TYPES OF HYPOXIA(HYPOXIC,ANEMIC,STAGNANT,HISTOTOXIC,TUMOUR)
AND DISSOCIATION CURVES IN THESE STATES
G.S.ZAKYNTHINOS
2nd faculty CharlesUniversity
TABLE OF CONTENTS
 QUICK DEFINITION
OF HYPOXIA
 SYMPTOMS OF
HYPOXIA
 SIGNS OF HYPOXIA
 TYPES OF HYPOXIA
QUICK DEFINITION OF HYPOXIA
HYPOXIA MEANS
INADEQUATE O2 SUPPLY TO THE BODY
TISSUES
(ENTIRE BODY) OR (LOCALIZED REGION)
SYMPTOMS OF HYPOXIA
• DEPEND ON:
RAPIDITY
AND
SEVERITY
OF THE
DECREASE OF ARTERIAL Po2
1) FULMINANT hypoxia
(Arterial Po2<20mmHg)
(eg.aircraft loses cabin pressure above 30,000 feet and no supplemental O2 available)
Occurs in seconds
Unconsciousness in 15-20 sec
Brain death in 4-5 min
2) ACUTE hypoxia
(25mmHg<Arterial Po2<40mmHg)
(eg.altitudesof 18,000-25,000 feet)
Symptoms similar to those of ethyl alcohol(lack of coordination,slowed
reflexes,overconfidence)
Unconsciousness
Coma and death(in minutes to hours)
if the regulatory mechanisms of the body are inadequate
3) CHRONIC hypoxia
(40mmHg<Arterial Po2<60mmHg)
(eg.at altitudes of 10,000-18,000 feet for extended periods of time)
FOR EXTENDED PERIODS OF TIME!!!
Most clinical causes of hypoxia are in these category
Symptoms similar to those of severe fatigue
DYSPNEA
SHORTNESS OF BREATH
+
RESPIRATORY ARRHYTHMIAS
SIGNS OF HYPOXIA
1. Cyanosis (bluish color of tissue)
caused by more than 5g of deoxyhemoglobin/dl in capillary blood(or less than
13ml O2 per 100ml of blood)
NOT RELIABLE SIGN OF HYPOXIA!!!
ANEMIC PATIENTS never develop
cyanosis but are extremely hypoxic
PATIENTS WITH POLYCYTHEMIA may be
cyanotic but they are perfectly oxygenated
2.
Tachycardia
(peripheral chemoreceptor reflex response to Po2 )
3. Tachypnea and Hyperpnea
(arterial chemoreceptor reflex response to Po2 )
TYPES OF HYPOXIA
ARTERIAL(HYPOXIC) HYPOXIA
RESULTS FROM:
INADEQUATE OXYGENATION OF THE ARTERIAL
BLOOD
CAUSED BY:
1)
Breathing gas with Po2
2)
One or more pathophysiologic mechanisms:
a) HYPOVENTILATION (not adequate alveolar ventilation)
alveolar and arterial Po2
alveolar and arterial Pco2
so
Hypercapnia
b)DIFFUSION LIMITATION
(diffusion capacity of lungs decreased by a pulmonary disease)
c) PHYSIOLOGIC SHUNTS [ VA/Q imbalance particularly VA
so VA/Q ]
most common cause of hypoxia
d) ANATOMIC SHUNTS
(mixing of venous and oxygenated(arterial)blood which dicreases
the Po2)
normally there is an anatomic shunt of about 3% of the cardiac output caused by the mixing
of the oxygenated blood coming from the lungs with the venous blood of bronchial veins before
entering the left atrium
Pathologically is caused by congenital cardiac malformations
diagnosis: arterial Po2<500mmHg when breathing 100% O2
ARTERIAL(HYPOXIC)HYPOXIA
Venous Po2
O2 in blood(volumes %)
Arterial Po2
Po2(mmHg)
STAGNANT(ISCHEMIC) HYPOXIA
RESULTS FROM:
INADEQUATE BLOOD FLOW
entire body
or
localized area
caused by
Congestive heart failure
Arteriosclerosis
Arterial Po2 may be normal BUT because Q (blood flow),tissues withdraw larger
amounts of O2 from the blood ,so, Venous Po2
STAGNANT(ISCHEMIC)HYPOXIA
Arterial Po2
BUT
O2 in blood(volumes %)
Venous Po2
Po2(mmHg)
ANEMIC HYPOXIA
RESULTS FROM:
INSUFFICIENT AMOUNT OF FUNCTIONAL HEMOGLOBIN
CAUSED BY:
1) Deficiency of essential nutrients(iron,B12 vitamin)
2) Blood loss
Patients with Anemic hypoxia have reduced O2 capacity so they have
reduced concentration of O2 in their blood
but
Arterial Po2is Normal
Venous Po2
ANEMIC HYPOXIA
BUT
Venous Po2
O2 in blood(volumes %)
Arterial Po2
Po2(mmHg)
HISTOTOXIC HYPOXIA
RESULTS FROM:
DISABILITY OF CELLS TO USE O2
CAUSED BY:
1) INACTIVATION OF CERTAIN METABOLIC ENZYMES
2) CHEMICAL POISONS
Tissues are unable to use O2 so Venous Po2
HISTOTOXIC HYPOXIA
BUT
Venous Po2
O2 in blood(volumes %)
Arterial Po2
Po2(mmHg)
SUMMARY
TYPE OF
HYPOXIA
Arterial
Po2
Venous
Po2
Arterial
Pco2
Arterial Po2
during exercise
Effect of 100%
O2
ARTERIAL
HYPOXIA
Hypoventilation
Arterial Pco2
Diffusion limitation
Arterial
Po2>600mmHg
Physiologic
shunt
Arterial
Po2>600mmHg
Anatomic shunt
Arterial
Po2<500mmHg
STAGNANT
HYPOXIA
dissolved O2
ANEMIC
HYPOXIA
dissolved O2
HISTOTOXIC
HYPOXIA
dissolved O2
TUMOUR HYPOXIA
1) Hypoxia is widespread in tumors
2) Most human solid tumors have pO2 values lower
than their normal tissues of origin.
THIS IS CAUSED BECAUSE
Tumor blood vessels are highly irregular and
disorganized.
SO
Tumours do not get enough O2 and nutrients
But tumor cells are usually proliferating
faster than normal cells.
SO
the ability of tumor cells to
sense and adapt to low oxygen (hypoxia)
is essential for tumor growth.
What is HIF-1?
HIF-1: Hypoxia Inducible Factor – 1
HIF-1 is a protein with DNA binding activity.
It is composed of two subunits:
HIF-1 and HIF-1.
Where is HIF-1?
It is transcripted in the m-RNA of every cell of the
human body
What does HIF-1 do?
•
Helps normal tissues as well as tumors to survive
under hypoxic conditions
•
HIF-1 is a transcription factor that turns on genes
needed for survival under hypoxic conditions.
•
So far, more than 40 target genes have been found
to be regulated by HIF-1.
•
These genes can be classified into 3 main groups:
HIF-1 Target Genes
Erythropoeitin (EPO)
Nitric oxide synthase 2
(NOS2)
Transferrin
Transferrin receptor
Vascular endothelial
growth factor (VEGF)
VEGF receptor FLT-1
Group 1:
O2 Delivery
Aldolase A
Aldolase C
Enolase 1 (ENO1)
Glucose transporter 1
Glyceraldehyde phosphate
dehydrogenase
Hexokinase 1
Hexokinase 2
Lactate dehydrogenase A
Phosphofructokinase L
Phosphoglycerate kinase 1
Pyruvate kinase M
Group 2:
Glucose
/Energy
Metabolism
Insulin-like growth
factor 2 (IGF-2)
IGF binding protein 1
IGF binding protein 3
p21
p35srj
Group 3:
Cell Proliferation
/Viability
How does HIF-1 do the job?
Oxygen Concentration
HIF-1 expression increases exponentially when O2
HOW DOES HIF-1 HELPS THE TUMOUR
CELL
Among the first responses at the onset of hypoxia
is an increase in the protein levels of
hypoxia-inducible factor-1 (HIF-1)
The oxygen and nutrients
display a gradient away
from the necrotic center
gradient
O2, glucose,
growth factors
An idealized diagram
of a tumor cross section
SUMMARY:
HIF-1 Correlates with Tumor Vascularity
The expression of HIF-1 is positively
correlated with tumor vascularity, indicating HIF-1
plays a crucial role in tumor angiogenesis
progression.
Low oxygen tension is associated with increased
metastasis and decreased survival of patients
REFERENCES
•
NMS PHYSIOLOGY(ed.2000)
•
GUYTON AND HALL MEDICAL PHYSIOLOGY
•
MIN WANG Hypoxia Inducible Factor – 1 (HIF-1):
A High Impact Factor
•
Review Article:Predictive assays for tumour hypoxia: where are we
going?from the 1993 Gray Laboratory Annual Report