Team 1 Stanley Oghoghorie - PowerPoint Presentation

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Team 1

Stanley Oghoghorie

Lina

Rajwani

Dinipre

Youdubagha

.

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Lipid Metabolism Disorders

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Definition of Lipid metabolism

Its simply the breakdown or synthesis of lipids in a cell

Lipids are broken down for energy and can be gotten from the diet, stored and synthesized in the liver.

Humans use all three methods to generate lipids as an energy source.

Often begins with hydrolysis, then absorption, packaging and chemical use.

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Normal lipid metabolism

Digestion of fat is the first step. Lipids ingested are almost always triglycerides and need to be broken down by lipase. Digestion starts in the mouth, continues into the stomach and majorly occurs in the small intestine.

Absorption occurs only in the small intestines, and can only happen when the fat has been broken down into smaller units (monoglycerides and fatty acids).

Transportation occurs after absorption of fatty acids. Fatty acids get converted to

tryglycerol

which are further packed into chylomicrons before being transported to

mucle

cells

Lipoproteins are special vehicles that help to transport lipids due to their hydrophobic nature and are classified by density.

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Lipoprotein surrounded by Apolipoproteins, containing triglycerides.

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Lipid metabolism disorders and types.

Any error in the normal process of lipid metabolism can result in a lipid metabolism disorder. Presentation varies extremely and most are due to enzyme deficiencies.

Disorders exist in many, detailed, technical forms but can be grouped into main branches:

Lipid storage disorders

COA dehydrogenase deficiency

Carnitine related deficiency

And Others:

Spinal muscular atrophy, acute fatty liver disease of pregnancy, and hyperlipidemias.

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Lipid storage diseases

Inherited metabolic disorders that cause the accumulation of harmful lipids in cells. Usually caused by enzyme deficiency or malfunction. Most are classified as

sphingolipidoses

and some fall under lysosomal storage diseases. Important types:

Gaucher disease

Nieman Picks disease

Fabry disease

Gangliosidoses

Krabbe

disease

Metachromatic leukodystrophy

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Gaucher disease

Accumulation of

glucoceribroside

in cells due to absence of the

glucoceribrosidase

enzyme responsible for breakdown

Inherited in an autosomal recessive fashion

The

glucoceribroside

accumulates in blood cells (most especially white blood cells and macrophages) and many organs (Especially the liver and spleen

Presents as painless hepatomegaly and splenomegaly, bruising, pancytopenia and osteoporosis. Usually does not present with neurological signs.

Diagnosis is by the clinical picture and can be confirmed by genetic testing and enzyme activity with less than 15% being diagnostic.

Treatment is by enzyme replacement and costs 200,000$

annualy

for IV recombinant

glucoceribrosidase

for life.

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Nieman-Pick Disease

Accumulation of

sphinglomyelin

in the cells due to absence or malfunction of the enzyme sphingomyelinase.

Inherited in an autosomal recessive fashion.

Presents based on organs in which sphingomyelin accumulates.

Hepatosplenomegaly, thrombocytopenia, unsteady gait slurred speech, dysphagia, gradual loss of intellectual abilities.

Diagnosis is by presentation and is classified into Type A, B and C

Tretament

: No treatment but type B can benefit from cholesterol reduction.

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Fabry disease

Rare lipid storage disease inherited in an X-linked manner.

Symptoms typically present in early childhood and get worse as the patient ages.

Caused by deficiency of alpha galactosidase A leading to the accumulation of

globotriaosyl

ceramide.

Presents as generalized body pain, kidney complications which are very common, cardiac complications, anhidrosis and angiokeratomas of the skin.

Diagnosis is by clinical suspicion and enzyme assay to confirm.

Treatment is by ERT with

Fabrazyme

, cost is similar to

gauchers

.

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Gangliosidoses

The most important form is GM2

gangliosidoses

(Tay-

sachs

disease). It is caused by a mutation in the gene coding for the enzyme beta hexosaminidase A which leads to the buildup of GM2 gangliosides in cells. It is inherited in an autosomal recessive fashion.

Classification is based on disease presentation and diagnosis is by genetic testing or measuring blood hexosaminidase A.

Infantile

tay-sachs

- Normal until 6 months, then experiences a severe loss of milestones which then progresses to blindness, deafness, atrophy and death before 4 years of age.

Juvenile

tay

-

sachs

-Presents at 2 to 10 years with cognitive and motor skill deterioration. Death usually occurs before 15

Late onset/Adult

tay

sachs

- Presents in the 30s or 40s with swallowing and speech difficulties, progressive cognitive disfunction and psychiatric illness.

No treatment but can be prevented.

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Krabbe

disease

Occurs due to deficiency of beta galactosidase enzyme leading to the accumulation leading to the accumulation of unmetabolized lipids which causes demyelination and loss of motor skills.

It is inherited in an autosomal recessive fashion. Infants are normal at birth ,symptoms begin between the ages of 3 and 6 months with irritability, fevers, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. In the first stages of the disease, doctors often mistake the symptoms for those of cerebral palsy.

Diagnosis is by characteristic grouping of certain cells (multinucleated globoid cells), nerve demyelination and degeneration, and destruction of brain cells.

No known cure but bone marrow transplant may benefit early in disease course.

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Metachromatic leukodystrophy

A type of leukodystrophy caused by a deficiency in aryl sulfatase a enzyme leading to the accumulation of sulfatides in tissue. It has an autosomal recessive pattern of inheritance and like all leukodystrophies, affects the synthesis of myelin.

In the late infantile form, which is the most common form of MLD, affected children begin having difficulty walking after the first year of life, usually at 15–24 months. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner.

The adult form commonly begins after age 16 often with an onset in the 4th or 5th decade of life and presents as a psychiatric disorder or progressive dementia. Adult-onset MLD usually progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.

No treatment.

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Cherry red spot on the macula as seen in both

tay-sachs

and

nieman

-pick disease

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Beta oxidation

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Steps in beta oxidation

Fatty acid chains can vary they may be classified as very long chain, long chain, medium chain and short chain depending on the length of their carbon.

The first step requires removal of hydrogen atoms from an

acyl

group, the enzyme complex id known as fatty

acyl

coA

dehydrogenase

.

Different enzymes are required to hold fatty acids of different lengths and the deficiencies connected with those proteins are:

Very long chain

acyl

coenzyme A

dehydrogenase

deficiency (VLCAD deficiency)

Long chain 3

hydroxyacyl

coenzyme A

dehydrogenase

deficiency (LCAD deficiency)

Medium chain

acyl

coenzyme A deficiency

dehydrogenase

deficiency (MCAD deficiency)

Short chain

acyl

coenzyme A

dehydrogenase

deficiency (SCAD deficiency)

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MCAD deficiency

Medium chain acyl coenzyme A dehydrogenase deficiency is the most common fatty acid oxidation disorder.

Non ketotic hypoglycemia should suggest a block in hepatic beta oxidation. Hallmarks of MCAD deficiency are:

Profound fasting hypoglycemia

Low or absent ketones

Lethargy, coma and death if untreated

C8-C10 acyl carnitine in blood

Episode may be provoked my overnight fast in an infant

In an older child provoked by illness acauses loss of appetite and vomiting.

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Treatment

Primarily you treat by giving IV glucose

Prevention: frequent feeding, high carbohydrate and low fat diet.

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Myopaththic carnitine acyltransferase CAT/CPT gene

Although all tissues contain mitochondria the most common form of this genetic deficiency is myopathic and due to a defect in muscle specific CAT/CPT gene.

Autosomal recessive condition with late onset

Muscle aches, mild to severe weakness

Rhabdomyolysis, myoglobinuria, red urine

Episode provoked by prolonged exercise especially after fasting, cold or associated stress.

Symptoms may be exacerbated by high fat low carbohydrate diet.

Muscle biopsy shows elevated muscle triglyceride detected as lipid droplets in cytoplasm

Primary treatment : cease muscle activity and give glucose

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Hyperlipidemia

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Elevated lipid (fat) levels in the blood. Hyperlipidemia can be inherited or acquired and increases the risk of disease of the blood vessels leading to stroke and heart disease.

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Atherosclerosis

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Causes of Hyperlipidemia

Diet

Hypothyroidism

Nephrotic syndrome

Anorexia nervosa

Obstructive liver disease

Obesity

Diabetes mellitus

Pregnancy

Obstructive liver disease

Acute hepatitis

Systemic lupus erythematousus

AIDS (protease inhibitors)

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Types of Hyperlipidemia

Primary

Familial hypertriglyceridemia

Familial hypercholesterolemia

Familial combined hyperlipidemia

Familial

dysbetalipoproteinemia

Secondary

Diabetes melitus

Drugs eg. Thiazides, protease inhibitors)

Nephrotic Syndrome

Alcohol

Hypothyroidism

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Dietary sources of Cholesterol

Type of Fat

Main Source

Effect on Cholesterol levels

Monounsaturated

Olives, olive oil, canola oil, peanut oil, cashews, almonds, peanuts and most other nuts; avocados

Lowers LDL, Raises HDL

Polyunsaturated

Corn, soybean, safflower and cottonseed oil; fish

Lowers LDL, Raises HDL

Saturated

Whole milk, butter, cheese, and ice cream; red meat; chocolate; coconuts, coconut milk, coconut oil , egg yolks, chicken skin

Raises both LDL and HDL

Trans

Most margarines; vegetable shortening; partially hydrogenated vegetable oil; deep-fried chips; many fast foods; most commercial baked goods

Raises LDL

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Hereditary Causes of Hyperlipidemia

Familial Hypercholesterolemia

Codominant

genetic disorder,

occurs

in heterozygous form

Occurs in 1 in 500 individuals

Mutation in LDL receptor, resulting in elevated levels of LDL at birth and throughout life

High risk for atherosclerosis, tendon

xanthomas

(75% of patients), tuberous

xanthomas

and

xanthelasmas

of eyes.

Familial Combined

Hyperlipidemia

Autosomal

dominant

Increased secretions of VLDLs

Dysbetalipoproteinemia

Affects 1 in 10,000

Results in

apo

E2, a binding-defective form of

apoE

(which usually plays important role in catabolism of

chylomicron

and VLDL)

Increased risk for atherosclerosis, peripheral vascular disease

Tuberous

xanthomas

,

striae

palmaris

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Checking lipids

Nonfasting lipid panel

measures HDL and total cholesterol

Fasting lipid panel

Measures HDL, total cholesterol and triglycerides

LDL cholesterol is calculated:

LDL cholesterol = total cholesterol – (HDL + triglycerides/5)

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When to check lipid panel

Two different Recommendations

Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP)

Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile consisting of total cholesterol, LDL, HDL and triglycerides

Repeat testing every 5 years for acceptable values

United States Preventative Services Task Force

Women aged 45 years and older, and men ages 35 years and older undergo screening with a total and HDL cholesterol every 5 years.

If total cholesterol > 200 or HDL <40, then a fasting panel should be obtained

Cholesterol screening should begin at 20 years in patients with a history of multiple cardiovascular risk factors, diabetes, or family history of either elevated cholesteral levels or premature cardiovascular disease.

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Goals for Lipids (mg/dL)

LDL

< 100

→Optimal

100-129 → Near optimal

130-159 → Borderline

160-189→ High

≥ 190 → Very High

Total Cholesterol

< 200 → Desirable

200-239 → Borderline

≥240 → High

HDL

< 40

→ Low

≥ 60 → High

Serum Triglycerides

< 150 → normal

150-199 → Borderline

200-499 → High

≥ 500 → Very High

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Determining Cholesterol Goal(LDL)

Look at Risk Factors

Cigarette smoking

Hypertension

(BP

≥

140/90 or on anti-hypertensives)

Low HDL cholesterol

(< 40 mg/dL)

Family History of premature coronary heart disease (CHD)

(CHD in first-degree male relative <55 or CHD in first-degree female relative < 65)

Age

(men

≥ 45, women ≥ 55)

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Determining Goal LDL

CHD Risk Equivalents:

Peripheral Vascular Disease

Cerebral Vascular Accident

Diabetes Mellitus

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LDL Risk Factor Goals

0-1 Risk Factors:

LDL goal is 160

If LDL

≥

160: Initiate TLC (therapeutic lifestyle changes)

If LDL

≥

190: Initiate pharmaceutical treatment

2 + Risk Factors

LDL goal is 130

If LDL

≥ 130: Initiate TLC

If LDL ≥ 160: Initiate pharmaceutical treatment

CHD or CHD Risk Equivalent

LDL goal is 100 (or 70)

If LDL

≥ 100: Initiate TLC and pharmaceutical treatment

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Treatment of Hyperlipidemia

Lifestyle modification

Low-cholesterol diet

Exercise

Reduce Alcohol Intake

Control Diabetes

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Medications for Hyperlipidemia

Drug Class

Agents

Effects (% change)

Side Effects

HMG CoA reductase inhibitors

Lovastatin

20–80 mg/d

Pravastatin

40–80 mg

qhs

LDL (18-55),

 HDL (5-15)

 Triglycerides (7-30)

Myopathy, increased liver enzymes

Cholesterol absorption inhibitor

Ezetimibe

10 mg

qd

 LDL( 14-18),  HDL (1-3)

Triglyceride (2)

Headache, GI distress

Nicotinic Acid

LDL (15-30),

 HDL (15-35)

 Triglyceride (20-50)

Flushing, Hyperglycemia,

Hyperuricemia, GI distress, hepatotoxicity

Fibric Acids

Gemfibrozil

600 mg bid

Fenofibrate

145 mg

qd

LDL (5-20), HDL (10-20)

Triglyceride (20-50)

Dyspepsia, gallstones, myopathy

Bile Acid sequestrants

Cholestyramine

4–32 g/d

 LDL

 HDL

No change in triglycerides

GI distress, constipation, decreased absorption of other drugs

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References

 

"Overview of Lipid Metabolism"

. Merck Manuals Professional Edition. Retrieved 2016-11-01

.

Freifelder

, David (1987). 

Molecular Biology, 2nd edition

. Boston: Jones and Bartlett

.

Arrese

, Estela L.;

Soulages

, Jose L. (2010). 

"INSECT FAT BODY: ENERGY, METABOLISM, AND REGULATION"