LDL) carry 3,000 to 6,000 fat molecules (phospholipids,

cholesterol, triglycerides, etc.) around the body.

5-(HDL) collect fat molecules (phospholipids, cholesterol,

triglycerides, etc.) from the body's cells/tissues, and take it

back to the liver.

It is also possible to classify lipoproteins as "alpha" and

"beta", according to the classification of proteins

in serum protein electrophoresis

Etiology of hyperlipidemias:

Primary: Following the exclusion of secondary causes

primary lipid abnormalities may be diagnosed.the

Fredrickson classification (types I to V) is no longer in

use because it adds little to clinical decision-making.

Instead, primary lipid abnormalities are classified

according to the predominant lipid problem:

hypercholesterolaemia , hypertriglyceridaemia or mixed

hyperlipidemia.

A- Predominant hypercholesterolaemia:

Classified into 1-Polygenic hypercholesterolaemia is the most common cause of mild to moderate increase in LDL-C This condition is caused by a susceptible genotype aggravated by 1 or more factors, including atherogenicdiet (excessive intake of saturated fat, trans fat, and, to a lesser extent, cholesterol), obesity, and sedentary lifestyle. Physical signs such as corneal arcus and xanthelasmamay be found.

Risk of cardiovascular disease is proportional to the degree of LDL-C elevation, together with other major risk factors, particularly low HDL-C.

2-Familial hypercholesterolaemia (FH) causes moderate to severe hypercholesterolaemia with a prevalence of at least 0.2%. in most It is usually due to an autosomal dominantly inherited mutation of the LDL receptor gene 3-defects in the apolipoprotein B100 or increased function of sterol-sensitive protease known as pcsk9 (Proprotein convertase subtilisin/kexin type 9) LDL-C is removed from the blood when it binds to an LDLR on the surface of liver cells, and is taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. But if PCSK9 does not bind, the receptor can return to the surface of the cell and remove more cholesterol.

Number of monoclonal antibody bind pcsk9 as evolocumab

& alirocumab.

Most patients with these abnormalities exhibit LDL levels that

are approximately twice as high as in unaffected subjects of

the same age and gender.

Family history reveals that approximately 50% of each

generation suffers hypercholesterolaemia, often with very

premature cardiovascular disease.

FH may be accompanied by xanthomas of the Achilles or

extensor digitorum tendons which are strongly suggestive

(but not pathognomonic) for FH. The onset of corneal arcus

before age 40 is also suggestive of this condition.

In populations in which there is a 'founder gene' effect or consanguineous marriage, homozygous FH occasionally occurs, resulting in more extensive xanthomas and precocious cardiovascular disease in childhood.

4-Hyperalphalipoproteinaemia refers to increased levels of HDL-C. In the absence of an increase in LDL-C, this condition does not cause CVS disease, so it should not be regarded as pathological. Familial combined hyperlipidaemia, and dysbetalipoproteinaemia, may present with the pattern of predominant hypercholesterolaemia

B-Predominant hypertriglyceridaemia:

Classified into

1-Polygenic hypertriglyceridaemia is the most common

primary cause of TG elevation. It also commonly occurs

secondary to

1-excess alcohol 2-medications

3-type 2 diabetes 4-impaired glucose tolerance

5-central obesity

It is often accompanied by post-prandial hyperlipidaemia

and reduced HDL-C, both of which may contribute to

cardiovascular risk.

Excessive dietary fat intake or other exacerbating factors

may precipitate a massive increase in TG levels, which, if

they exceed 10 mmol/l (880 mg/dl), may pose a risk of

acute pancreatitis.

2-Lipoprotein lipase deficiency: Lipoprotein lipase

deficiency is an infrequent autosomal recessive

disorder due to hereditary deficiency of lipoprotein

lipase (LPL) resulting in elevated chylomicrons,

3-Familial apoprotein CII deficiency a condition

caused by a lack of lipoprotein lipase activator. Or

due to circulating inhibitor of lipoprotein lipase.

It causes massive hypertriglyceridaemia that is

resistant to drug treatment.

usually presents in childhood with eruptive

xanthomata and abdominal colic.

Complications: 1-retinal vein occlusion 2-acute pancreatitis 3-steatosis(abnormal retention of lipids within a cell) 4-hepatosplenomegaly 5-lipaemia retinalis( milky appearance of the veins and arteries of the retina

4-Familial hypertriglyceridemia: is an autosomaldominant condition occurring in approximately 1% of the population. Triglyceride levels, but not cholesterol, are elevated as a result of excess hepatic production of VLDL or heterozygous LPL deficiency. Unlike familial hypercholesterolemia, there is no association with premature coronary disease..

However, affected individuals are at risk for

chylomicronemia syndrome, characterized by elevated

chylomicrons in the blood. It has been suggested that it

may represent a secondary response to impaired bile

acid resorption

On the other hand, it predisposes to levels of

hypertriglyceridaemia that are sufficient to pose a risk of

pancreatitis .Familial combined hyperlipidaemia, and

dysbetalipoproteinaemia, may present with the pattern

of predominant hypertriglyceridaemia.

C-Mixed hyperlipidaemia :The term 'mixed' usually

implies the presence of hypertriglyceridaemia as well as

an increase in LDL-c or IDL-c. classified into

1- polygenic :Primary mixed hyperlipidaemia is usually

polygenic and, like predominant hypertriglyceridaemia,

often occurs in association with type 2 diabetes,

impaired glucose tolerance, central obesity HT.

2-Familial combined hyperlipidaemia is a dominantly

inherited disorder caused by overproduction of

atherogenic apolipoprotein B-containing lipoproteins.

It results in elevation of cholesterol, TG or both in

different family members at different times.

It is associated with an increased risk of cardiovascular

disease but it does not produce any pathognomonic

physical signs. In practice, this relatively common

condition is substantially modified by factors such as

age and weight.

3-Dysbetalipoproteinaemia

It is caused by homozygous inheritance of the

apolipoprotein E2 allele, which is the isoform least

avidly recognised by the LDL receptor. In conjunction

with other exacerbating factors such as obesity and

diabetes, it leads to accumulation of atherogenic IDL

and chylomicron remnants.

Premature cardiovascular disease is common and it

may also result in the formation of palmar xanthomas,

tuberous xanthomas or tendon xanthomas.

hyperlipopr

oteinemia

defect Increased

lipoprotei

n

Main

symptoms

serum

Appeara

nce

Treatment

Type Ia or

Buerger-

Gruetz

syndrome or

familial

hyperchylom

icronemia

Decreased lip

oprotein

lipase (LPL)

Chylomicro

ns

Acute

pancreatitis, lipe

mia retinalis,

eruptive

skin xanthomas,

hepatosplenom

egaly

Creamy

top layer

Diet control

Type Ib

Familial

apoprotein

CII

deficiency

Altered ApoC2 Chylomicro

ns

Same as a Creamy

top layer

Diet control

Type Ic LPL inhibitor in

blood

Chylomicro

ns

Same as a

Type IIa or

F.Hypercho.

LDL

receptordeficie

ncy

LDL Xanthelasma, ar

cus senilis,

tendon

xanthomas

Clear Bile acid

sequestrants

,statins, niaci

n

Type IIb or

Familial

combined

Decreased LD

L receptor and

increased ApoLDL and V

=======

=

Statins, niaci

hyperlipopr

oteinemia

defect Increased

lipoprotein

Main

symptoms

serum

Appearance

Treatment

Type III OR

Familial

dysbetalipop

roteinemia

Defect

in Apo E

2synthesis

IDL Tuboeruptive

xanthomas

and palmar

xanthomas

Turbid

Fibrate,

statins

Type IV or

Familial

hypertriglyce

ridemia

Increased

VLDL

production &

decreased

elimination

VLDL Can

cause pancr

eatitis at

high

triglyceride

levels

same Fibrate,

niacin,

statins

Type V Increased

VLDL

production

and

decreased L

PL

VLDL and

chylomicrons

Creamy top

layer and

turbid bottom

Niacin,

fibrate

Rare dyslipidaemias: Several rare disturbances of lipid metabolism have been described .They provide important insights into lipid metabolism and its impact on risk of cardiovascular disease. Fish eye disease and Apo A1 Milano demonstrate that very low HDL levels do not necessarily cause cardiovascular disease, but Apo A1 deficiency, Tangier disease and LCAT deficiency demonstrate that low HDL-C can be atherogenic under some circumstances. Sitosterolaemia and cerebrotendinousxanthomatosis demonstrate that sterols other than cholesterol can cause xanthomas and cardiovascular disease, while abetalipoproteinaemia and hypobetalipoproteinaemia suggest that low levels of apolipoprotein B-containing lipoproteins reduce the risk of cardiovascular disease at the expense of fat-soluble vitamin deficiency, leading to retinal lesions and peripheral neuropathy.

16.23 CAUSES OF SECONDARY HYPERLIPIDAEMIA Secondary hypercholesterolaemiaA-Moderately common 1- Hypothyroidism

2-Pregnancy

3-Cholestatic liver disease

4-Drugs (diuretics, ciclosporin, corticosteroids, androgens)

B-Less common 1-Nephrotic syndrome

2-Anorexia nervosa

3-Porphyria

4-Hyperparathyroidism

Secondary hypertriglyceridaemia1-Diabetes mellitus (type 2)

2-Chronic renal disease

3-Abdominal obesity

4-Excess alcohol

5-Hepatocellular disease

6-Drugs (β-blockers, retinoids, corticosteroids)

LIPIDS AND CARDIOVASCULAR DISEASE

Plasma lipoprotein levels are major modifiable risk factors

for cardiovascular disease.

1-Increased levels of atherogenic lipoproteins, especially

LDL, but also IDL and possibly chylomicron remnants,

contribute to the development of atherosclerosis.

2-Increased plasma concentration and reduced diameter

favour subendothelial accumulation of these lipoproteins.

3-Following chemical modifications such as oxidation, the

lipoproteins are no longer cleared by normal mechanisms,

They trigger a self-perpetuating inflammatory response during which they are taken up by macrophages to form foam cells(lipid laden macrophage) a hallmark of the atherosclerotic process.

cholesterol-laden cells release cholesterol to HDL for reverse cholesterol transport to the liver for excretion. HDL may also counteract some components of the inflammatory response, such as the expression of vascular adhesion molecules by the endothelium. Consequently, low HDL cholesterol levels also predispose to atherosclerosis.

DiagnosisLIPID MEASUREMENT

Measurement of plasma cholesterol alone is not sufficient for comprehensive assessment. Levels of total cholesterol (TC), triglyceride (TG) and HDL cholesterol (HDL-C) should be obtained after a 12-hour fast to permit the calculation of LDL cholesterol (LDL-C) according to the Friedewald formula LDL-C = TC - HDL-C - (TG/2.2) mmol/l Before the formula is applied, lipid levels in mg/dl can be converted to mmol/l by dividing by 38 for cholesterol and 88 for triglycerides.

The formula becomes unreliable when TG levels exceed 4 mmol/l (350 mg/dl). Non-fasting samples are unaffected in terms of TC and measured LDL-C, but they differ in terms of TG and HDL-C, and hence the calculation of LDL-C is invalidated.

Consideration must be given to influencing factors such

as recent illness, after which cholesterol levels

temporarily decrease in proportion to severity.

Measurements that will affect major decisions, such as

initiation of drug therapy, should be confirmed with a

repeat measurement. Elevated TG, which is common

in obesity, diabetes and insulin resistance is frequently

associated with low HDL and increased 'small, dense'

LDL. Under these circumstances, LDL-C may

underestimate risk. This is one situation in which

measurement of apolipoprotein B may provide

additional useful information.

MANAGEMENT OF DYSLIPIDAEMIA

Lipid-lowering therapies have a key role in the secondary

and primary prevention of cardiovascular diseases.

1-Assessment of absolute risk

2-treatment of all modifiable risk factors

3-optimisation of lifestyle factors, especially diet and

exercise, are central to management in all cases.

Public health organisations recommend thresholds for

the introduction of lipid-lowering therapy based on the

identification of patients in very high-risk categories or

those calculated to be at high absolute risk according to

algorithms or tables such as the Joint British Societies

Coronary Risk Prediction Chart.

1-patients who already have cardiovascular disease 2-diabetes mellitus 3-an absolute risk of cardiovascular disease of greater than 20% in the ensuing 10 years, regarded as having sufficient risk to justify drug treatment. Public health organisations also recommend target levels for patients receiving drug treatment. High-risk patients should aim for 1-HDL-C > 1 mmol/l (38 mg/dl) 2-fasting TG < 2 mmol/l (∼180 mg/dl) 3-LDL-C have been reduced from 2.5 to 2.0 mmol/l (76 mg/dl) or less.In general, total cholesterol should be < 5 mmol/l (190 mg/dl) during treatment, and < 4 mmol/l (∼150 mg/dl) in high-risk patients and in secondary prevention of cardiovascular disease.

Non-pharmacological treatment Patients with lipid abnormalities should receive medical advice and, if necessary, dietary counselling to: 1-reduce intake of saturated and trans-unsaturated fat to less than 7-10% of total energy

2-reduce the intake of cholesterol to less than 250 mg/day

3-replace sources of saturated fat and cholesterol with alternative foods such as lean meat, low-fat dairy products, polyunsaturated spreads and low glycaemicindex carbohydrates

4-reduce energy-dense foods such as fats and soft drinks, whilst increasing activity and exercise to achieve stable or negative energy balance (i.e. weight maintenance or weight loss)

5-increase consumption of cardioprotective and nutrient-

dense foods such as vegetables, unrefined

carbohydrates, fish, pulses, legumes, fruit etc.

6-adjust alcohol consumption, reducing intake if excessive

or if associated with hypertension, hypertriglyceridaemia

or central obesity

7-achieve additional benefits with supplementary intake of

foods containing lipid-lowering nutrients such as n-3 fatty

acids, dietary fibre and plant sterols.

Response to diet is usually apparent within 3-4 weeks but

dietary adjustment may need to be introduced gradually.

Hyperlipidaemia in general, and hypertriglyceridaemia in

particular, can be very responsive to these measures.

Explanation, encouragement and other measures

should be undertaken to reinforce patient compliance.

Even minor weight loss can substantially reduce

cardiovascular risk, especially in centrally obese

patients .

All other modifiable cardiovascular risk factors should

be assessed and treated.

Where possible, intercurrent drug treatments that

adversely affect the lipid profile should be replaced.

Pharmacological management: The main diagnostic categories provide a useful framework for management and the selection of first-line pharmacological treatment

1-HMG( 3-hydroxy-3-methyl-glutaryl)CoA reductaseinhibitors (statins) Statins inhibit cholesterol synthesis, thereby up-regulating activity of the LDL receptor. This increases clearance of LDL and its precursor, IDL, thereby causing a secondary reduction in LDL synthesis. As a result, statins1-reduce LDL-C by up to 60% 2-reduce TG by up to 40% 3-increase HDL-C by up to 10%. They also reduce the concentration of intermediate metabolites such as isoprenes, which may lead to other effects such as suppression of the inflammatory response.

There is clear evidence of protection against 1-stroke 2-total and coronary mortality 3-reduction in CVS events in high-risk patients..

Simvastatin (20-80 mg/day) Atorvastatin (10-80 mg/day)

Pravastatin (20-80 mg/day) Fluvastatin (20-80 mg/day)

Lovastatin (20-80 mg/day) Rosuvastatin (10-40 mg/day

SE:Statins are generally well tolerated and serious side-effects are rare (well below 2%). 1-Myalgia 2-asymptomatic increase in creatine kinase (CK) 3-myositis 4-infrequently rhabdomyolysis along with liver function test abnormalities are the most important category,. Side-effects are more likely in patients who are elderly, debilitated or receiving other drugs that interfere with statindegradation, which usually involves cytochrome P450 3A4.

2-Cholesterol absorption inhibitors, such as ezetimibeThese inhibit the intestinal mucosal transporter NPC1L1 that absorbs dietary and biliary cholesterol. Depletion of hepatic cholesterol up-regulates hepatic LDL receptor activity. This mechanism of action is synergistic with the effect of statins. Monotherapy with the standard 10 mg/day dose reduces LDL-C by 15-20%. Slightly greater (17-25%) incremental LDL-C reduction occurs when ezetimibe is added to statins.

SE Hepatitis, abdominal pain, back pain, arthralgias

3-Bile acid sequestering resins, such as colestyramine

and colestipol

These prevent the reabsorption of bile acids, thereby

increasing de novo bile acid synthesis from hepatic

cholesterol. As with ezetimibe, the resultant depletion of

hepatic cholesterol up-regulates LDL receptor activity

and reduces LDL-C in a manner that is synergistic with

the action of statins.

High doses (24 g/day colestyramine) can achieve

substantial reductions in LDL-C and modest increases

in HDL-C, but TG may rise.

Resins are safe, but they are poorly tolerated because of

their gastrointestinal effects and they may interfere with

bio-availability of other drugs.

4-Nicotinic acid (vitamin B3)

In pharmacological doses

1-reduces peripheral fatty acid release

2- decrease cholesterol and TG

3-HDL-C increases

side-effects

1-Flushing occurs universally

2- gastric irritation

3-liver function disturbances

4- exacerbation of gout and hyperglycaemia Slow-

release formulations and low-dose aspirin may reduce

flushing. Trials suggest a beneficial effect on

atherosclerosis and cardiovascular events.

Routine treatment of predominant hypercholesterolaemia

generally requires continuation of diet + statin in

sufficient doses to achieve target LDL-C levels.

Therapy may have to be interrupted or ceased if there

are

1-clear-cut muscle side-effects

2- CK elevation beyond 10 times the upper limit of

normal

3-sustained ALT elevation beyond 2-3 times the upper

limit of normal (and not accounted for by fatty liver).

Patients who do not reach LDL targets on the highest

tolerated statin dose may receive ezetimibe, plant

sterols, nicotinic acid or resins, and these agents may

also be added when patients are intolerant of statins.

Nicotinic acid may also be used as an alternative in

statin intolerance. It is also very effective in

combination with a statin, but caution is required

because the risk of side-effects is increased.

Post-menopausal oestrogen replacement therapy,

which may reduce LDL-C and increase HDL-C and

TG, is no longer recommended for cardiovascular

disease prevention

Predominant hypertriglyceridaemia

1-Fibrates: Bezafibrate, Ciprofibrate,Clofibrate, GemfibrozilFenofibrate

These stimulate peroxisome proliferator activated receptor (PPAR)-alpha, which controls the expression of gene products that mediate the metabolism of triglyceride and HDL.

As a result, synthesis of fatty acids, triglyceride and VLDL is reduced whilst that of lipoprotein lipase, which catabolisesTG, is enhanced. leading to increased reverse cholesterol transport via HDL. Consequently fibrates1-reduce TG by up to 50% 2-increase HDL-C by up to 20% 3-LDL-C changes are variable.

reduced rates of cardiovascular disease have been

reported in studies amongst patients with low HDL-C

levels and in subgroups of patients with the clinical

picture of insulin resistance

The FIELD trial suggests that fibrates represent

selective adjuvant therapy rather than first-line lipid-

lowering therapy in most patients with type 2 diabetes.

Fibrates are generally well tolerated side-effects:

1-myalgia 2-myopathy

3-abnormal liver function tests

4-they may increase the risk of cholelithiasis

5-prolong the action of anticoagulants.

2-highly polyunsaturated long-chain n-3 fatty acids

Eicosapentaenoic acid (EPA) and docosahexaenoic acid

(DHA) comprise approximately 30% of the fatty acids in fish

oil.

1-EPA and DHA are potent inhibitors of VLDL TG formation.

Intakes of greater than 2 g n-3 fatty acid (equivalent to 6 g of

most forms of fish oil) per day lower TG in a dose-dependent

fashion.

Up to 50% reduction in TG may be achieved with 15 g fish

oil per day. Changes in LDL-C and HDL-C are variable.

2- Fish oil fatty acids have also inhibit platelet aggregation

3- improve models of ventricular arrhythmia.

4-Dietary and pharmacological trials indicate that n-3 fatty

acids reduce mortality from coronary heart disease..

Mixed hyperlipidaemia

Mixed hyperlipidaemia can be difficult to treat. Statins

alone are less effective first-line therapy once fasting

TG exceeds approximately 4 mmol/l (∼350 mg/dl).

Fibrates alone are first-line therapy for

dysbetalipoproteinaemia, but they may not control the

cholesterol component in other forms of mixed

hyperlipidaemia. Combination therapy is often required.

Statin plus fish oil is relatively safe and effective when

TG is not too high and in future fibrate plus ezetimibe

may be effective.

Statin plus nicotinic acid or statin plus fibrate is effective,

but the risk of myopathy is greater.

Monitoring of therapy

The effect of drug therapy can be assessed after 6 weeks

(12 weeks for fibrates), and it is prudent to review

1-side-effects 2-lipid response

3-CK 4-LFT

5- cardiovascular symptoms or signs

6- measurement of weight

7- blood pressure

Follow-up should encourage continued compliance

(especially diet and exercise)

THANKS FOR LISTENING

Presented by:

Haider Ferown