DISORDERS OF LIPID METABOLISM pdf - ثناء محمد جودة السويدي

Clinical biochemistry second stage Lipid lecture Dr.Thana Alswedy

DISORDERS OF LIPID METABOLISM

Abnormality of cholesterol metabolism may lead to cardiovascular accidents

and heart attacks,.epidemiological studies demonstrated that low concentrations of

HDL cholesterol are associated with a higher risk of atherosclerosis. This is the so-

called ‘good cholesterol. It is believed that HDL may protect against

atherosclerosis via the promotion of reverse cholesterol transport. Conversely,

higher concentrations of LDL cholesterol have been associated with increasing

severity of cardiovascular disease,. This is the ‘bad cholesterol’. The

apolipoproteins and associated enzymes of HDL are believed to be important for

the maintenance of health in many further ways, including antioxidant, anti-

inflammatory and antithrombotic effects.

Hormone control of lipogenesis and lipolysis

the balance (ratio between lipogenesis and lipolysis) is a product of

continuous

neurohumoral regulation reflecting feeding/fasting cycling and

immediate

energy requirements of the body

(A) normal adipocytes in a fed(postprandial) state

– glucose is taken up by adipocytes via GLUT4 stimulated by

insulin

– FFA are released from TAG rich lipoproteins (mainly chylomicrons) by the

action of LPL stimulated by

insulin

– surplus of glucose is the main source for TAG production

(B) normal adipocytes in a fasted state

– the stored TAG undergoes lipolysis mediated by hormone sensitive lipase (

HSL) into glycerol and FFA, the latter are released for utilization in liver and

muscle

– activity of HSL is stimulated by catabolichormones (

glucocorticoids

catecholamines

HYPERLIPIDAEMIA

Lipid disorders are caused by excess lipids or fatty substances in the blood,

and are an important risk factor in developing atherosclerosis and heart

disease. Certain types of lipid disorders may be caused by genetic factors, as

in certain familial diseases, or by secondary factors, such as fatty diets and

diabetes.

The simplest aetiological classification of hyperlipidaemias divides them into 2

categories:

Clinical biochemistry second stage Lipid lecture Dr.Thana Alswedy

i. Primary hyperlipidaemia – where the hyperlipidaemia is not due to an

identifiable underlying disease, but due to an inherited disorder of lipoprotein

metabolism.

ii. Secondary hyperlipidaemias – where the hyperlipidaemia is caused by an

identifiable underlying disease or drug regimen which interferes with normal

lipid metabolism.

PRIMARY HYPERLIPIDAEMIAS

Primary FAMILIAL HYPERCHOLESTEROLAEMIA (FH)

Inherited defect of the LDL receptor.Clinically patients usually have positive

family histories of CAD, and often have

deposition of lipids in subcutaneous

tissue leads to xanthomas

Deposits of lipids in cornea lead to

corneal arcus; The LDL receptor defect may be due to the following reasons

1. LDL receptor deficiency.

2. Defective binding of B-100 to the receptor.

3. Receptor-LDL complex is not internalised.

unable to transport LDL into the cell and Failure of receptor-mediated

internalisation of LDL results in failure to down regulate HMG-CoA reductase

at normal plasma cholesterol levels.. The result is cholesterol is synthesised

in uncontrolled, Plasma LDL levels are inversely proportional to LDL receptor

activity in these patients due to impaired uptake and catabolism of LDL This

causes increased macrophage uptake of oxidised LDL, in the intima, via the

scavenger receptor, and formation of foam cells resulting in xanthomata and

initiation of atheroma.

FAMILIAL COMBINED HYPERLIPIDAEMIA (FCHL) (Multiple lipoprotein-

type hyperlipidaemia)

There is elevation of both cholesterol and triglycerides with excessive

production of apo-B. Therefore, LDL and VLDL are elevated. The

abnormalities are manifested only by the third decade of life.

Clinical biochemistry second stage Lipid lecture Dr.Thana Alswedy

FAMILIAL HYPERTRIGLYCERIDAEMIA

This is a common autosomal dominant defect causing increased VLDL in the

plasma. The basic defect may be decreased VLDL catabolism in some cases,

or excess TG synthesis by the liver and increased VLDL secretion in others.

Clinically these patients are often obese, hyperglycaemic and

hyperinsulinaemic and may have hyperuricaemia and hypertension. 50% of

first degree adult relatives have elevated TG with little or no elevation of

cholesterol.

FAMILIAL LIPOPROTEIN LIPASE DEFICIENCY

This is due to an autosomal recessively inherited defect of the enzyme

lipoprotein lipase. Chylomicrons are not cleared from the blood resulting in

very high TG levels, which causes plasma to have a thick layer of "cream"

above a clear infranatant on standing at 4°C

FAMILIAL APO C-II DEFICIENCY

This is due to an autosomal recessive inherited defect in apo C-II, which is an

essential cofactor for LPL. This deficiency thus causes a similar picture to LPL

deficiency. Chylomicrons accumulate in plasma pattern), and sometimes

VLDL also accumulate .

FAMILIAL DYSBETALIPOPROTEINAEMIA apoE gene mutations causes

accumulation of excess IDL and chylomicron remnants due to defect in liver

clearance of this lipoprotien.

Hypoalphalipoproteinemia

Low levels of high-density lipoprotein cholesterol (HDL), or

hypoalphalipoproteinemia (HA), includes a variety of conditions, ranging from

mild to severe, in which concentrations of alpha lipoproteins or high-density

lipoprotein (HDL) are reduced. The etiology of HDL deficiencies ranges from

secondary causes, such as smoking, to specific genetic mutations, such as

Tangier disease and fish-eye disease

Clinical biochemistry second stage Lipid lecture Dr.Thana Alswedy

SECONDARY HYPERLIPIDAEMIA

In many patients hyperlipidemia is caused by some underlying "non-lipid"

etiology rather than a primary disorder of lipid metabolism.

These account for ±40% of hyperlipidaemias and main causes are

1-HYPOTHYROIDISM

Predominantly hypercholesterolaemia with normal or slightly raised

triglyceride levels due to Decreased catabolism of VLDL, IDL and LDL.

2-RENAL DISEASE

Nephrotic syndrome – protein loose as a consequence of proteinuria large

molecules lipoproteins are not lost in the urine at the same rate as other

proteins, thus patients become hypercholesterolaemic

3-LIVER DISEASE

In cholestasis diversion of biliary cholesterol and phospholipids into the blood-

stream occurs, leading to severe hypercholesterolaemia and variable

hypertriglyceridaemia.

4-DIABETES mellitus

Diabetes is characterised by an over-production of VLDL, leading to

hypertriglyceridaemia. Prolonged insulin deficiency also decreases LPL

activity, and if VLDL rise markedly, chylomicrons accumulate due to

competition for LPL

5-ALCOHOL

Usually causes hypertriglyceridaemia due to increased VLDL synthesis.

Hepatic triglyceride synthesis is increased due to increased fatty acid

synthesis and decreased fatty acid oxidation. Increased fatty acid synthesis is

due to increased acetyl CoA from metabolism of ethanol.

6-OBESITY

Increased fatty acid delivery to the liver (dietary excess or insulin resistance)

results in increased VLDL synthesis which leads to hypertriglyceridaemia

Risk of dyslipidemia

Dyslipidemia itself usually causes no symptoms but can lead to symptomatic

vascular disease, including coronary artery disease (CAD), stroke, and

peripheral arterial disease. High levels of TGs (> 1000 mg/dL [> 11.3 mmol/L])

can cause acute pancreatitis.

Clinical biochemistry second stage Lipid lecture Dr.Thana Alswedy

Diagnosis of lipid disorder by lipid profile

. Lipid profile (TChol, TG, HDL-C, LDL-C):

Total cholesterol and triglyceride are measured enzymatically.

HDL cholesterol is measured enzymatically

LDL cholesterol is calculated using Friedewald's formula:

LDL cholesterol = total cholesterol - HDL cholesterol - TG / 2.2

Not valid if TG > 4.5 mmol/l

Apolipoprotein measurement:

Apo A-I, apo B-100 and Lp(a) are measured by protein measuring technique

(RIA, nephelometry, or turbidimetry)

Prevention

Screening for hyperlipidemia should be a part of a routine health evaluation.

Recommendations vary, but usually patients should be screened every two

years, starting sometime between the ages of 20 and 30.

- reduce saturated fats (no more than 30% of total fat intake) and increase
mono- and polyunsaturated fats PUFA are required for the esterification and
final excretion of cholesterol. diet should contain correct type and quantity; the
optimum ratio of omega-6 to omega-3 fatty acids is 4:1. Very high intake of
omega-6 oils will cause lowering of HDL, elevation of plasma triglycerides,
and will promote platelet aggregation
- reduce dietary cholesterol

- reduce excess body weight

- avoid excess alcohol

- avoid excess salt

- increase dietary fibre

Reducing dietary risk factors by maintaining ideal body weight, eating a well

balanced, low fat diet, and limiting cholesterol intake will help prevent the

onset of hyperlipidemia.

Clinical biochemistry second stage Lipid lecture Dr.Thana Alswedy

Lipid Profile - Normal Values

Test

Normal Values

Serum

Cholesterol

American Heart Association

recommendation

Normal upto 200

mgs/dl

Borderline

Upto 239 mgs/dl

Elevated if > 240 mgs/ dl. on repeated values

Serum

Triglycerides

<180 mgs/dl. normal. Values vary depending on

diet, alcohol, metabolic state, exercise etc.

Elevation of values to be considered only if

repeated values are high.

HDL

Cholesterol

30-60 mgs/dl

LDL

Cholesterol

100-190 mgs/dl

Borderline

>190 mgs/dl

Risk

Formula for calculating LDL Cholesterol is

INVALID if TGL> 400 mgs/dl

Total/HDL

ratio

Normal

4-6

Low Risk

> 6

High Risk

Case study

a 49 year old male referred for on-going care after having suffered an cardiac

disease. The notes from the cardiologist states the patient is apparently not

hypercholesterolaemic but is somewhat obese and his father died of a ‘heart

attack’ at 59 years of age. On clinical examination confirm the obesity (BMI =

Clinical biochemistry second stage Lipid lecture Dr.Thana Alswedy

31), the patients BP is 165 /105 mmHg, he admits to smoking between 20 and

30 cigarettes a day until his AMI,.. A fasting cholesterol is 202mg/dl, HDL-C

25mg/dl, trigs 237 mg/dl.

i. Discuss the LP profile in terms of its risk potential and causation.

ii. Discuss the overall risk of the patient.

discussion

Total cholesterol is borderline normal, HDL cholesterol is low and TG is

elevated

This combination of normal total cholesterol, low HDL cholesterol and

elevated TG is a classic “atherogenic” profile which carries a high risk of CAD

Dietary sources of C holesterol

Raises both LDL and HDL

Whole milk, butter, cheese, and ice cream; red meat;

chocolate; coconuts, coconut milk, coconut oil , egg

yolks, chicken skin

Saturated

Raises LDL

M ost margarines; vegetable shortening; partially

hydrogenated vegetable oil; deep-fried chips; many

fast foods; most commercial baked goods

Trans

Lowers LDL, Raises HDL

Corn, soybean, safflower and cottonseed oil; fish

Polyunsaturated

Lowers LDL, Raises HDL

Olives, olive oil, canola oil, peanut oil, cashews,

almonds, peanuts and most other nuts; avocados

Monounsaturated

E ffect on C holesterol

levels

Main Source

Type of F at