Ivano-Frankivsk

National Medical
University

1. Regulation of lipid metabolism.

2. Classes of lipoproteins.
3. Hyperlipidemias.
4. Atherosclerosis.
5. Complications of
atherosclerosis.
6. Obesity
7. Genetic disorders
8. Fat-soluble
vitamins

Atherosclerosis exceptionally widespread disease. On data WHO,

mortality of the patients in the age 35-44 years for damages of heart and
vessels connected with atherosclerosis, increased lately by 60%.
The knowledge of the reasons
and mechanisms of atherosclerosis
development is necessary for the
doctors of various profession for
prophylaxis and treatment of this
disease.
According to modern notions,
main etiological factors of
atherosclerosis is dyslipoproteinemia
and increased permeability arterial
wall for lipoproteins.

Metabolic Rate - the amount of energy liberated per unit of time.

The amount of energy liberated by the catabolism of food in the body is the same as the amount liberated when
food is burned outside the body.
The energy liberated by catabolic processes in the body is used for maintaining body functions, digesting and
metabolizing food, thermoregulation, and physical activity. It appears as external work, heat, and energy storage:
=
+
+
Isotonic muscle contractions perform work at a peak efficiency approximating 50%:
=
/
Calories
The standard unit of heat energy is the calorie (cal), defined as the amount of heat energy necessary to raise the
ENERGYof 1 g of water 1 degree,
EXTERNAL
ENERGY
HEAT
temperature
from 15 C to 16 C . This unit
is also called the gram calorie, small
calorie,
WORK
STORAGE
or OUTPUT
standard calorie. The unit commonly
used in physiology and medicine
is the Calorie (kilocalorie; kcal), which
equals 1000 cal.

EFFICIENCY

WORK
DONE

TOTAL ENERGY
EXPENDED

Measuring the Metabolic Rate

In determining the metabolic rate, O 2
consumption is usually measured with
some form of oxygen-filled spirometer and
a CO2-absorbing system.
The spirometer bell is connected to a pen
that writes on a rotating drum as the bell
moves up and down. The slope of a line
joining the ends of each of the spirometer
excursions is proportionate to the O 2
consumption.
The amount of O2 (in milliliters) consumed
per unit of time is corrected to standard
temperature and pressure and then
converted to energy production by
multiplying by 4.82 kcal/L of O2 consumed.

 The metabolic rate determined at rest in a room at a

comfortable temperature in the thermoneutral zone 12-14 hours
after the last meal is called the basal metabolic rate (BMR).
This value falls about 10% during sleep and up to 40%
during prolonged starvation. The rate during normal daytime
activities is, of course, higher than the BMR because of
muscular activity and food intake.
The maximum metabolic rate reached during exercise is often
said to be ten times the BMR, but trained athletes can increase
their metabolic rate as much as 20-fold.
The BMR of a man of average size is about 2000 kcal/d.

Fatty acids
and their
derivatives

Sterols (steroid
(
hormones &
cholesterol)

Saturated
(no double
bonds)

Neutral fats
(triglyceride
s)

Lipids

Phospholipids
and related
compounds

Unsaturated (dehydrogenated,
with various numbers of double
bonds)

Composition (%)

Lipoprotein

Size
(nm)

Protein

Free
Cholesteryl
Cholesterol
Esters

Chylomicrons

751000

Chylomicron
remnants

30-80

...

Very low
density
lipoproteins
(VLDL)

30-80

Intermediatedensity
lipoproteins
(IDL)

Triglyceride

Phospholipid

Origin

90

...

...

...

...

Capillaries

16

55

17

Liver and
intestine

25-40

10

25

40

20

VLDL

Low-density
lipoproteins
(LDL)

20

20

46

21

IDL

High-density
lipoproteins
(HDL)

7.5-10

50

16

25

Liver and
intestine

Intestine

 Transports diet-derived triglyceride (TG) in the blood

Composition:
(1) Protein (2%); (2) TG (87%); (3) Cholesterol (CH;3%); (4) Phospholipid (8%)
Synthesized in intestinal epithelium
(1) Requires apolipoprotein (apo) B-48 for assembly and secretion
(2) Nascent chylomicrons in the circulation obtain apo C-Il and apo E from high
density lipoprotein (HDL)
Absent during fasting
If increased, it forms a creamy supranate.
1) Test tube must be left upright in a refrigerator overnight,
2) Chylomicron floats on top of plasma because it has very little protein (low
density).
Source of fatty acids and glycerol
Used to synthesize TG in the liver and adipose
Hydrolysis by capillary lipoprotein lipase (CPL) leaves a chylomicron remnant,
Chylomicron remnants arc removed by apo E receptors in the liver.

Lipoprotein
Chylomicrons

VLDL
IDL
(VLDL
remnants)

Functions

Apoproteins

Transport dietary triglyceride and

cholesterol from intestine to
tissues

apoB-48
apoC-II
apoE

Secreted by intestine
Activates lipoprotein lipase
Uptake of remnants by the
liver

Transports triglyceride from liver

to tissues

apoB-100
apoC-II
apoE

Secreted by liver
Activates lipoprotein lipase
Uptake of remnants (IDL) by
liver

Picks up cholesterol from HDL to

become LDL
Picked up by liver

apoE
apoB-100

Uptake by liver

Delivers cholesterol into cells

ApoB-100

Uptake by liver and other

tissues via LDL receptor
(apoB-100 receptor)

LDL

HDL

Functions

Picks up cholesterol accumulating

in blood vessels
Delivers cholesterol to liver and
steroidogenic tissues via
scavenger receptor (SR-B1)
Shuttles apoC-II and apoE in
blood

apoA-1

Activates lecithin cholesterol

acyltransferase (LCAT) to
produce cholesterol esters

 Transports liver-synthesized TG in the blood

- Requires apolipoprotein B-100 for assembly and secretion
Composition:
(1) Protein (9%); (2) TG (55%); (3) CH (17%); (4) Phospholipid (19%).
Source of fatty acids and glycerol
1) Used to synthesize TG in the adipose tissue
2) Hydrolysis by CPL produces intermediate-density lipoprotein (IDL) and low density lipoprotein (LDL).
3) Some of the IDL is removed from blood by apo E receptors in the liver.
Cholesterol ester transport protein (CETP)
(1) Transfers CH from HDL to VLDL;
(2) Transfers TG from VLDL to HDL;
(3) An increase in VLDL always causes a decrease in HDL-CH.
If increased, it forms a creamy infranate.
Note that the protein is greater in VLDL than in chylomicrons, so it sinks rather than floats in plasma.
TG levels
(1) Optimal level < 150 mg/dL
(2) Borderline high level 150 to 199 mg/dL
(3) High level 200 to 499 mg/dL,
(4) Very high level > 500 mg/dL

 Transports cholesterol in the blood

Derives from continued hydrolysis of IDL
by CPL
Removed from blood by LDL receptors in
peripheral tissue
Composition: 1) Protein (22%); 2) TG
(10%); CH (47%); (4) Phospholipid (21%)
Calculated LDL = CH - HDL - TG/5
1) Presence of chylomicrons falsely lowers
calculated LDL by increasing diet-derived
triglyceride; hence, fasting is required for
an accurate calculated LDL.
2) To reduce the chance for a falsely low
calculated LDL, LDL is directly measured
if the serum TG > 400 mg/dL.
Functions of cholesterol:
1) Component of the cell membrane.
2) Synthesis of vitamin D, adrenal cortex
hormones, bile salts and acids.

Ranges of LDL:
1) Optimal level < 100 mg/dL.
Risk for coronary heart
disease (CHD) markedly
reduced
2) Near optimal level is 100 to 129
mg/dL.
3) Borderline high level is 130 to
159 mg/dL.
4) High level is 160 to 189 mg/dL.
5) Very high level > 190 mg/dL.
Greatest risk for CHD
Fasting is not required for an
accurate serum CH.
Note that the CH content in
chylomicrons is <3%; hence,
fasting does not have a
medically significant effect on
the serum level.

 Good cholesterol
Increased by exercise, wine, estrogen
Composition: 1) Protein (50%); 2) TG (3%; unless VLDL is increased); 3) CH (20%);
4) Phospholipid (27%)
Synthesized by the liver and small intestine
Functions of HDL
1) Source of apolipoproteins for other lipoprotein fractions
2) Removes cholesterol from atherosclerotic plaques
a) Delivers CH from peripheral tissue to the liver
b) CH is either excreted into bile or converted into bile acids/salts.
Measured in the laboratory as HDL-CH

1) Inverse association of levels of HDL-CH and incidence and prevalence of CHD

2) Decreased if VLDL is increased
3) Ranges of HDL-CH

(a) High level (optimal) 60 g/dL

(b) Low level (suboptimal) < 40 mg/dL

4) Fasting is not required for an accurate serum HDL-CH.

Same reason as for serum CH.

 In the body, fatty acids are broken down to acetyl-CoA, which enters the citric acid cycle.
The main breakdown occurs in the mitochondria by -oxidation.
Fatty acid oxidation begins with activation of the fatty acid, a reaction that occurs both inside and
outside the mitochondria.
Medium- and short-chain fatty acids can enter the mitochondria without difficulty, but long-chain
fatty acids must be bound to carnitine in ester linkage before they can cross the inner
mitochondrial membrane.
Carnitine is -hydroxy--trimethylammonium butyrate, and it is synthesized in the body from
lysine and methionine.
A translocase moves the fatty acid-carnitine ester into the matrix space in exchange for free
carnitine.
In the matrix space, the ester is hydrolyzed, making the activated fatty acid molecule available for
-oxidation and providing free carnitine for further exchange.
-Oxidation proceeds by serial removal of two carbon fragments from the fatty acid. The energy
yield of this process is large.

Deficient -oxidation of fatty acids can be

produced by carnitine deficiency or genetic
defects in the translocase or other enzymes
involved in the transfer of long-chain fatty
acids into the mitochondria.
This causes cardiomyopathy.
In addition, it causes hypoketonemic
hypoglycemia with coma, a serious and
often fatal condition triggered by fasting, in
which glucose stores are used up because of
the lack of fatty acid oxidation to provide
energy, and ketone bodies are not formed in
normal amounts because of the lack of
adequate CoA in the liver.

In many tissues, acetyl-CoA units condense to form acetoacetyl-CoA.

acetoacetyl-CoA
In the liver,
liver which (unlike other tissues) contains a deacylase,
deacylase free aceto-acetate is formed.
This -keto acid is converted to -hydroxybutyrate and acetone,
acetone and because these compounds are
metabolized with difficulty in the liver, they diffuse into the circulation.
Acetoacetate is also formed in the liver via the formation of 3-hydroxy-3-methylglutaryl-CoA, and this
pathway is quantitatively more important than deacylation.
Are
Acetoacetate,
Acetoacetate -hydroxybutyrate,
-hydroxybutyrate and acetone are called ketone bodies (KB).
(KB)
osmotic!
Tissues other than liver transfer CoA from succinyl-CoA to acetoacetate and metabolize the "active"
acetoacetate to CO2 and H2O via the citric acid cycle. There are also other pathways whereby ketone
bodies are metabolized.
Acetone is discharged in the urine and expired air.
The normal blood ketone level in humans is low (about 1 mg/dL) and less than 1 mg is excreted per
24 hours, because the ketones are normally metabolized as rapidly as they are formed. However, if the
entry of acetyl-CoA into the citric acid cycle is depressed because of a decreased supply of the products of
glucose metabolism,
metabolism or if the entry does not increase when the supply of acetyl-CoA increases, acetylCoA accumulates, the rate of condensation to acetoacetyl-CoA increases, and more acetoacetate is
formed in the liver.
liver
The ability of the tissues to oxidize the ketones is soon exceeded, and they accumulate in the bloodstream
(ketosis).

KB in the blood
KETONEMIA

pH Acidosis

KB in urine
KETONURIA

Dehydratation

Acetone
breath

80 g TGs

High-fat meal

recommended daily
max

T
G

Cant pass membrane by they

own, they need be divided by
breakdown

Bile (liver)
Pancreatic lipase
Colipase (protects lipase from the bile)

MONOGLICERIDE

2 MG
+
2 FA

INTESTINE

Steatorrhea
Fatty stool (6% of
fats)

TG

LYMP
H

CHYLOMICRO
NS

Via thoracic
duct
Blood
stream

Atherosclerosis is a form of arteriosclerosis

in which thickening and hardening of the
vessel are caused by the accumulation of lipidladen macrophages within the arterial wall,
which leads to the formation of a lesion called a
plaque.
Atherosclerosis is not a single disease but
rather a pathologic process that can affect
vascular systems throughout the body, resulting
in ischemic syndromes that can vary widely in
their severity and clinical manifestations.
It is the leading contributor to coronary artery
and cerebrovascular disease.

Hatiay, a male Egyptian scribe who lived during

the New Kingdom (1570-1293 BCE), enters the CT
scanner. [The Lancet]

Evidence of
carotid artery
disease in
Hatiay

And yet ancient people of

Egypt, Peru, southwest
America, and Alaska
commonly suffered from
hardened arteries, too.
Using CT scans,
researchers examined
the remaining arteries of
137 mummies, and found
signs of probable or
definite atherosclerosis in
34 % of them.

The mummified Egyptians, were likely to have been wealthy, and

therefore probably consumed a lot of saturated fat. This is in fact not the first
time that hardened arteries were identified in Egyptian mummies. And yet
the Unangans, of the Aluetian Islands in Alaska, subsisted almost entirely on
marine life. They, and the other mummies, were preserved naturally through
climate factors, not because they had attained any special status that would
have privileged them with extra-rich foods.
But that ancient people, too, had calcified arteries, "suggests that the
disease is an inherent component of human aging and not necessarily
associated with any specific diet or lifestyle." Indeed, the mummies with
signs of calcification tended to be older, or what in those days counted as
age: they died at around 43 years as opposed to 32. For each decade of life

Role of blood monocytes. Though blood monocytes do

not possess receptors for normal LDL, LDL does appear in
the monocyte cytoplasm to form foam cell. Plasma LDL on
entry into the intima undergoes oxidation. The oxidised
LDL formed in the intima performs the following allimportant functions on monocytes and endothelium:
For monocytes: Oxidised LDL acts to attract, proliferate,
immobilise and activate them as well as is readily taken up
by scavenger receptor on the monocyte to transform it to a
lipid-laden foam cell.
For endothelium: Oxidised LDL is cytotoxic.
Death of foam cell by apoptosis releases lipid to form lipid
core of plaque.

PATHOPHYSIOLOGY

Once injury has occurred, endothelial dysfunction and inflammation

lead to the following pathophysiologic events:
1. Injured endothelial cells become inflamed and
cannot make normal amounts of antithrombotic
and vasodilating cytokines.
2. Numerous inflammatory cytokines are released,
including tumor necrosis factor-alpha (TNF-),
interferongamma (IFN-), interleukin-1 (IL-1), toxic
oxygen radicals, and heat shock proteins.
3. Macrophages adhere to injured endothelium by
way of adhesion molecules, such as vascular cell
adhesion molecule-1 (VCAM-1).
4. These macrophages then release enzymes and
toxic oxygen radicals that create oxidative stress,
oxidize LDL, and further injure the vessel wall.
5. Growth factors also are released, including
angiotensin II, fibroblast growth factor, and
platelet-derived growth factor, which stimulate
smooth muscle cell proliferation in the affected
vessel.

Endothelial Dysfunction in Atherosclerosis

Macrophages play main
role:
1. They have scavengerreceptors so cholesterol
comes in macrophage
only due to concentration
difference.
2. They can accumulate a
lot of Chl inside (this
process is controlled by
HDLP only)
3. Changed LDLP
stimulate macrophages
activity

Ross R. N Engl J Med 1999; 340:115126.

Fatty-Streak Formation in
Atherosclerosis

Ross R. N Engl J Med 1999; 340:115126.

Formation of an Advanced,
Complicated Lesion in
Atherosclerosis

Ross R. N Engl J Med 1999; 340:115126.

Cholesterol and
lisosomal enzymes
irritates intimae
(because they are the
alien bodies)

Excreation of
proliferation factors
by macrophages,
ndotheliocytes,
lymphocytes,
thrombocytes

SMC migration in intimae

and active
proliferation
collagen and elastin
(capsule for
Cholesterol and
injured vessel wall
isolation)

4 stage COMPLICATIONS

1.
THROMBOSIS
(due to endothelium
damage)
2. Ulceration
(necrosis of and
releasing of
lisosomal enzymes
causes damage of
plaque wall)
3. Calcinations
(deposit of insoluble
calcium salts)

LDL Particles Promote Atherogenesis

Particle
Particle Movement
Movement into
into Intima
Intima

Gradient
Gradient driven
driven

Enhanced
Enhanced
Endothelial
Endothelial
Dysfunction
Dysfunction

The
The rate
rate of
of passive
passive diffusion
diffusion is
is
increased
when
the
circulating
increased when the circulating
levels
levels of
of LDL
LDL are
are elevated.
elevated. 11
Adhesion
molecules

PAI-1 MCP-1

Colonystimulating
factors

Mildly modified LDL

Tissue
factor

Monocyte

Lumen

Endothelial cells

Intima

Extensively modified LDL

Particle
Particle Retention
Retention

Particle
Particle Oxidation
Oxidation

Lipoprotein
Lipoprotein particle
particle
binding
to
proteoglycans
binding to proteoglycans

Particle
Particle Uptake
Uptake by
by
Macrophage
Macrophage

1 Weissberg

PL, Rudd JH. Textbook of Cardiovascular Medicine. 2002. p. 6.

Cholesterol
Cholesterol Deposition;
Deposition;
Increased
Increased Plaque
Plaque Burden
Burden

The clinical effects of atherosclerosis depend

upon the size and type of arteries affected. In
general, the clinical effects result from the
following:
1. Slow luminal narrowing causing ischaemia
and atrophy.
2. Sudden luminal occlusion causing
Major sites of atherosclerosis (serially
infarction necrosis.
numbered) in descending order of frequency.
3. Propagation of plaque by formation of
thrombi and emboli.
4. Formation of aneurysmal dilatation and
eventual rupture.
Accordingly, the symptomatic atherosclerotic
disease involves most often the heart, brain,
kidneys, small intestine and lower extremities
The effects pertaining to these organs are:
1) AortaAneurysm
formation, thrombosis and
Aorta
embolisation to other organs.
2) HeartMyocardial
infarction, ischaemic heart
Heart
disease.
3) BrainChronic ischaemic brain damage,
cerebral infarction.
4) Small intestineIschaemic
bowel disease,
intestine
infarction.
5) Lower extremitiesIntermittent
claudication,
extremities
gangrene.

Clinical Effects

or dyslipoproteinemia refers to abnormal

concentrations of serum lipoproteins

It is estimated that nearly half of the U.S. population has

some form of dyslipidemia, especially among white and
Asian populations. These abnormalities are the result of a
combination of genetic and dietary factors.
Primary or familial dyslipoproteinemias result from genetic
defects that cause abnormalities in lipid-metabolizing
enzymes and
abnormal cellular lipid receptors.
Secondary causes of dyslipidemia include several
common systemic disorders, such as diabetes,
hypothyroidism, pancreatitis, and renal nephrosis, as well
as the use of certain medications such as certain diuretics,
beta-blockers, glucocorticoids, interferons, and
antiretrovirals.
Optimal

Near Optimal Desirable

Total cholesterol
LDL
Triglycerides
HDL

<100

Low

Borderline

High

<200

200-239

240

<150

130-159
150-199

160-189
200-499
60

100-129
<40

Very High

190
500

Name
Type I: exogenous
hyperlipidemia;
fat-induced
hypertriglyceridemia

Laboratory Findings

Clinical Features

Therapy

Abdominal pain
Cholesterol normal
Hepatosplenomegaly
Triglycerides increased
Skin and retinal lipid
Low-fat diet
three times
deposits
Chylomicrons increased
Usual onset: childhood

Triglycerides normal
Type IIa:
LDL increased
hypercholesterolemia
Cholesterol increased

Premature vascular
disease
Xanthomas of tendons
and bony prominences
Common
Onset: all ages

Type IIb: combined

LDL, VLDL increased
hyperlipidemia;
Cholesterol increased Same as IIa
carbohydrate-induced
Triglycerides increased
hypertriglyceridemia

Low-saturated-fat and lowcholesterol diet

Cholestyramine (a); Colestipol (b);
Lovastatin (c); Nicotinic acid (d) ;
Neomycin (e).
Intestinal bypass
Same as IIa; plus carbohydrate
restriction
Clofibrate (f); Gemfibrozil (g)
Lovastatin

a) Cholestyramine (Questran), anion exchange resin; binds bile acids; enhances cholesterol excretion.
b) Colestipol (Colestid), same as cholestyramine.
c) Lovastatin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor; decreases cholesterol synthesis in
the liver.
d) Nicotinic acid (niacin), decreases release of free fatty acids from adipose tissue; increases lipogenesis in liver;
decreases glucagon release; most effective for type V disorder.
e) Neomycin, experimental medication; questionable mode of action; decreases LDLs.
f) Clofibrate (Atromid-S), decreases release of free fatty acids from adipose tissue; decreases hepatic secretion of VLDL
and increases catabolism of VLDL.
g) Gemfibrozil (Lopid), similar to clofibrate but increases HDLs more.

Name

Laboratory Findings
IDL or chylomicron
remnants increased
Cholesterol increased

Clinical Features
Premature vascular
disease
Xanthomas of tendons
and bony prominences
Uncommon
Onset: adulthood

Therapy
Weight control
Low-carbohydrate, lowsaturated-fat, and
low-cholesterol diet
Alcohol restriction
Clofibrate; Gemfibrozil;
Lovastatin; Nicotinic acid;
Estrogens (h)
Intestinal bypass

Type III:
dysbetalipoproteinemia

Triglycerides increased

Type IV: endogenous

hyperlipidemia;
carbohydrate-induced
hypertriglyceridemia

Glucose intolerance
Hyperuricemia
Cholesterol normal or
increased
VLDL increased
Triglycerides increased

Premature vascular
disease
Skin lipid deposits
Obesity
Hepatomegaly
Common onset: adulthood

Weight control
Low-carbohydrate diet
Alcohol restriction
Clofibrate; Nicotinic acid
Intestinal bypass

Type V: mixed
hyperlipidemia;
carbohydrate and fatinduced
hypertriglyceridemia

Glucose intolerance
Hyperuricemia
Chylomicrons increased
VLDL increased
LDL increased
Cholesterol increased
Triglycerides increased
three times

Abdominal pain
Hepatosplenomegaly
Skin lipid deposits
Retinal lipid deposits
Onset: childhood

Weight control
Low-carbohydrate and
low-fat diet
Clofibrate; Lovastatin;
Nicotinic acid;
Progesterone (i)
Intestinal bypass

(h) Estrogens, decrease IDL levels in type III disorders; experimental.

(i) Progesterone, decreases plasma triglycerides in type V disorders; experimental.

a. Epidemiology
1) Autosomal recessive
2) Rare childhood disease
b. Pathogenesis
1) Deficiency of CPL or
2) Deficiency of apo C-ll
c. Clinical findings
1) Chylomicrons are primarily increased
in early childhood.
2) VLDL increases later in life.
3) Presents with acute pancreatitis
Pancreatic vessels filled with
chylomicrons rupture.
d. Laboratory findings
1) Increase in serum TG > 1000 mg/dL
(primarily chylomicrons)
2) Turbid supranate (chylomicrons) and
clear infranate (early childhood)
3) Normal (usual case) to moderately
increased serum CH

A: Lateral borders of thickened

Achilles' tendons are shown with
arrows.
B: Tendinous xanthomas can also
occur in the extensor tendons of
the hands (shown), feet, elbows
and knees.
C: Xanthelasmas are cholesterol
deposits in the eyelids.
D: Arcus cornealis results from
cholesterol infiltration around the
corneal rim (arrow).

a. Laboratory findings
1) Serum LDL > 190 mg/dL
2) Serum CH > 260 mg/dL
a) Serum TG < 300 mg/dL (called type IIa)
b) Serum TG > 300 mg/dL (called type lIb)
b. Pathogenesis
Decreased synthesis of LDL receptors.
c. Acquired causes of hypercholesterolemia
1) Primary hypothyroidism
Decrease in LDL receptor synthesis or
function
2) Nephrotic syndrome
Increase in LDL correlates with the degree of
hypoalbuminemia
3) Extrahepatic cholestasis (obstruction of bile)
Bile contains CH for excretion
d. Familial hypercholesterolemia
1) Autosomal dominant (AD) disorder
2) Deficiency of LDL receptors
3) Clinical findings

a) Premature coronary- artery- disease and

stroke
b) Tendon xanthomas

Cholesterol deposit located over tendons

(e.g. Achilles) and extensor surfaces of joints
c) Xanthelasma
Yellow, raised plaque on the eyelid
e. Polygenic hypercholesterolemia (type Ila)
1) Most common hereditary cause (85% of
cases)
2) Multifactorial (polygenic) inheritance
3) Alteration in regulation of LDL levels
4) Normal serum TG
f. Familial combined hypercholesterolemia
(type lIb)
1) AD inheritance.
2) Serum CH and TG begin to increase around
puberty.
3) Associated with metabolic syndrome.
4) Increase in CH and TG and decrease in HDL.

Laboratory findings
1) Serum CH and TG > 300 mg/L
2) Serum CH 250 to 500 mg/dL
3) LDL< 190 mg/dL
Familial dysbetalipoproteinemia ("remnant disease")
1) AD inheritance
2) Deficiency of apo E
3) Decreased liver uptake of chylomicron remnants and IDL
Clinical findings
1) Palmar xanthomas in flexor creases
2) Increased risk for coronary artery disease
3) Increased risk for peripheral vascular disease (unlike type II disorders)
Laboratorv findings
1) Serum CH and TG > 300 mg/dL
2) Serum CH 250 to 500 mg/dL
3) LDL< 190 mg/dL
4) Confirm diagnosis with ultracentrifugation to identify remnants
Lipoprotein electrophoresis and identification of apo E gene defect are other studies
that can be used.
Treatment
Fibric acid derivatives

Laboratory findings
1) Serum TG > 300 mg/dL; 2) Serum CH 250 to 500 mg/dL; 3) Serum LDL < 190 mg/dL;
4) Turbid infranate after refrigeration
Increase in VLDL - due to increase in synthesis or decrease in catabolism
Acquired causes of hypertriglyceridemia
1) Excess alcohol intake
2) Oral contraceptives - estrogen increases synthesis of VLDL
3) Diabetes mellitus - decreased muscle and adipose CLP
4) Chronic renal failure - increased synthesis of VLDL
5) Thiazides, -blockers - possible inhibition of CPL
Familial hypertriglyceridemia
1) Autosomal dominant disorder
2) Clinical findings
a) Eruptive xanthomas - yellow, papular lesions
(b) Increased risk for coronary artery- and peripheral
vascular disease

Tubero-eruptive

a. Pathogenesis
1) Increase in chylomicrons and VLDL
2) Due to decreased activation and release of CPL
b. Familial hypercholesterolemia (type IV) + exacerbating disorder
Exacerbating disorders diabetic ketoacidosis (DKA: most common),
alcohol
c. Increased serum TG > 1000 mg/dL; normal CH and LDL.
d. Turbid plasma
1) Supranate after refrigeration, due to increased chylomicrons
2) Infranate after refrigeration, due to increased VLDL.
e. Hyperchylomicronemia syndrome
1) Eruptive xanthomas
2) Increased incidence of acute pancreatitis
3) Lipemia retinalis - retinal vessels look like milk: blurry vision
4) Dyspnea and hypoxemia - impaired gas exchange in pulmonary
capillaries
5) Hepatosplenomegaly
6) Increase in serum TG (usually >1000 mg/dL)
7) Normal serum CH and LDL
8) Turbid supranate and infranate after refrigeration
f. Treatment
(1) Treat exacerbating disorder (e.g.. DKA)
(2) Nicotinic acid or fibric acid derivatives

Apolipoprotein B deficiency
(abetalipoproteinemia)
a. Autosomal recessive
b. Deficiency of apolipoprotein B-48 and B-100
(1) Deficiency of chylomicrons, VLDL and LDL
(2) Decrease in serum CH and TG
c. Clinical findings
1) Malabsorption
a) Chylomicrons accumulate in villi and prevent
reabsorption of micelles.
b) Marked decrease in vitamin E
2) Ataxia (spinocerebellar degeneration),
hemolytic anemia with thorny RBCs
(acanthocytes) related to vitamin E deficiency.
d. Treatment - vitamin E

Obesity an excess of adipose tissue that imparts health

risk; a body weight of 20% excess over ideal weight for age,
sex and height is considered a health risk.

Body mass index (BMI) which is equal to weight in

kg/height in m2

1. Body mass index (BMI)

> 30kg/m2 (normal, 19.5-24.9kg/m2)
1) Excess fat in the waist and flanks is more
important than an excess in the thighs and
buttocks.
2) Excess visceral fat in the abdominal
cavity has greater significance than excess
subcutaneous fat.
Magnetic resonance imaging is used to
access the amount of visceral fat.

ETIOLOGY
Obesity results when caloric intake

exceeds utilisation.
The imbalance of these two
components can occur in the
following situations:

1. Inadequate pushing of oneself away from the dining table causing

overeating.
2. Insufficient pushing of oneself out of the chair leading to inactivity and
sedentary life style.
3. Genetic predisposition to develop obesity.
4. Diets largely derived from carbohydrates and fats than protein-rich diet.
5. Secondary obesity may result following a number of underlying diseases
such as hypothyroidism, Cushings disease, insulinoma and hypothalamic
disorders.

Hormones (Adipokines)
(Adipokines
Leptin
Satiety (hunger/appetite
suppression) and regulation of eating
behavior by hypothalamus
Sympathoactivation
Insulin sensitizing
Modulating role in reproduction,
angiogenesis, immune response,
blood pressure control, and
osteogenesis
Adiponectin
Insulin sensitizing
Anti-inflammatory
Anti-atherogenic
Resistin
Promotes insulin resistance and
increased blood glucose levels
Inhibits adipocyte differentiation
and may function as a feedback
regulator of adipogenesis
Visfatin (from visceral fat)
Mimics insulin and binds to insulin
receptors in rats
Vaspinmay be insulin sensitizing

Regulators of Lipoprotein
Metabolism

Lipoprotein lipase
Apolipoprotein E
Cholesterol ester transfer
protein

Inflammatory
Cytokines

Tumor necrosis factor-alpha

Interleukins (IL-6, IL-8, IL-10)
Plasminogen activator inhibitor-1
Monocyte chemoattractant protein-1

Other Hormones and

Cytokines
Estrogen
Angiotensinogen
Tissue factor
Transforming growth factor-beta
Insulin-like growth factor
Nitric oxide synthase
Acylation stimulating protein
Adipophilin
AdipoQ
Monobutyrin
Agouti protein

 Regulation of appetite and satiety occurs through

neuroendocrine regulation of eating behavior, energy

metabolism, and body fat mass. The system is complex and
controlled by a dynamic circuit of signaling molecules from the
periphery acting on central controls including the brain stem,
hypothalamus, and autonomic nervous system. An imbalance in
this system is usually associated with excessive caloric intake in
relation to exercise with the consequence of weight gain and
obesity.
The arcuate nucleus (ARC) in the hypothalamus has two sets
of neurons with opposing effects that interact to regulate and
balance food intake and energy metabolism.
One set of neurons produces neuropeptide Y (NPY) and
agoutirelated protein (AGRP), which stimulates eating
and decreases metabolism (anabolic).
Another set of neurons synthesizes pro-opiomelanocortin
(POMC)-producing peptide and cocaineand-amphetamineregulated transcript (CART), collectively known as
POMC/CART neurons. They inhibit eating and increase
metabolism (catabolic).
Both sets of neurons express their effects by activating secondorder neurons in the hypothalamus, which increases or
decreases appetite and energy metabolism.

 Fat cell mass

[Leptin/insulin]
expression
[Leptin/insulin] action in
hypothalamus

NPY/AGRP
neurons

Arcuate
nucleus

NPY/AGRP
expression
NPY release

AGRP release

Food intake
Sympathetic activity
Catabolism

POMC/CART
neurons

-MSH expression
and release

Paraventricul
ar
nucleus

CART

-MSH binding and

activation of melanocortin
MC4R receptors
Food intake
Energy expenditure

Leptin and insulin normally decrease appetite, increase satiety, and increase energy expenditure (catabolism).
Leptin/insulin inhibits NPY/AGRP gene expression resulting in decreased appetite and food intake; and
stimulates POMC/CART gene expression with resulting -MSH release and decrease in appetite and food
intake. With leptin resistance as occurs in obesity, these effects are depressed and food intake increases in
excess of energy expenditure. AGRP, agouti-related peptide; -MSH, alpha-melanocyte stimulating hormone;
NPY, neuropeptide Y; POMC/CART, proopiomelanocortin/cocaine-and-amphetamine-related transcript

molecules that stimulate eating

Neuropeptide Y
(NPY)
Melaninconcentrating hormone
(MCH)
Agouti-related
protein (AGRP)
Ghrelin
Galanin
Orexins A and B
Peptide YY (PYY)

molecules that inhibit

eating

Leptin
Insulin
Cholecystokinin (CCK)
Corticotropin-releasing
hormone (CRF)
Urocortin (a CRF satiety
signaling hormone)
Cocaine- and
amphetamine-regulated
transcript (CART)
Alpha-melanocytestimulating hormone (-MSH)
Bombesin
Serotonin

Ghrelin is produced by the stomach in response to hunger and stimulates

food intake and induces metabolic changes leading to an increase in body
weight and body fat mass. Ghrelin also stimulates release of growth hormone
(GH) from anterior pituitary cells, the release of gastric acid and gastric
motility, and affects pancreatic functions. It has vasodilatory, cardioprotective,
and antiproliferative effects.
Adiponectin has insulin-sensitizing properties and plasma levels decrease
with visceral obesity, contributing to insulin resistance, cardiovascular disease,
and metabolic syndrome.
Obese individuals, particularly those with expansion of visceral adipose
tissue, are at increased risk for coronary artery disease resulting from
hyperlipidemia, hypertension, and factors that promote thrombosis and
inflammation.
Decreased adiponectin levels are associated with increased levels of
inflammatory markers, such as IL-6 and TNF-.
Adiponectin may serve as an anti-inflammatory and anti-atherogenic plasma
protein and may have an important role in vascular remodeling that is limited
with obesity.
Obesity is associated with insulin resistance, which predisposes an individual
to type 2 diabetes mellitus. The insulin resistance may be related to an
insulin receptor defect or to postreceptor effects with alteration in glucose
transporter functions. Excess insulin also may be a response to excessive
caloric intake.
Resistin is greatly increased in those with obesity and may be an antagonist
to insulin action and a mediator of inflammation.

Pathogenesis

a. Genetic factors account for 50% to 80% of eases.

Examplesdefects in the leptin gene, syndrome X (obesity,

hypertension, diabetes)
b. Acquired causes
(1) Endocrine disordershypothyroidism, dishing syndrome
(2) Hypothalamic lesions, menopause
c. Leptin
1) Leptin is a hormone.
a) Secreted by adipose tissue
b) Maintains energy balance (intake and output)
2) Leptin increases when adipose stores are adequate.
a) Decreases food intake (inhibits satiety center)
b) Increases energy expenditure (stimulates ( -oxidation of
fatty- acids)
3) Leptin decreases when adipose stores are inadequate.
a) Increases food intake (stimulates the satiety center)
b) Decreases energy expenditure (inhibits -oxidation of
fatty acids)
4) Obesity related to leptin dysfunction may be caused by the
following;
a) Resistance to leptin effects
b) Mutations resulting in inhibition of leptin release

 1. Hyperinsulinaemia. Increased
insulin secretion is a feature of
obesity. Many obese individuals exhibit
hyperglycaemia or frank diabetes despite
hyperinsulinaemia. This is due to a state
of insulin-resistance consequent to
tissue insensitivity.
2. Type 2 diabetes mellitus. There
is a strong association of type 2
diabetes mellitus with obesity. Obesity
often exacerbates the diabetic state and
in many cases weight reduction often
leads to amelioration of diabetes.
3. Hypertension. A strong
association between hypertension
and obesity is observed which is perhaps
due to increased blood volume. Weight
reduction leads to significant reduction
in systolic blood pressure.

4. Hyperlipoproteinaemia. The plasma

cholesterol circulates in the blood as lowdensity lipoprotein (LDL) containing most of
the circulating triglycerides. Obesity is strongly
associated with VLDL and mildly with LDL.
Total blood cholesterol levels are also
elevated in obesity.
5. Atherosclerosis. Obesity predisposes to
development of atherosclerosis. As a result
of atherosclerosis and hypertension, there is
increased risk of myocardial infarction and
stroke in obese individuals.
6. Nonalcoholic fatty liver disease
(NAFLD). Obesity contributes to
development of NAFLD which may progress
further to cirrhosis of the liver.
7. Cholelithiasis. There is six times higher
incidence of gallstones in obese persons,
mainly due to increased total body
cholesterol.

 8. Hypoventilation syndrome (Pickwickian

syndrome). This is characterised by

hypersomnolence, both at night and during day
in obese individuals along with carbon dioxide
retention, hypoxia, polycythaemia and
eventually right-sided heart failure. (Mr Pickwick
was a character, the fat boy, in Charles Dickens
Pickwick Papers. The term pickwickian
syndrome was first used by Sir William Osler for
the sleepapnoea syndrome).
9. Osteoarthritis. These individuals are more
prone to develop degenerative joint disease
due to wear and tear following trauma to joints
as a result of large body weight.
10. Cancer. Diet rich in fats, particularly
derived from animal fats and meats, is
associated with higher incidence of cancers of
colon, breast, endometrium and prostate.

CLINICAL FINDING

COMMENTS

Cancer

Increased incidence of estrogen-related cancers (e.g., endometrial, breast)

because of increased aromatization of androgens to estrogens in adipose tissue

Cholelithiasis

Increased incidence of cholecystitis and cholesterol stones: bile is

supersaturated with cholesterol

Diabetes mellitus,
type 2

Increased adipose downregulates insulin receptor synthesis

Hyperinsulinemia increases adipose stores
Weight reduction upregulates insulin receptor synthesis

Hepatomegaly

Fatty change accompanied by liver cell injury and repair by fibrosis

Hypertension

Hyperinsulinemia increases sodium retention, leading lo increase in plasma

volume
Left venlricular hypertrophy and stroke complicate hypertension
Hypertriglyceridemia decreases serum high-density lipoprotein levels,

Hypertriglyceridemia
increasing risk of coronary artery disease

Increased low-density
Hypercholesterolemia predisposes lo coronary artery disease
lipoprotein levels
Obstructive sleep
apnea

Weight of adipose tissue compresses upper airways causing respiratory

acidosis and hypoxemia
Potential for developing cor pulmonale (pulmonary hypertension and right
ventricular hypertrophy)

Osteoarthritis

Degenerative arthritis in weight-bearing joints (e.g., femoral heads)

Prader-Willi syndrome (PWS) is a single gene imprinting disorder

(Psora/ Syphilis) caused by defects in chromosome 15. These defects
may be of two types:
1. Paternally inherited deletion or disruption of genes in the proximal arm
of chromosome 15. (Syphilis)
2. Maternal disomy in the proximal arm of chromosome 15. (Psora)
Related words
Cryptorchidism-dwarfism-subnormal mentality; hypogenital dystrophy
with diabetic tendency; hypotonia-hypomentia-hypogonadism-obesity
syndrome; Labhart-Willi syndrome; Prader-Labhart-Willi Fancone
syndrome; Willi-Prader syndrome.
Historical Background
The first patient with Prader-Willi syndrome was described by Langdon-Down In
1887 as an adolescent girl with mental impairment (Psora), short stature (Psora),
hypogonadism (Psora), obesity (Psora). He called these symptoms to polysarcia.
In 1956, Prader et al reported some patients with similar phenotypes.
In 1981, Ledbetter et al identified microdeletions (Syphilis) within chromosome 15
and determined it to be the site for Prader-Willi syndrome.

Pathophysiology
Prader-Willi syndrome is the first
human disorder recognized to
genomic imprinting. In such
disorders, genes are expressed
differentially based on the parent of
origin. It results from the loss of
imprinted genomic material within
the paternal 15q11.2-13 locus.
The loss of maternal genomic
material (Syphilis) at the 15q11.2-13
locus results in Angelman
syndrome.
Most cases of Prader-Willi
syndrome that involve deletions
(Syphilis), unbalanced
translocations (Psora), and
uniparental (maternal) disomy
(Psora) are sporadic.

Children
Hyperphagia (Psora) with
progressive development of obesity
(Psora).
Short stature (Psora) with lack of
pubertal growth shot (Syphilis).
Sleep disturbances (Psora),
obstructive sleep apnea and
narcolepsy (Psora).
Growth hormone deficiency (Psora).
Premature growth of pubic and
axillary hair (Psora) but other
features of Prader-Willi syndrome are
Testicular descent late (Psora) ; menarche
maydelayed
occur as
as age 30
usually
orlate
incomplete.
(Psora).
Features of psychosis and behavioural problems- temper outbursts (Psora),
stubborn (Psora), and obsessive-compulsive behaviour (Psora), eating
garbage (Psora) and frozen food (Psora), and stealing resources to obtain
food (Psora) leading to gastric complications, gastric necrosis (Psora/Syphilis)
and even death.
Mild mental retardation (Psora).

SPINGOLIPIDS.
DISORDERS
Classes of sphingolipids and their hydrophilic groups include:
Sphingomyelin: phosphorylcholine
Cerebrosides: galactose or glucose
Gangliosides: branched oligosaccharide chains terminating in
the 9-carbon sugar, sialic acid (N-acetylneuraminic acid,
NANA)
Sphingolipids released when membrane is degraded are
digested in endosomes after fusion with lysosomes.
Lysosomes contain many enzymes, each of which removes
specific groups from individual sphingolipids. Genetic
deficiencies of many of these enzymes are known, and the
diseases share some of the characteristics of I-cell disease.

Disease

Lysosomal
Enzyme Missing

Substrate
Accumulating in
Inclusion Body

Symptoms

Tay-Sachs

Hexosaminidase A

Ganglioside GM2

Cherry red spots in

macula; blindness

Glucocerebrosidase

Type 1: Adult
Hepatosplenomegaly
Erosion of bones,
fractures; Pancytopenia or
Glucocerebroside
thrombocytopenia;
Characteristic
macrophages (crumpled
paper inclusions)

Gaucher

NiemannPick

Sphingomyelinase

Sphingomyelin

Cherry red spot in macula

Hepatosplenomegaly,
Microcephaly, severe
mental retardation; Zebra
bodies in inclusions;
Characteristic foamy
macrophages; Early death

The bright light at right enters through the pupil of the

eye; at left, the red spot in diagnosis of
Tay-Sachs disease

Adult onset Niemann-Pic

k disease type C presen
ting with psychosis

Vitamin

EFFECTS OF DEFICIENCY

EFFECTS OF TOXICITY

Ocular lesions: night blindness, xerophthalmia - dry and

scaly scleral conjunctiva; keratomalacia - corneal ulcers
may occur which may get infected; Bitots spots - focal
triangular areas of opacities due to accumulation of
keratinised epithelium; blindness - squamous metaplasia
of corneal epithelium)
Cutaneous lesions: xeroderma - the skin develops
papular lesions giving toad-like appearance, due to
follicular hyperkeratosis and keratin plugging in the
sebaceous glands;
Other lesions: squamous metaplasia of respiratory
epithelium, pneumonia; urothelium and pancreatic ductal
epithelium, subsequent anaplasia; retarded bone growth;
renal calculi

Papilledema and seizures (due to

an increase In intracranial
pressure), hepatitis, bone pain (due
to periosteal proliferation)

Retinol

D
Calcitriol

Pathologic fractures, excess osteoid, bow legs

Children: rickets; craniotabes (soft skull bones); rachitic
rosary (defective mineralization and overgrowth of
Hypercalcemia with metastatic
epiphyseal cartilage in ribs)
calcification, renal calculi
Adults: called osteomalacia
Continuous muscle contraction (hypocalcaemic tetany)

Vitamin

EFFECTS OF DEFICIENCY

Hemolytic anemia (damage to RBC membrane), reduced red cell

lifespan;
E
Peripheral neuropathy, degeneration of posterior column (poor joint
Tocophe- sensation) and spinocerebellar tract (ataxia), retinal pigments,
rol
degeneration axons of peripheral nerves; denervation of muscles
Sterility in male and female animals

Newborns: Hypoprothrombinaemia in hemorrhagic disease of newborn

(CNS bleeding, ecchymoses);
Adults: gastrointestinal bleeding, ecchymoses; prolonged prothrombin
time and partial thromboplastin time
biliary obstruction - bile is prevented from entering the bowel due to
biliary obstruction which prevents the absorption of this fat-soluble
vitamin. Surgery in patients of obstructive jaundice, therefore, leads to
marked tendency to bleeding.
malabsorption of fat develop vitamin K deficiency e.g. coeliac
disease, sprue, pancreatic disease, hypermotility of bowel etc.
anticoagulant therapy - patients on warfarin group of anticoagulants
have impaired biosynthesis of vitamin K-dependent coagulation factors.
antibiotic therapy - the use of broad-spectrum antibiotics and sulfa
drugs reduces the normal intestinal flora.
diffuse liver disease - (e.g. cirrhosis, amyloidosis of liver,
hepatocellular carcinoma, hepatoblastoma) have
hypoprothrombinaemia due to impaired synthesis of prothrombin.
Administration of vitamin K to such patients is of no avail since liver,
where prothrombin synthesis utilising vitamin K takes place, is
diseased.

EFFECTS OF TOXICITY
Decreased synthesis of
vitamin K-dependent
procoagulant factors;
synergistic effect with
warfarin anticoagulation

Hemolytic anemia and

jaundice in newborns if
mother receives excess
vitamin K

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Brashers, Neal S. Rote - 6th ed. 2010.
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