? Obesity- Metabolic Syndrome
? Dyslipoproteinemias/Dyslipidemias
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? Fatty Liver
? Atherosclerosis
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? Coronary Heart Diseases? Myocardial Infarction
? Stroke
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Causes of Lipid Associated Disorders? Diseases associated with abnormal lipid
concentrations may be due to:
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?Nutritional Imbalances
?Lifestyle habits
?Genetic abnormalities
?Secondary causes as a consequence of
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other disease
Disorders Of Lipoproteins
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Dyslipoproteinemias/DyslipidemiasTypes Of Lipoprotein Disorders
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HyperlipoproteinemiasAnd
Hypolipoproteinemias
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Dyslipoproteinemias/ Dyslipidemias
? Dyslipoproteinemias can be subdivided
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into two major categories1. Hyperlipoproteinemias
? Hypercholesterolemia
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? Hypertriglyceridemia? Combined Hyperlipoproteinemia
2. Hypolipoproteinemias
Hyperlipoproteinemia
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? Hyperlipoproteinemia is an
abnormal condition
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? With an increased abnormallevels of circulating
Lipoproteins in blood.
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Dyslipidemias
? Dyslipidemias are due to defect in
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Lipoprotein metabolism? May include both excess and deficiency
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of Lipoproteins.? Associated mostly in increase of one or
more Lipid forms in blood circulation.
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Classification OfDyslipidemias
Based On
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Number Of Gene Involvement
Primary Hyperlipoproteinemia
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?Monogenic defect?Polygenic Defect
Monogenic Disorders
vFamilial Hypercholesterolemia
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vHomozygous or Heterozygous
vDefect: inactive LDL receptor
vFamilial Lipoprotein Lipase deficiency
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vDefect: inactive lipoprotein lipase
vFamilial combined Hyperlipidemia
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vDefect: UnknownPolygenic/Multifactorial
? These are commonly
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encountered
vHypercholesterolemia
vHypertriglyceridemia
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Causes Of Dyslipoproteinemias/Dyslipidemias
? Dyslipidemias are generally caused by
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impaired Lipoprotein metabolism :
?Biosynthesis (Increased)
?Transformation and Transport (Improper )
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?Uptake and Utilization (Decreased)Causes of Hyperlipoproteinemia
? Increased formation of Lipoprotein
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? Reduced clearance of LP from circulation? Factors Causing These
? Excessive dietary intake of Carbs and Lipids
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? Biochemical defects in LP metabolism? Deficient Protein to form Apoproteins
? Defect in Enzymes and Proteins Associated to LP
? Defect in Receptors for LP
? Use of drugs that perturb LP formation or
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catabolism
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Secondary Causes Of DyslipidemiasTypes of
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HyperlipoproteinemiasFredrickson Classification
of
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HyperlipoproteinemiaType I
Lipoprotein Lipase Deficiency
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Increased Chylomicrons and
Hyperlipoproteinemia VLDL
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HypertriglyceridemiaType II a Defect in LDL Receptors
Increased LDL levels in blood
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Hyperlipoproteinemia Hyperbetalipoproteinemia
Hypercholesterolemia
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Type II b Increased production of Apo BIncreased production of
Hyperlipoproteinemia VLDL and impaired LDL
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catabolism Increased VLDL and
LDL
Type I I
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Defect in ApoE
Familial Dysbeta Broad Beta Disease
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Lipoproteinemias Increased IDLType IV
Impaired VLDL metabolism.
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Increased VLDL
Hyper-pre-b-
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LipoproteinemiaDue to acquired conditions viz
q Obesity
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q Alcoholism
q Diabetes mel itus
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Increased VLDL andChylomicrons
Due to acquired
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Type V conditions viz
q Obesity
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Combinedq Alcoholism
Hyperlipoproteinemia
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q Diabetes mel itus
Deficiency Of Lipoprotein Lipase
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Leads To
Familial Type I Hyperlipoproteinemia
? Defect in Lipoprotein Lipase activity
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? Does not clear circulatingChylomicrons and VLDL;
? Increases levels of circulating
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Chylomicrons and VLDL
? Associated Hypertriglyceridemia
? This is termed as Familial Type I
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Hyperlipoproteinemia.
Type I Hyperlipoproteinemias
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? Shows a dramatic accumulation (1000mg/dl) of Chylomicrons and VLDL in
plasma
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? Usual y associated withacute abdomen pain due
to acute pancreatitis
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? plasma TAG even in the
fasted state
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Type I I Hyperlipoproteinemia? Familial dysbetalipoproteinemia
? Due to Apo E deficiency
? Associated with
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Hypercholesterolemia &
premature Atherosclerosis
Hypolipoproteinemias
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Hypolipoproteinemias
? Hypolipoproteinemias are
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abnormal conditions? With decreased levels of
circulating Lipoproteins in
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blood.
Conditions Of Hypolipoproteinemias
? Decreased synthesis of
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Lipoproteins
? Deficiency of Lipotropic factors
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required for Lipoproteinbiosynthesis.
Types Of Hypolipoproteinemias
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Familial Hypobetalipoproteinemia?Impairment in synthesis
of Apo B
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?Characterized with low
LDL levels.
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Abeta Lipoproteinemia? Rare disorder
? No synthesis of Apo B (Total
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Absence)
? Absence of LDL (Beta Lipoprotein) in
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blood circulation? Defect in TAG-transfer protein
? Accumulation of TAG in liver
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Familial Alpha Lipoprotein DeficiencyTangiers Disease
? Absence of HDL (Alpha Lipoprotein)
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in blood
? Affects severely Reverse transport
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of Cholesterol? Hypercholesterolemia
? Increased risk of Atherosclerosis and
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its Complications.
Combined Hyperlipoproteinemia
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? Presence of elevated levels of both serumTotal Cholesterol and Triacylglycerols.
? Genetic form of this condition
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?Familial Combined Hyperlipoproteinemia
(FCH)
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?Type V Hyperlipoproteinemia? An accumulation of Cholesterol-rich VLDL
and Chylomicron remnants as a result of
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defective catabolism of those particles
38
Diagnosis And Therapeutic
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Strategy Of Dyslipidemias
A. Identify patients at risk
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1. Routine screening of Serum Lipidprofile
2. Assessment of contributing risk factors
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B. Non-Pharmacologic therapy1. Diet modification
2. Lifestyle modification
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C. Pharmacologic therapy? Lipids and lipoproteins are
important indicators of CHD risk,
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? This is major reason for their
measurement in research, as well
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as in clinical practice.Lipid Profile and Lipoprotein Analyses
Estimation Of Lipid Profile
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? Serum Triacylglycerol? Serum Total Cholesterol
? Serum VLDL
? Serum LDL Cholesterol
? Serum HDL Cholesterol
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Hypertriglyceridemia
? Serum Triacylglycerol
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? Borderline = 150-200 mg/ dl? High 200-500 mg/dl
? Very High > 500 mg/dl
? Familial Hypertriglyceridemia
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? Genetic
? Secondary Hypertriglyceridemia
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? Hormonal imbalances? Imbalance between synthesis and clearance of VLDL
44
Hypertriglyceridemia
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? Generally caused by deficiency of LPL or
LPL cofactor.
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? LPL hydrolyzes TAG in Chylomicrons andVLDL
? Deficiency of LPL prevents processing and
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clearing of Lipoproteins.
? Elevated even with fasting condition.
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45Hypercholesterolemia
? Familial Hypercholesterolemia (FH)
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?Homozygous rare 1/million
?Total cholesterol 800-1000 mg/dl
?Heart attack as early as teenage years
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?Heterozygous cholesterols 300-600
mg/dl
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?Heart attacks 20-50 yearsHypercholesterolemia
? Familial hypercholesterolemia (FH)
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?Primarily LDL elevations?Synthesis is normal but decrease or lack
LDL receptors
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?Therefore LDL builds-up in serum?Since cells cannot acquire from LDL
increase internal synthesis
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LDL Methods? Friedewald Calculation
? VLDL is estimated as TAG/5
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LDL = Total Cholesterol ? HDL ? TAG/5
Lipoprotein Assay Methods
? Separate Lipoprotein Fractions By:
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? Electrophoresis ? Agarose or Polyacrylamide
? Chromatographic
? Precipitation
? Ultracentrifugation
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? ImmunochemicalSerum Triglycerides
Normal
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? Less than 150 mg/dL
Borderline High
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? 150-199 mg/dLHigh
? 200-499 mg/dL
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Very High
? 500+ mg/dL
Serum Total Cholesterol
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Normal
?Less than 200 mg/dL
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Borderline High?200-239 mg/dL
High
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?240 mg/dL or higher
HDL Cholesterol
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Optimal:?60+ mg/dL for both males and females
At Risk for Heart Disease:
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?Women: less than 50 mg/dL
?Men: less than 40 mg/dL
LDL Cholesterol
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Optimal
? Less than 100 mg/dL
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Near or above Optimal? 100-129 mg/dL
Borderline High
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?130-159 mg/dL
High
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?160-189 mg/dLVery High
? 190+ mg/dL
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?Cholesterol Levels of:
?Healthy person = < 200 mg/dl
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?Heterozygous individuals = 300 mg/dl?Homozygous individuals = 680 mg/dl
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Consequences Of
Dyslipoprotein Metabolism
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?Fish Eye Disease
?Fatty Liver
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?Atherosclerosis andits Complications
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Fish Eye DiseaseFatty Liver
Role Of Liver In Lipid Metabolism
? Liver is the Biochemical Factory of
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Human Body.
? Liver plays an important role in
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Lipid metabolism.? Major pathways of Lipid
metabolism are efficiently carried
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out in Liver.
Lipid Metabolism
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At LiverIn Well Fed Condition
? Liver in well fed condition efficiently carries
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out various metabolic pathways of LipidMetabolism.
?De Novo biosynthesis of Fatty acids
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?Triacylglycerol Biosynthesis?Cholesterol Biosynthesis
?Phospholipid Biosynthesis
?Glycolipid Biosynthesis
?VLDL Biosynthesis
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Lipid Metabolism
At Liver
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In Emergency Condition? Liver in emergency condition carries
following metabolic pathways of
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Lipid metabolism efficiently:?Beta Oxidation of Fatty acids
?Ketogenesis
?Bile Acid and Bile Salt Formation
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? Though Liver is predominant site
for Lipid biosynthesis.
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? Liver is not the storage organ forLipids.
?Normally 3-5% of Lipids are
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present in Hepatocytes.? Endogenously biosynthesized
Lipids in Liver are
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? Mobilized out in the form of
VLDL molecule.
? Efficient formation of VLDL
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in Liver
? Does not al ow the excess
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of Lipids to remain in Livertissue.
Fatty Liver/
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Fatty Liver Disease/
Hepatosteatosis
What Is Fatty Liver?
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? Fatty Liver is an abnormal
condition
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? Where there is more than 5% ofLipids retained in Hepatocytes.
What Is Fatty Liver Disease?
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? Fatty Liver disease (FLD), is a reversible
condition of Liver
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? Wherein large vacuoles of Lipidsaccumulate in Liver cel s
? Via the process of Steatosis (Abnormal
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retention of Lipids within a cell)
What Is Steatohepatitis ?
? Progressive inflammation of
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Liver (Hepatitis),
? Due to abnormal accumulation of
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Lipids(Steatosis) is termed asHepatosteatosis/Steatohepatitis
.
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Causes Of Fatty Liver
Clinical Conditions
Leading To Fatty Liver
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OR
Risks For Developing Fatty Liver
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?Defect in Hepatic?Biosynthesis of Lipids
?No Mobilization of
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Endogenously
biosynthesized Lipids in
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Liver?Accumulates Lipids in Liver
? Increased biosynthesis of Lipids than
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the mobilization capacity ,due toincreased Carbohydrates.
? Decreased mobilization of Lipids
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from Liver cells due to decreased
VLDL formation.
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?Deficiency of Lipotropicfactors affects
?The VLDL formation and
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mobilization of Lipids
out of Hepatocytes.
Conditions Leading To Fatty Liver
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? Metabolic Syndrome
?Obesity
?Hypertension
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?Dyslipidemias?Diabetes mel itus
? Alcoholism
? Malnutrition
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(Deficiency of Lipotropic Factors)? Wilsons Disease
? Hepatitis A
? Hepatitis C
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? Hepatotoxic Drugs : MTX, VA,Acetaminophen, TC, Tamoxifen,
Nefidepine, Amiodarone, CCl4 etc
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Lipotropic Factors and Their Role
Adequate Presence of
Lipotropic factor
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Prevents Retention of Lipids
in Liver
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There by preventing Fatty Liver.? Lipotropic Factors are chemical
substances which helps in
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formation of Phospholipids.
? This in turn helps in proper
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formation and mobilization ofVLDL out from Liver.
Names Of Lipotropic Factors
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? Lipotropic Factors are chemicalsinvolved in biosynthesis of
Phospholipids:
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?Choline
?Betaine forms Choline
?Inositol
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Amino Acids As Lipotropic Agents?Glycine
?Serine
?Methionine
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Vitamins As Lipotropic Factors?Vitamin B 12
?Folic Acid
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Types Of Fatty Liver4 Types Of Fatty Liver
? Alcoholic Fatty Liver
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? Non Alcoholic Fatty Liver Disease (NAFLD)? Non Alcoholic Steatohepatitis (NASH)
? Acute Fatty Liver of Pregnancy
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Consequences Of Fatty Liver
? Fatty liver is a reversible condition
and usual y goes away on its own.
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? Generally Fatty liver often has no
symptoms and
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? Does not cause any permanentdamage.
Consequences Of Fatty Liver
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? Constant accumulation ofabnormal excess amount of
Lipids in Hepatocytes
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? Affects the normal Liver
functions
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? Leads to Parenchymal damageto Liver Tissues
? Causes Liver Cirrhosis.
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? Excess of Lipids deposition in Hepatocytes
? Interferes the biochemical functions
? Brings inflammation of Liver (Hepatitis)
? Changes the cytological features
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? Damages the cell components? Causes Liver Fibrosis
? Leads to Liver Cirrhosis
? Liver Carcinoma
Natural History of Fatty Liver Disease
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Fatty liver
Steatohepatitis
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Steatohepatitis + Fibrosis (First Stage of Scar)Steatohepatitis + Cirrhosis
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Cryptogenic Cirrhosis
When there is repeated damage to
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the LiverPermanent scarring of Hepatocytes
takes place
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This is cal ed Liver Cirrhosis
Diagnostic Features
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OF
Fatty Liver Disease
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Laboratory AbnormalitiesIn Fatty Liver Disease
? 2 - 4 fold ALT &
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? Normal Albumin. PT
AST
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? Low ANA + < 1 in 320? AST: ALT Ratio < 1
? Serum Ferritin
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? ALP slight in 1/3
? Iron saturation
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? Dyslipidemia - TAG ? AST: ALT Ratio > 1? FBG and PPBG
if Cirrhosis sets in
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? BUN & Creatinine - N
Fatty liver Normal liver
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