Exam 4 Biochem

Hemostasis and Blood Coagulation

Page 2: Contents

• Introduction to Hemostasis

• Clotting pathways: Intrinsic, Extrinsic, and Common pathways

• Role of Vitamin K in coagulation

• Role of platelets in coagulation

Page 3: Learning Objectives

• Define hemostasis and coagulation

• Describe hemostasis and its function

• Evaluate the role of thrombin

• Outline intrinsic, extrinsic, and common pathways

• Role of vitamin K in blood clotting

• Effects of aspirin, warfarin, and dicoumarol

• Platelets in blood coagulation and wound healing

• Factors in platelet activation and aggregation

• Role of von Willebrand factor

• Anti-platelet effect of aspirin

• Anti-coagulation action of warfarin

Page 4: Introduction to Hemostasis

• Physiological response to vascular endothelial injury

• Rapid clotting response and lesion closure

• Platelet adherence and fibrin mesh formation

• Clot dissolution by Protein C & Protein S

Page 5: Hemostasis Requirements

• Rapid and large response to a small stimulus

• Effective physical plug at the cut site

• Limited in location, extent, and duration

• Minimized unwanted clot formation by blood flow dilution

Page 6: Blood Vessel Damage Response

• Platelet adherence and chemical signals release

• Formation of platelet plug and fibrin network

• Platelet aggregation and coagulation leading to a blood clot

Page 7: Coagulation Overview

• Injury exposes collagen and initiates cascade

• Fibrinogen converted to fibrin

• Fibrin molecules aggregate and cross-link

• Cascade shut off by inhibitory proteins

• Clot dissolution by proteolytic reaction

Page 8: Blood Coagulation Cascade

• Thrombin enhances its own production through positive feedback

Page 9: Role of Serine Proteases

• Proenzymes converted to active enzymes

• Selective serine proteases with substrate specificity

Page 10: Coagulation Nomenclature

• Coagulation factors made in the liver

• Roman numerals designate factor forms

• Numbering based on order of discovery

Page 11-14: Clotting Pathways

• Intrinsic, Extrinsic, and Common pathways described

• Factors and processes involved in each pathway

Page 15-17: Thrombin and Fibrin Formation

• Thrombin production and role in blood clotting

• Fibrinogen conversion to fibrin by thrombin

• Fibrin monomers cross-linked by factor XIIIa

Page 18

• Crosslinking catalyzed by fibrinolygase, a transglutaminase - factor XIIIa forms a mature water-insoluble clot

  • Stimulated by thrombin

  • Formation of isopeptide bond by transglutaminase

Page 19

• Vitamin K and coagulation

  • Fat-soluble vitamin synthesized by gut bacteria and present in green leafy vegetables

  • Required for activation of prothrombin, factor VII, factor IX, and factor X

  • Role in clot dissolution and Protein C formation

  • Vitamin K-dependent clotting factors contain gamma-carboxyglutamate (GLA) residues

  • GLA residues facilitate calcium and clotting factor binding to platelets

  • Vitamin K serves as a coenzyme for clotting factors activation

  • GLA residues formed from glutamate residues post-synthesis

  • Causes of vitamin K deficiency

Page 20

• Gamma carboxyglutamate (GLA) - containing proteins

  • Important in blood clotting and clot dissolution

  • Protein C requires Protein S cofactor

Page 21

• Function of GLA residues

  • Provide high affinity binding sites for calcium

  • Conformational change upon calcium binding

  • Role in prothrombin conversion to thrombin

  • Causes of vitamin K deficiency

Page 22

• Role of GLA peptides in coagulation factor synthesis

  • Warfarin as a vitamin K antagonist

  • Heparin's immediate effect by binding antithrombin

Page 23

• Blood clotting problem: Case 9

  • Symptoms and diagnosis of vitamin K1 deficiency in Mabel

  • Sources of vitamin K1 in the diet

  • Treatment with vitamin K supplements

Page 24

• Drugs used to treat DVT

  • Warfarin and dicoumarol prevent GLA residues formation

  • Heparin binds antithrombin for immediate effect

  • Vitamin K antagonists inhibit vitamin K epoxide reductase

Page 25

• Role of platelets in blood clotting

  • Origin and function of platelets

  • Granules in platelets and their contents

  • Activation and aggregation of platelets

Page 26

• Platelets activated by vascular damage

  • Adhesion, activation, degranulation, and aggregation of platelets

Page 27

• Action of platelets in blood coagulation

  • Platelet factors and their activities

  • Role of platelet factor IV in clotting

Page 28

• Daily low dose aspirin

  • Mechanism of action of low dose aspirin on platelets

  • Widely used regimen for cardiovascular risk reduction

Page 29

• Summary of blood clotting process

  • Intrinsic, extrinsic, and common pathways

  • Fibrinogen cleavage by thrombin and crosslinking

  • Vitamin K-dependent synthesis of clotting factors

  • Role of platelets in hemostasis

  • Formation of platelet plug and low dose aspirin therapy

Page 30

• CLOT DISSOLUTION Chapter Sixty-four

Page 31

• Contents of clot dissolution chapter

  • Natural defenses against clotting

  • Control of thrombin activity

  • Plasmin's role in removing preformed clots

Page 32: Learning Objectives

• Define fibrinolysis.

  • Fibrinolysis is the process of breaking down blood clots.

• Explain the roles of tPA, urokinase, plasminogen, and plasminogen activator inhibitor in fibrinolysis.

  • tPA and urokinase activate plasminogen to plasmin, which dissolves clots. Plasminogen activator inhibitor regulates this process.

• Analyze the physiological role of anticoagulants like Antithrombin, Protein C and S, etc.

  • These anticoagulants prevent excessive clotting by inhibiting clotting factors.

• Evaluate the anticoagulant effect of heparin.

  • Heparin enhances the activity of antithrombin, preventing clot formation.

Page 33: Introduction

• Excessive clot formation can be fatal.

• Clots are limited by factors like blood flow and natural anticoagulants.

• Antithrombin and proteins C and S play a role in fibrinolysis.

Page 34: The endothelial cell

• Endothelial cells prevent clot formation and promote clot dissolution.

• They produce prostacyclin, which inhibits platelet adhesion and promotes vasodilation.

Page 35: Heparin-like molecules

• Heparin binds to antithrombin, enhancing clot dissolution.

• Heparin has been a major antithrombotic drug since the 1930s.

Page 36: Control of thrombin activity

• Antithrombin inhibits thrombin and other factors, with heparin enhancing this process.

• Deficiency of antithrombin can lead to deep vein thrombosis and pulmonary embolism.

Page 37: Switching off the clotting cascade

• Thrombomodulin, Protein C, and Protein S play roles in inhibiting clot formation.

• Protein C deficiency can lead to uncontrolled coagulation.

Page 38: Patients with infections and neoplastic disease

• Protein S is a cofactor for active Protein C.

• Infections and neoplastic diseases can affect the function of Protein S in anti-coagulation.

Page 39: Protein C stimulates clot dissolution

• Activated Protein C inactivates clotting factors and promotes clot dissolution.

• Protein C deficiency can lead to conditions like Purpura fulminans.

Page 40: Plasmin removes preformed clots

• Plasminogen is activated to plasmin, which dissolves clots.

• Inhibitors like Protein C and S complex regulate the activity of plasminogen.

Page 41: Reactions involved in clot dissolution

• Fibrinolytic system degrades fibrin and inhibits thrombin.

Page 42: Summary

• Multiple mechanisms exist to limit clot formation and dissolve existing clots.

• Thrombomodulin and proteins like Protein C and S play crucial roles in inhibiting clot formation.

Page 45: Learning Objectives

• Describe the distribution pattern of plasma proteins.

• Outline tests for analyzing blood samples.

• Evaluate the importance of plasma albumin.

• Define the functions of different protein fractions in plasma.

Page 46: Introduction

• Plasma is the largest component of human blood, containing proteins synthesized in the liver.

• Plasma proteins have key functions like maintaining blood osmotic pressure and blood clotting.

Plasma Proteins and Protein Investigation

Page 47:

• Diagnostic plasma proteins

  • Over 100 proteins in plasma with physiological functions.

  • Classified by migration in electrophoresis at pH 8.6 into Albumin and globulins.

  • Globulins further divided into alpha, beta, and gamma classes.

  • Variation in levels may indicate disease.

Page 48:

• Methods of plasma protein investigation

  • Protein electrophoresis for semi-quantitative assessment and paraprotein detection.

  • Direct colorimetric assay.

  • Immunoassay.

  • Radioimmunoassays.

  • ELISA.

Page 49:

• Serum protein electrophoresis

  • Separates proteins into bands based on net charge.

  • Major peaks for albumin, alpha1, alpha2, beta-globulins, and gamma-globulins.

  • Peak magnitude variation with disease.

Page 50:

• Typical electrophoretic pattern for plasma proteins

  • Shows gamma, beta, alpha2, alpha1, Albumin, and various proteins.

Page 51:

• Electrophoresis pattern of plasma proteins at pH 8.6

  • Shows the migration of various proteins.

Page 52:

• Lists various plasma proteins and their classifications.

Page 53:

• Lists more plasma proteins and their classifications.

Assay of Plasma Proteins and Clinical Significance

Page 54:

• Assay of plasma protein levels

  • Direct colorimetric assays like the Lowry method and immunoassays are specific and selective.

Page 55:

• Radioimmunoassay

  • Competition between radioisotope-labelled and unlabelled antigens.

  • Determination of antigen levels from a standard curve.

Page 56:

• ELISA

  • Antibody to protein coated on solid phase.

  • Second antibody with enzyme linked for measuring specific protein.

Page 57:

• Selection of plasma proteins of clinical significance

  • Includes Albumin, Alpha-1-globulins, Alpha 2-globulins, Beta-globulins, and Immunoglobulins.

Page 58:

• Albumin

  • Synthesized in hepatocytes, most abundant plasma protein.

  • Used to assess nutritional support and liver function.

Page 59:

• Hypoalbuminemia

  • Reduction in serum albumin may lead to edema and is associated with proteinuria.

Page 60:

• Alpha-1-globulins (Alpha1-protease inhibitor)

  • Inhibitor of proteases, made in the liver.

  • Deficiency linked to emphysema.

Page 61:

• Alpha-1-protease inhibitor deficiency

  • Common genetic disease causing emphysema and neonatal cirrhosis.

  • Under-diagnosed with significant impact.

Page 62:

• Alpha-1-globulins (Alpha 1-Fetoprotein)

  • Present in fetus tissues and plasma.

  • Diagnostic importance in screening for neural tube defects and Down syndrome.

Plasma Proteins and Their Functions

Page 63: Alpha 2 globulins Haptoglobin

• Binds free hemoglobin during intravascular hemolysis

  • Conserves body's iron stores

• Increases in hypoalbuminemic states like nephrotic syndrome

• Selectively increases in response to stress, ulcerative colitis, or surgical trauma

• Levels fall in sickle cell and intravascular hemolysis

Page 64: Alpha 2-Macroglobin

• High molecular weight protein, inhibitor of proteases

• Increased levels in nephrotic syndrome and cirrhosis

• Reduced levels in prostate cancer and acute pancreatitis

Page 65: Ceruloplasmin

• Copper-carrying alpha2-globulin

  • Carries 95% of copper in plasma

• Has ferroxidase activity, hepatic acute phase protein

• Deficiency seen in Wilson's disease, nephrotic syndrome, and malnutrition

• Increased in pregnancy, by estrogen-containing oral contraceptives, chronic liver disease, and neoplastic disease

Page 66: Beta-globulins Transferrin

• Major iron-transporting protein in plasma

  • Normally 30% saturated with iron

• 100% saturated with iron in hemochromatosis

• Useful in assessing patient's response to nutritional support

• Elevated in iron deficiency and acute hepatitis, depressed in inflammation and nephrotic syndrome

Page 67: Gamma globulins Immunoglobulins

• Gamma globulin fraction contains immunoglobulins

• Function as antibodies recognizing and binding foreign antigens

• Can be overproduced (hypergammaglobulinemia) or underproduced (hypogammaglobulinemia)

• Common structure with heavy and light chains linked by disulfide bridges

Page 69: Paraproteins

• Monoclonal immune globulin fragments produced by malignant plasma cells

• Seen as a discrete band on electrophoresis

• Dimers of light chains in urine are Bence Jones Proteins, indicative of Multiple myeloma

• Heavy Chain dimers produced in Franklin's disease or Heavy Chain Disease

Organ Function Tests

Page 75: Learning Objectives

• Define Organ Function Test and the "Shotgun" approach to disease diagnosis

• Define sensitivity and specificity

• Describe kidney function tests using BUN and plasma creatinine

• Outline liver function tests and distinguish direct and indirect bilirubin

• Name markers of heart muscle damage

Page 76: Introduction

• Organ function tests evaluate organ function

• Useful for detecting disease presence, monitoring treatment response, and assessing prognosis

Page 77: Strategy

• Avoid a 'shotgun approach' to diagnosis

• Perform reliable tests to diagnose organ malfunction

• Suspect organ disease only with abnormal results from independent tests

Page 80: The ideal OFT

• Should be accurate, precise, sensitive, and specific

• Cheap, simple, quick, painless, and low risk

• High sensitivity and specificity rarely coexist

Page 81: Kidney function

• Functions include waste removal, water balance regulation, pH maintenance, and toxin excretion

• Glomerular filtration rate (GFR) is an important index

• Clinical conditions like diabetes and prostate problems affect kidney function

Kidney Function Tests

• Blood Tests

  • Plasma creatinine and muscle turnover are measured.

  • Levels should be constant for normal function.

  • Concern arises when creatinine levels exceed 2.0 mg/dL for men and 1.5 mg/dL for women.

• Urine Tests

  • Various tests like routine urinalysis, creatinine clearance, urea clearance test, and urine protein test are conducted.

  • Glomerular Filtration Rate is measured using inulin or creatinine.

  • Decline in GFR is observed with age.

Urine Protein Test

• Healthy kidneys filter around 30mg/L of protein.

• Proteinuria, significant protein in urine, indicates renal disease.

• Best to test early morning urine.

• Proteinuria is usually detected using dipsticks.

• A 24-hour urine collection should contain no more than 150 mg of protein.

Urinalysis

• Inexpensive but useful test for urinary tract and systemic diseases.

• Dipstick tests by Ames Co. and Boehringer Corporation are common.

• Fresh morning urine should be acidic and free from glucose, proteins, hemoglobin, or metabolites.

Plasma Creatinine

• Derived from muscle tissue, it is a preferred test for kidney function.

• Levels vary between individuals and normal ranges differ by gender.

• More specific indicator of kidney function compared to BUN.

Blood Urea Nitrogen (BUN)

• Measures the amount of nitrogen in urea.

• Elevated levels indicate kidney dysfunction or increased protein catabolism.

• BUN levels are influenced by various factors like renal function, dietary protein intake, dehydration, fever, trauma, and liver function.

Creatinine Clearance Test

• Gives an approximation of GFR by evaluating how efficiently kidneys clear creatinine from the blood.

• Creatinine clearance values vary with age and gender.

• Not a perfect measure of GFR due to some unfiltered creatinine and secretion into the proximal tubule.

Liver Function Tests

• Evaluate liver damage or deficiency, monitor treatment response, and assess prognosis.

• Include tests for bilirubin, prothrombin time, albumin, and enzyme assays.

• Enzyme assays like ALT, AST, AP, and GGT are markers for liver function.

Bilirubin

• Breakdown product of hemoglobin, with normal levels below 1mg/dL.

• Elevated levels can indicate liver cell problems or bile flow issues.

• Excess bilirubin can lead to jaundice.

Methods of Plasma Bilirubin Detection

• The van den Bergh reaction is used for direct bilirubin measurement.

• Conjugated bilirubin can be assayed with azo dyes, and elevated levels indicate liver issues.

Plasma Enzyme Diagnostics

Page 96

• Methods of plasma bilirubin detection

  • Indirect Van den Bergh reaction used for measuring indirect or unconjugated bilirubin.

  • An accelerator agent is added to free unconjugated bilirubin from serum albumin before the reaction.

  • Elevated levels of unconjugated bilirubin can impair cell membrane function.

Page 97

• Ammonia

  • Normally converted to urea in the liver.

  • Blood ammonia analysis useful in diagnosing severe liver diseases like cirrhosis and hepatitis.

  • Blood ammonia levels help in diagnosing Reye's syndrome and hepatic encephalopathy.

  • Normal values for ammonia vary widely based on age and laboratory.

Page 98

• Tests of cardiac function

  • Creatine kinase-MB, Troponin T and I, C-reactive protein, myoglobin, and B-type natriuretic peptide are used.

  • Troponin T and I are specific for cardiac damage.

  • C-reactive protein is elevated in atherosclerosis and can predict MI or stroke.

  • Myoglobin is elevated in plasma and urine.

  • BNP assay is used for suspected congestive heart failure.

Page 99

• Summary

  • Organ Function Tests evaluate organ functionality and disease progression.

  • Ideal tests are accurate, sensitive, specific, and easy to perform.

  • Kidney function tests include plasma and urine samples.

  • BUN and plasma creatinine assay indicate kidney function.

  • Plasma assays for bilirubin, ammonia, and prothrombin time reflect liver function.

  • C-reactive protein and troponins indicate cardiac muscle damage.

Page 100

• Enzyme diagnostics Chapter sixty-seven

Page 101

• Contents

  • Introduction to plasma enzyme assays like ALP, GGT, AST, ALT, CK, amylase, and LDH.

  • Discussion on heart attack and hepatic anoxia.

Page 102

• Learning Objectives

  • Differentiate plasma enzymes, factors affecting enzyme leakage, and diagnostic roles.

  • Describe physiological roles of enzymes in diseases and the importance of assay time frame.

Page 103

• Introduction

  • Plasma enzyme assays are sensitive for diagnosis.

  • Enzyme leakage into plasma can result from various causes.

  • Enzyme activity increases in disease states due to leakage from cells.

Page 104

• Relative enzyme activities

  • AST, ALT, LDH, and CK activities in different tissues.

Page 105

• Plasma enzyme assays

  • Enzyme concentration is difficult to measure accurately in plasma.

  • Enzyme activity is measured as substrate converted per unit time.

  • Enzymatic assays often use NAD or NADP for UV light absorption.

Page 106

• Absorption spectra of niacin and flavin coenzymes

Page 107

• Alkaline phosphatase (ALP)

  • Membrane-bound isoenzymes with varying activity.

  • Useful for assessing hepatobiliary and bone diseases.

  • Increased levels in hepatic and bone diseases.

Page 108

• Assay of alkaline phosphatase

  • Useful in diagnosing biliary tract obstruction, hepatitis, cirrhosis, and pregnancy.

Page 109

• Gamma glutamyl transferase (GGT)

  • Cell membrane-bound enzyme with high concentrations in liver and kidney.

  • Elevated levels indicate cholestasis, cirrhosis, hepatitis, and alcohol abuse.

Page 110

• Aspartate transaminase

  • Present in various tissues, primarily in skeletal and cardiac muscle, liver, and kidney.

  • Elevated in alcoholic liver disease and used for diagnosing myocardial infarction and acute liver damage.

Page 111

• Assay of AST

  • AST activity coupled to MDH for diagnosing myocardial infarction, acute liver damage, and muscular dystrophy.

Page 112

• Alanine transaminase (ALT) is a cytoplasmic enzyme.

  • Generally lower concentrations than AST in tissues.

  • ALT levels increase more than AST in early hepatocellular disease.

  • Useful for acute liver damage like viral hepatitis.

  • Monitoring liver disease treatments.

  • Useful for cardiac failure and muscle disease.

  • De Ritis Ratio (AST/ALT) can reach 6.0 in alcohol-related liver disease.

  • Plasma levels increase in cirrhosis, liver tumors, obstructive jaundice, burns, and shock.

Page 113

• Assay of ALT involves Ala + aKG producing Pyruvate + Glutamate + NADH.

• Lactate dehydrogenase (LDH) change in absorbance at 340nm is measured.

Page 114

• Creatine kinase (CK) is crucial for phosphagen metabolism.

  • Plasma CK levels are proportional to muscle mass.

  • Important in skeletal muscle and heart disease.

  • Isoenzyme assay is necessary for differentiation between skeletal muscle and heart disease.

Page 115

• CK tissue distribution varies in different tissues.

  • MMCK3 is predominant in skeletal muscle.

  • MB CK2 is found in myocardium.

  • BBCK1 is present in the brain.

Page 116

• Plasma CK levels increase in muscle disease.

• Myocardial infarction leads to a significant increase in plasma CK levels.

• Various factors like surgery, muscular trauma, heavy exercise, and muscle dystrophy affect CK levels.

• Different types of muscular dystrophy, especially Duchenne, show increased CK levels.

• Plasma CK levels also increase in diseases of the CNS and hypothyroidism.

• Hyperthyroidism leads to a decrease in plasma CK levels.

Page 117

• Mean post-exertion CK values in football players show variations.

• Elevated CK levels are observed in muscle diseases and conditions like myocardial infarction.

Page 118

• Plasma cardiac troponin T is better than CK-MB in diagnosing and predicting heart failure.

Page 119

• Amylase is sourced from salivary glands and the exocrine pancreas.

• Plasma amylase levels can help in the differential diagnosis of acute abdomen.

• Acute pancreatitis elevates plasma amylase significantly.

Page 120

• Lactate dehydrogenase (LDH) is present in the cytoplasm of most cell types.

• Five distinct isoenzymes of LDH exist.

• LDH is important in anaerobic metabolism.

• Plasma levels of LDH isoenzymes vary in health and disease.

Page 121

• LDH tissue distribution varies among different tissues.

• LDH 1 is found in myocardium and erythrocytes.

• LDH 2 is present in myocardium and erythrocytes.

• LDH 3 is found in the brain and kidney.

Page 122

• Assay of lactate dehydrogenase involves measuring the change in absorbance at 340nm.

Page 123

• Classic plasma LDH changes occur in diseases like myocardial infarction and liver disorders.

• LDH levels can be elevated in patients with malignant diseases like muscular dystrophy.

Page 124-126

• Densitometer scans and kinetics of release of cardiac enzymes following myocardial infarction show the time course of appearance of various markers in the blood.

Plasma Enzyme Activity (Page 127)

• Measurement of plasma enzyme activity is valuable for diagnosing and managing diseases.

• Enzymes leaking into plasma due to tissue damage serve as disease markers.

  • Spectrophotometrically measurable enzyme assays are most useful.

• ALP activity assesses hepatobiliary and bone diseases.

• GGT activity rise in cholestasis indicates biliary obstruction and cirrhosis.

• AST and ALT are markers of liver dysfunction.

• CK activity diagnosis skeletal muscle and heart disease.

• Amylase and pancreatic lipase activity diagnose acute pancreatitis.

• LDH activity aids in differential diagnosis of myocardial infarction and liver disorders.

Case Study (Page 128)

• Two patients with suspected myocardial infarction admitted.

• Blood samples taken for CK and LDH assay.

• Acute admission with no available bed in coronary unit.

Ethanol Metabolism (Page 129)

• Introduction to ethanol metabolism.

• Factors influencing alcohol absorption and metabolism.

• Alcoholic-related damage discussed.

Learning Objectives (Page 131)

• Enzymatic reactions for alcohol dehydrogenase, acetaldehyde dehydrogenase, and CYP2E1.

• Comparison of alcohol dehydrogenase and CYP2E1 actions.

• Impact of ethanol metabolism on NADH/NAD+ ratio.

• Metabolic changes during acute and chronic ethanol consumption.

Alcohol Consumption Statistics (Page 132)

• Statistics on alcohol use and its impact on health and society.

• Alcohol-related deaths and diseases.

• Alcoholism definitions and criteria.

Absorption and Metabolism of Ethanol (Page 135)

• Rapid absorption of ethanol without modification.

• Influence of fatty foods and milk on absorption.

• Distribution to body tissues proportional to blood flow.

• Excretion of unmetabolized alcohol through various bodily fluids.

Alcohol Metabolism (Page 137)

• Metabolism slower than absorption, requiring control.

• Liver enzymes catalyze breakdown of alcohol to CO2 and H2O.

• First pass metabolism affected by certain medications.

• Chronic alcoholics develop tolerance to alcohol.

Effects of Alcohol Metabolism (Page 140)

• NADH production inhibits gluconeogenesis and fatty acid metabolism.

• Excess NADH leads to fat deposits in the liver.

• Shift in lactate dehydrogenase equilibrium and accumulation of lactate.

• Pyruvate shortage affects gluconeogenesis, worsened by starvation.

Minor Pathway of Alcohol Metabolism (Page 141)

• Alcohol metabolized by cytochrome P450 isoenzymes.

• Increased activity in chronic drinking and tolerance development.

• Unmetabolized alcohol allows measurement in breath and urine.

Factors influencing alcohol absorption and metabolism

• Food

  • The higher the dietary fat proportion, the longer absorption takes.

• Age

  • Senior citizens have decreased body water, muscle tissue, and metabolism.

• Gender

  • Women have higher blood alcohol concentrations due to smaller body water and lower alcohol dehydrogenase activity.

• Body Weight

  • Greater body weight means more body water, leading to more dilute alcohol effects.

• Medications

  • Chronic heavy drinking activates cytochrome P450, impacting liver function.

Alcoholic-related damage

• Short term

  • CNS effects, fat deposition, and hepatic effects like steatosis.

• Long term

  • Induction of cytochrome P450, alcohol-induced hypoglycemia, and alcoholic hepatitis.

Other toxic effects of alcohol

• Decreases liver protein synthesis, extends prothrombin time, and decreases hepatic activation of vitamins.

• Acetaldehyde is carcinogenic, leading to various health issues.

• Chronic alcoholism in men can cause gynecomastia and testes hypotrophy.

Cirrhosis

• Replacement of liver tissue with fibrous tissue, leading to irreversible loss of liver function.

• About 10-15% of alcoholics have cirrhosis at the time of death.

• Portal hypertension and inadequate prothrombin production contribute to complications.

"Advantages" of light alcohol ingestion

• Reduced heart disease incidence due to increased HDL levels and antioxidant effects.

Alcohol as a “medicine”

• Historical uses of alcohol for medicinal purposes.

Summary

• Ethanol is an intoxicating ingredient consumed by over 50% of U.S. adults.

• Factors like food, gender, and medications influence alcohol absorption and metabolism.

• Ethanol metabolism affects liver function and glucose production.

Exercise metabolism

• Different types of exercise: aerobic and anaerobic.

• Energy sources, substrate utilization, and hormone levels during exercise are crucial.

• Three metabolic systems provide energy for exercise: phosphagen, glycogen-lactate, and aerobic systems.

Page 159

• The aerobic system is powered by a combination of fuel reserves.

  • Utilizes pyruvate from glucose or other substrates through the Krebs cycle and oxidative phosphorylation.

• The aerobic pathway is essential for prolonged athletic activities.

  • Provides 95% of energy at rest.

• Energy systems used for activities can be estimated based on activity vigor and duration.

Page 160

• Glucose is the preferred substrate for exercising muscle.

  • Derived from intramuscular glycogen stores and the plasma glucose pool.

• Muscles can also utilize fatty acids, ketone bodies, and amino acids for energy.

  • Increased muscle GLUT 4 expression and contraction-stimulated glucose uptake.

Page 161

• Muscle glycogen and blood glucose are the primary energy nutrients for short, intense muscle activity.

• Liver glycogen can be released to muscles during the early stages of long-distance events.

• Switch from carbohydrate oxidation to lipolysis as glycogen reserves deplete.

Page 162

• Blood glucose is crucial for fuel.

• Intake of 30-60 gm CHO/hour during strenuous endurance activity delays fatigue.

• Maintaining plasma glucose levels and high rates of glucose oxidation spares hepatic glycogen reserves.

Page 165

• Fat is the major fuel for prolonged low-intensity activities.

• Trained muscles have more mitochondria to utilize fat as fuel.

• Marathon running utilizes a 50:50 ratio of fat to CHO for energy.

Page 166

• Hormones like glucagon, cortisol, adrenaline, noradrenaline, and growth hormone are elevated during exercise.

• Insulin is depressed, promoting the conversion of liver glycogen to glucose for fuel.

• Glucose is available for uptake by exercising muscle cells.

Page 170

• Exercise has various health benefits, including cardiovascular health, improved sleep patterns, stress reduction, and enhanced insulin action.

• Moderate intensity exercise aiming for weight loss is crucial for managing type II diabetes.

Page 172

• Two types of exercise are aerobic and anaerobic, differing in intensity and duration.

• Energy for exercise is obtained from plasma glucose, intracellular glycogen reserves, and hepatic gluconeogenesis.

• Carbohydrate loading can replenish muscle and liver glycogen stores, enhancing performance during prolonged events.

Page 174

• Aging is a progressive deterioration of biological systems leading to increased age-related mortality.

• Life expectancy has increased due to improvements in sanitation and medical care.

• The U.S. population has an increasing fraction of individuals over 65 years of age.

Goddess Aurora and Tithonus

• Aurora took Tithonus and granted him immortality by Zeus.

• Tithonus aged rapidly without eternal youth, becoming decrepit.

• Eventually, Aurora transformed him into a grasshopper.

The Hayflick Limit

• Normal cells have a finite replicative capacity.

• The Hayflick phenomenon contributes to cellular aging.

• Mutated cancer cells can bypass the Hayflick limit.

Aging Theories

• Aging is influenced by extrinsic factors and intrinsic molecular programs.

• Cellular functions deteriorate with age due to various factors.

  • Reduced oxidative phosphorylation and protein synthesis.

  • Lesions in the MAP kinase pathway.

  • Diminished nutrient uptake and repair capacity.

  • Altered gene expression.

Programmed Cellular Aging Theories

• Internal biological clock or genetic program governs aging.

• Aging follows a predetermined biological timetable.

Somatic Mutation Hypothesis

• DNA errors accumulate due to environmental factors.

• Errors in DNA structure increase with age.

• Methylation of cytosine residues decreases with cell age.

Telomere Theory

• Telomeres shorten during DNA synthesis.

• Telomerase enzyme maintains telomere length.

• Telomeres shorten until cells reach a critical length, leading to cell death.

• Mutations evoking telomerase activity can help cells escape crisis.

Damaging Agents

• Oxygen radicals, glycation end products, mutagens, and UV light contribute to aging.

• Enzyme systems repair damaged DNA, defects in repair mechanisms linked to cancer susceptibility.

Free Radicals and Aging

• Free radicals play a role in degenerative disorders.

• Antioxidant defense mechanisms reduce damage from free radicals.

• High levels of antioxidants correlate with slower aging.

• Inserting SOD gene into fruit flies extends lifespan.

Mitochondrial DNA

• Mitochondria accumulate changes with age.

• Mitochondrial DNA is damaged at a higher rate than nuclear DNA.

• Type II diabetes is associated with mitochondrial defects.

Cellular Changes with Age

• Irregular nuclei, changes in mitochondrial shape, decreased endoplasmic reticulum, distorted Golgi apparatus, and accumulation of lipofuscin occur with age.

Advanced Glycation

• Glycation of proteins associated with aging.

• AGEs toughen tissues and contribute to aging-related deterioration.

• AGEs are linked to various disease states and appear earlier in diabetes.

Diabetes and Aging

• Diabetes accelerates aging processes.

• Diabetic complications mimic physiological changes of aging.

• Metformin shows promise in anti-aging studies.

• Macrophages defend against AGEs, but this defense weakens with age.

Diseases and Aging

• Aging population is increasing rapidly.

• Older age groups face higher mortality rates and healthcare costs.

• Leading causes of death in older age groups include heart disease, cancer, and cerebrovascular disease.

• Mortality rates for men can be significantly higher than women at any age.

Page 194:

• Main Ideas:

  • Hypothesis of cellular aging mechanisms

  • Factors contributing to aging

• Supporting Details:

  • Cellular aging mechanisms include metabolic capacity, oxidative stress, protein, lipid, and DNA damage (adducts, peroxidation)

  • Aging is influenced by genetic and environmental factors, clock genes, diet (calories), DNA repair, intercurrent mechanisms, disease, stress, and exogenous stresses (radiation, chemicals)

  • Antioxidant defenses play a role in combating aging processes

Page 195:

• Main Ideas:

  • Summary of aging process

  • Theories explaining aging

• Supporting Details:

  • Aging is defined as accruing maturity over time and is generally disliked

  • Aging is suggested to progress linearly from age thirty