TYPES OF HYPOXIA(HYPOXIC,ANEMIC,STAGNANT,HISTOTOXIC,TUMOUR) AND DISSOCIATION CURVES IN THESE STATES G.S.ZAKYNTHINOS 2 nd 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 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) 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 Hypercapnia b)DIFFUSION LIMITATION (diffusion capacity of lungs decreased by a pulmonary disease) so

c) PHYSIOLOGIC SHUNTS [ V A /Q imbalance particularly V A so V A /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 blood(volumes %) ARTERIAL(HYPOXIC)HYPOXIA Arterial Po2Venous 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 blood(volumes %) 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 blood(volumes %) Arterial Po2BUTVenous 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 blood(volumes %) Arterial Po2Venous 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 limitationArterial 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: O 2 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 Relative HIF-1 Expression 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) gradient O 2, glucose, growth factors The oxygen and nutrients display a gradient away from 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