TYPES OF HYPOXIA(HYPOXIC,ANEMIC,STAGNANT,HISTOTOXIC,TUMOUR) AND DISSOCIATION CURVES IN THESE STATES G.S.ZAKYNTHINOS 2 nd faculty CharlesUniversity.

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

INADEQUATE O2 SUPPLY TO THE BODY TISSUES

(ENTIRE BODY) OR (LOCALIZED REGION)

HYPOXIA MEANS

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

eventually

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) HYPOXIARESULTS 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 Hypercapnia b)DIFFUSION LIMITATION

(diffusion capacity of lungs decreased by a pulmonary disease)

so

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

Po2(mmHg)

O2

in b

lood

(vol

umes

%)

ARTERIAL(HYPOXIC)HYPOXIA

Arterial Po2 Venous Po2

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

Po2(mmHg)

O2

in b

lood

(vol

umes

%)

STAGNANT(ISCHEMIC)HYPOXIA

Arterial Po2

Venous Po2

BUT

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

Arterial Po2is Normal Venous Po2

but

ANEMIC HYPOXIA

Po2(mmHg)

O2

in b

lood

(vol

umes

%)

Arterial Po2 BUT Venous Po2

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

Po2(mmHg)

O2

in b

lood

(vol

umes

%)

Arterial Po2 Venous Po2 BUT

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.

Tumor blood vessels are highly irregular and disorganized.

Tumours do not get enough O2 and nutrients

THIS IS CAUSED BECAUSE

SO

But tumor cells are usually proliferating

faster than normal cells.

the ability of tumor cells to

sense and adapt to low oxygen (hypoxia)

is essential for tumor growth.

SO

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

Rel

ativ

e H

IF-1

Exp

ress

ion

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)

gradientO2, glucose,growth factors

The oxygen and nutrientsdisplay a gradient awayfrom the necrotic center

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