Midterm Flashcards
Pathophysiology
the study of the physical and functional changes that occur during a disease process
Etiology
study of the causes and reason for a particular disease or injury
Idopathic
cause is unknown
Iatrogenic
resulting from medical treatment
Risk Factor
Increase likelihood of disease
Latent Period
Time between exposure and first appearance of S & S
Prodromal Period
When S&S first appear, indicating onset of disease
Acute Phase
Disease/illness is at full intensity
-May be short-lived but intense manifestation
Chronic Illness
May last months to years, sometimes after acute course
Exacerbation
A sudden increase in severity of disease or Signs and symptoms
Remission
Decrease in severity, S&S: may indicate disease is cured
Convalescent
Stage of recovery after a disease, injury or surgey
4 Factors that Affect Health and Disease
Cultural Consideration
Age Difference
Gender Differences
Situational Differences
Epidemiology
Study of the patterns of disease involving populations
- Examines the occurance, incidence, prevalence, transmission, and distribution of disease in large groups of populations/people
Endemic disease
Consistently present within a particular geographic area or population
Often associated with specific environmental or social factors
Epidemic
Sudden increase in the number of cases of a disease above what is normally expected in a specific region or population
- Can be caused by a new strain of a pathogen, changes in the environment or lapses in vaccination coverage
Pandemic
Epidemic that has spread across multiple countries or continents, affecting a large portion of the global population
- Involves a new pathogen to which most people have little or no immunity
Levels of Organiztion
Nucleus - Heart muscle cell - Heart muscle - Heart - Circulatory system
Organelles - Cell - Tissue - Organ - System
Cell Structure (3 Main Parts)
Cell Membrane: Encase the cell and regulates the movement of substances in and out of the cell
Nucleus: Houses the majority of the cells DNA/genetic material
Cytoplasm: Gel-like fluid inside the cell that contains various cell components with specific functions (DOES NOT INCLUDE NUCLEUS)
5 Stages of Cell Cycle
G-0 (Resting Stage)
G-1
S (Synthesis)
G-2 (Pre-mitotic Phase)
M (mitosis)
G-0 (Resting Stage)
Phase where cells conduct their everyday activities specific to cell type (Eg, metabolism, contraction etc)
- Cells spend most of their lifetime in this phase**
G-1 Phase
- First Step after receiving signal to divide
- Cell synthesizes ribonucleic acid (RNA), proteins, and other components needed for DNA duplication
S (Synthesis)
Cells duplicate its DNA
G-2 (Pre-Mitotic Phase)
Cell makes additional proteins and the components necessary for cell division/mitosis
M (mitosis) Phase
Cell undergoes mitosis (prophase, metaphase, anaphase, & telophase)
- Results in the cell splitting into 2 identical cells
Cell Proliferation
Cells multiply through mitosis where one cell divides to make two new daughter cells identical to the parent cell
- Allows the body to grow, repair, and replace cells
- Tightly regulates to ensure that cells divide only when necessary
Cell Differentiation
Process by which a cell becomes more specialized with distinct functions and characteristics
- Ensures cells can perform specialized functions necessary for organisms survival
- Stem Cells: are special cells with the ability to develop into various cell types
- They receive signals directing them to become a specific type of cell
Cell Types
Labile
Stable
Permanent
Labile Cells
Constantly dividing and replacing cells that are lost
Eg. the skin, intestinal epithelial cells
Stable Cells
Do not divide under normal conditions but can be stimulated to divide after injury
Eg. Hepatocytes and liver regeneration (Zeus vs Prometheus)
Permanent Cells
Lack regeneration ability
Eg, cardiac, neural, and skeletal cells
- Cardiac tissues don’t heal after MI, causing reduced cardiac capacity
4 Types of Tissues
Epithelial
Muscular
Connective
Nervous
Epithelial Tissues
Line all internal and external surfaces
Muscular Tissues
Specialized for contraction, allowing movement and force generation in the body
Connective Tissue
Supports, connects, or separates different types of tissues and organs in the body
Nervous Tissue
Specialized tissues that transmit electrical impulses to coordinate bodily functions by facilitating communication between different body parts
Cellular Adaption
A cells ability to adjust in response to different stimuli and challenging environmental conditions that threaten their structure or function
- Stimuli can be Physiological (breast during pregnancy), or pathological (aging)
- Cells may change in size, number, or type, to adapt
- If stress is too severe or the adaptations are not effective, the cell may become injured or die
5 Cellular Adaptations
Atrophy
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia
Atrophy
- Decreases in cell size leading to tissue degeneration
- Atrophied cells = decrease in cell content = reduced oxygen consumption
- Caused by: Disuse, denervation, loss of endocrine stimulation, inadequate nutrition, ischemia
Hypertrophy
Enlargement of cells increase in size and functional components
Eg. Bigger muscle = more ATP, more actin and myosin filaments
- Results from increased functional demands or specific hormonal stimuli
- Caused by: Exercise & muscle mass, uterus enlargement in pregnancy (physiological), myocardial hypertrophy from hypertension (pathological)
Hyperplasia
- “plasia” = Cell formation or growth
- Controlled increase in the number of cells in an organ or tissue
- Occurs in wound healing with proliferation fibroblasts of connective tissues
- Different from hypertrophy BUT may occur TOGETHER (Eg. uterus)
- Cause by: Stimulation of endometrium in the follicular stage of menstrual cycle (physio), Benign prostate hyperplasia (patho), endometrial hyperplasia (patho)
Metaplasia
Reversible replacement of mature, differentiated cell-type by another cell-type that is better suited to tolerate a particular stimuli or environment
- Reprogramming of undifferentiated stem cells present in tissue, but conversion of cell type remains within boundaries of primary tissue (epithelial cells CANNOT be converted to cardiac cell)
- Caused by: Barret’s Oesophagus (in response to reflux), replacement of ciliated pseudostratified columnar epithelium in bronchi w/ stratified squamous epi (smoking)
Neoplasia
When signals cause metaplasia to persist, they frequently lead to the development of neoplasia
Dysplasia
Disordered growth in tissue, resulting in cells that vary in size, shape and organization
- Caused by irritation (smoke), or inflammation (radiation causes damage to cell DNA)
- Mild-moderate cases may regress if underlying cause if alleviated but severe dysplasia can be a precursor to irreversible malignancy
Intracellular Accumulation
- Describes the build-up of substance that the cells cannot immediately use or eliminate
Normal Body Substance
Substance is produced faster than it can be metabolized or excreted
Eg. Obesity = high delivery of free fatty acids from adipose tissues to the liver = accumulation of FFA = Fatty liver
Abnormal Endogenous Products
May result from disorders that disrupt metabolism due to abnormal or missing enzyme
Eg, Von Gierke disease where a deficiency in Glucose-6-phosphatase leads to accumulation of glycogen in the liver and kidneys
Exogenous Products
Environmental agents and pigments
Eg. Accumulation of carbon dust blackens the lung tissue and may cause serious lung disease
Pathological Calcifications
2 Types: Dystrophic & Metastatic
Involve abnormal tissue deposition of calcium salts, and other minerals in tissues
Dystrophic Calcification
Occurs in damaged or necrotic tissues despite normal calcification levels in the blood
- Happens in areas of tissue like damaged heart valves, atherosclerotic plaques, or areas of chronic inflammation
Metastatic Calcification
Occurs in healthy tissues due to elevated levels of calcium in the blood (hypercalcemia)
Physical Agents of Cellular Injury
Can generally be reversed up to a specific point, after which the damage becomes irreversible, leading to cell death
- MECHANICAL FORCE: Trauma due to body’s impact w/ external force (split and tear tissues, fracture bones, disrupt blood flow etc)
- EXTREMES OF TEMP: Heat (burns) disrupt cell membrane. Cold may lead to hypoxic tissue injury due to vasoconstriction
- ELECTRICAL INJURIES: Extensive tissue injury. Disruption of neural and cardiac impulses
Radiation of Cellular Injury
ULTRAVIOLET RADIATION: Photon is a particle of electromagnetic radiation energy
- UV radiation contain high energy photons that can disrupt release free radicals, damage DNA and damage melanin-producing processes in skin cells
IONIZING RADIATION:
-Radiation energy above the UV range
- L.R. photons cause ionization of molecules and atoms in the cell by knocking off elections from them
Eg. Localized irradiation in cancer treatment
NONIONIZING RADIATIONS:
- Radiation energy BELOW the UV range (Eg. Ultrasound, welding, microwaves)
- Uses energy from vibration of atoms and molecules o generate thermal energy
- Resulting thermal energy can disrupt the cell depending on duration and extent of exposure
Cell Injury (Chemical and Biologic)
CHEMICAL INJURY:
- May injure cells membrane, block enzymatic pathways, disrupt cell metabolism etc
- Air and water pollutants. tobacco smoke, drugs and alcohol, CO, Lead toxicity, mercury toxicity
BIOLOGIC INJURY:
- Viruses incorporate themselves into a cell’s DNA machinery
- Bacteria may release toxins that increase cardiac permeability, interfere with ATP production or other cellular processes
Mechanisms of Cell Injury
FREE RADICAL INJURY:
- Highly reactive with molecules in their vicinity and can convert other molecules into additional free radicals
Reactive Oxygen Species (ROS) = Free radical in the body
Oxidative Stress
When the generation of free radicals exceeds the ability of the body to neutralize it
- High blood sugar can cause oxidative stress on blood vessels
- In cancer, oxidative stress damages the DNA in healthy cells
- Also linked to Aging neurodegenerative disease
Antioxidants
Vit A,C,E, Zinc, Beta-carotene
Hypoxic Cell Injury
Oxygen Deficiency: lack of O2 in the air, respiratory disease, anemia, ischemia
Deprives the cell of O2 thereby interrupting the generation of ATP
Genetic Defect
Cause cell injury due to deficiency in function proteins or the accumulation of damaged DNA or misfolded proteins (both trigger cell death)
EG, sickle cell anemia
Reversible Cell Injury
Cellular Swelling
Fatty Changes
Cellular Swelling
Impairment of the sodium-potassium-ATPasepump leads to accumulation of Na and water inside the cell
- Hydropic degeneration. Change is reversible if O2 delivery resumes alongside ATP production
Fatty Changes
Intracellular accumulation of fat, causing small vacuoles of fat disperse throughout the cell
-Increased fat load (obesity)
-Impairment of fat metabolism
Apoptosis
Highly selective process that controls tissue regeneration by eliminating injured and aged cells. Cellular suicide
- Does NOT trigger the inflammatory process
- Responsible for several physiologic processes: Programmed destruction of cells during embryonic development (separates webbed-toes and fingers in embryo), Hormone-dependent involution of tissue, Control immune cells
Necrosis
Refers to cell death in an organ or tissue that is still part of a living tissue
- Usually due to ischemia or toxic injury
- Interferes with cell replacement and tissue regeneration
- Triggers inflammatory process**
Gangrene
When a considerable mass of tissue undergo necrosis
Neoplasm
Cels regulate growth (proliferation) by turning growth-promoting and growth suppressing genes on and off
Neoplasia
Abnormal cell proliferation/tissue growth caused by damage or mutation of regulators
Metastasis
Movement of abnormal cells to other parts of the body, where they populate new tumors
Benign (Non-cancerous)
Uncontrolled cell proliferation enclosed in a fibrous capsule and does not infiltrate or affect tissue of origin directly
- Slow growing and localized
- Does not metastasize and can be removed
Eg. Benign prostatic hyperplasia
Malignant Tumors (cancerous)
Rapid and uncontrolled cell proliferation that invades the tissue of origin and can invade other remote tissues via lymph or blood
- Always requires treatment
Cancer Cells
Uncontrolled proliferation
- De-differentiation (loss of normal function)
- Invasiveness
- Metastases: Cancer cells break away, travel through the blood or lymph system, form new tumors, metastatic tumor is the same type of cancer as the primary tumor
Angiogenesis
Formation of new capillaries out of existing blood vessels
- Cancer cells establish their own blood supply to bring nutrients and escape during metastasis
Telomere
Section of DNA that safeguards the chromosome ends from damage and entanglement
- They shorten with each cell division and eventually become too short for proper cell division = cell death
Telomerase
An enzyme that lengthens the telomere chains and allow continued replication
- Found in stem cells
- Cancer cells produce large amounts = Indefinite replication
Types of Cancer
Solid - Abnormal tissue mass, difficult to assess in blood at 1st, Eg. Breast, prostate, lung CA
Hematological - Formed in the blood or bone marrow, not a mass (liquid), Eg. Leukemia, lymphoma
Types of Carcinogens
Chemical: Tobacco smoke & Asbestos = Lung CA
Physical: Sun’s UV rays = Skin carcinoma, Xrays = Leukemia
Biological: Genetic predisposition to damaged growth promoter/suppressor, viruses/HPV = Cervical CA
Diagnostic Tools
Blood Test: CBC & Differential (Hb, WBC, blood smears)
Imaging: Ultrasound, CT scan, MRI, PET, Mammogram
Others: Biopsy, Colonoscopy
CA Staging
Identifies the location and extent of cancer invasion within the body
- Assessed at initial diagnosis to help understand the disease’s prognosis and the most effective treatment options
- CA is assigned values for the tumor (T), node (N), Metastasis (M) and then a stage
- Assigned stage does not change even if CA progresses***
4 Stages of CA
Stage 1: Least Invasive, most favourable outlook. No lymph involvement, no metastasis, tumors are less than 2 cm in size
Stage 2: Local lymph involvement, no metastasis, tumors are less than 5 cm in size
Stage 3: Nodal involvement, no metastasis, tumors over 5 cm
Stage 4: (Most aggressive = least favourable outlook), nodal involvement, metastasis tumors greater than 5 cm
CA Grading aka Biopsy
Involves examining cancer cells under microscope and comparing their appearance to that of normal, mature cells it came from
G1 = differentiated and very similar to the parent cells
G4 = Very abnormal and different from normal cells. Aggressive CA cells with worst prognosis
Grading can change as the tumor evolves
Clinical Manifestations
Obstruction: Anorexia and necrosis of tissue leading to loss of function
Hematologic Alterations: Impairs functions of blood cells. Leukemia, GI tumors, Renal cell carconoma
Anorexia-cachexia Syndrome: “wasting syndrome” - malnutrition, weight loss, neoplastic cells divert nutrition to own use
Paraneoplastic Syndromes: malignant tumor secretes hormones or proteins that affects organ systems away from tumor sites (symptoms occur away from tumor site)
Psychological Stress
Pain
Drugs Targeting DNA Formation/Repair (Anti-neoplastic Agents)
Alkylating Drugs: Non-cycle specific
Anti-metabolites (-ate/purine, bine): Interrupts S-phase
Cytotoxic Antibiotics (-mycin/bicin): Block DNA replication enzymes or produce free-radicals
Vinca Alkaloids (Vin-): Targets Mitosis-phase
Hormonal Anti-neoplastic Agents
Used to treat cancers that are linked to hormonal stimulation
- Prevents cell proliferation by disrupting testosterone/estrogen/progesterone
Immunotherapy
Immuno-stimulants: Stimulate immune system against certain tumor cells
Antibodies
Improving Success of Chemotherapy
Combination Drugs
Dosing Schedule
Route of Administration
Chemo Toxicity
Growth Fraction: ratio of replicating cells (growth) to resting cells in a tissue
- Anti-neoplastic drugs are more toxic to tissues and tumors with high growth fractions
Neutrophils
Very sensitive to chemo due to need for constant replacement. short life span 7-12hrs
Neutropenia: Diagnosed when neutrophil count is below 1500 cells/mL
- Requires reverse iso
- Colony Stimulating factors
Platelets
Lifespan = 7-8 days (needs constant replenish)
- Thrombocytopenia: diagnosed when platelet count drops below 100,000/milliletre of blood
- Low platelets can cause increased bleeding
Erthythrocytes
Lifespan = 90-120 days (anemia appears later in chemo)
- Anemia affects O2 delivery to tissues
- RBC infusions and medications like epoetin alfa can be administered
Extravasation
Unintended leakage of blood, lymph, or other fluids (including chemo drugs) from a blood vessel or catheter into the tissue surrounding IV site
Vesicants
Drugs that have the potential to cause blistering, severe tissue injury or necrosis when they infiltrate into surrounding tissue
Irritants
Agents that may cause inflammation and/or pain at venipuncture site or along the vein
- DO NOT cause tissue necrosis
Stress
Any physical or psychological stimuli that disrupts homeostasis
Sympathetic NS
Fight or flight
Parasympathetic NS
Rest and Digest
Synaptic Transmission
- Pre-synaptic neuron initiates signal that is received by the post-synaptic neuron
- Pre-synaptic neurons contain neurotransmitters (stored in vesicles) that are released into the synaptic cleft when stimulated by action potential
- Binding of neuroT’s to receptors on post-synaptic neuron or target tissues at neuroeffector junction induces response (Activate or inhibit AP)
Synaptic Transmission
Termination of neurotransmitter action
- NeuroT separates from receptor, returning it to baseline activity
- NeuroT is removed from synapse through: Reuptake back into pre-synaptic neuron OR Degradation in synaptic cleft by enzymes
- Acetylcholine degraded by AchE
- Norepinephrine degraded by MAO or COMT in synapse
What do ANS Drugs do?
- Alter synthesis of the neurotransmitter in the preganglionic nerve
- Prevent storage of neurotransmitter in vesicles within the preganglionic nerve
- Influence release of the neurotransmitter from the preganglionic nerve
- Bind to the neurotransmitter receptor site on the postganglionic nerve
- Prevent the normal destruction or reuptake of the neurotransmitter
ANS Receptors
- Cholinergic Receptors (Respond to Ach)
- Adrenergic Receptors (Responds to Epin and Norepin)
Cholinergic Receptors
Nicotinic:
- Found on postganglionic neurons in ANS
- Promotes sympathetic and parasym. effects
- Found at neuromuscular junction of skeletal muscle cells
Muscarinic:
- Found on parasymp. target tissues
- Promotes parasymp. effects
Adrenergic Receptors
Alpha and Beta Subtypes
- Found on target tissues of sympathetic nervous system
**Promotes sympathetic effects
3 Responses to Stress
Alarm Reaction
Resistance/Adaptation
Exhaustion
Alarm Reaction
Stressor = activation of Symp NS (fight or flight)
- SNS = Norepin and Epin
= Increased Symp NS functions and decrease in parasymp innervation
Resistance/Adaptation
Persistant stress activates the Hypothalamus-pituitary-Adrenal (HPA) axis which promotes the secretion of ACTH (which stimulates adrenal cortex to make Cortisol
Cortisol: helps body deal with long-term stress by increasing blood sugar, enhancing metabolism and suppressing non-essential functions like digestion and immune response
Exhaustion
HPA axis may become dysregulated
- Sustained elevation of BP and HR may lead to cardiovascular diseases
- Prolonged inhibition of digestive and urinary functinons = GI and Renal disorders
- Decreased muscle mass and fat = weight loss
Bad immune system
Cortisol
Helps body deal with stress by increasing energy supply
Liver: promotes metabolism
Muscle: reduces glucose uptake and promotes breakdown of muscle proteins into amino acids to make energy
Fat Cell: promotes lipid breakdown for additional energy
Pancreas: decreases insulin and increases glucagon to increase blood glucose
Others: Increase BP by upping vasoconstriction
and reduces inflammation and suppresses immune system
Innate Immunity
Physical barriers: skin and mucous membranes
Cellular Barriers: phagocytes, cytokines
Process barriers: inflammation, opsonins, fever
Adaptive/Acquired Immunity
- Memory (Remembers immune response)
- Relies on Lymphocytes (B cells and T cells) to recognize specific antigens presented by pathogens
(antigens are the foreign substance that provokes the immune response) - B cells produce the antibodies and T cells directly attack infected cells or help regulate the immune response
Plasma
55% of whole blood volume
- Contains 90% water, blood protein and solutes (electrolytes and nutrients)
Cells Contain…
45% of whole blood
- RBCs, WBCs, platlets
- Synthesized via Hemopoiesis
WBCs and Types
-Synthesized from hematopoietic stem cells
- Migrate out of blood vessels into tissues and towards stimulus
- 2 Types:
Granulocytes and Agranulocytes
Granulocytes
Neutrophils:
-First order at the site of injury (within 90min)
- Make up 50-70% of WBC (short-lived)
- Phagocytose and digest pathogens then apop
Eosinophils:
- Respond to parasites involved in allergic reactions
Mast Cells:
- Localized in tissue for allergic responses (player in anaphylaxis)
Basophils:
- Amplifies allergic response
Agranulocytes
Monocytes:
- Inactively circulate bloodstream until chemotaxis signal is received about damage
- Move into interstitial space as macrophages
- **Macrophages phagocytose invaders and produce signals to prolong immune response
Lymphocytes:
- Involved in systemic response
- T Lymphs = kill infected or damaged cels and stores memory
- B Lymphs = secrete antibodies which physically interest with antigens to neutralize or mark them for destruction
Inflammation
Reaction of vascular tissues to harmful stimuli
- Eliminate the initial cause of cell injury, remove the damaged tissue, and generate new tissue
Cells of Inflammation
Endothelial Cells: for a selective permeable barrier between the circulating blood in vessels and the surrounding tissues
Platlets: Release potent inflammatory mediators which increase vascular permeability
Neutrophils and Macrophages:
Eosinophils, Basophils and Mast Cells
Mast Cells
Mostly found in con tissue and blood vessels (skin, mucosa)
- Degranulation may be caused by injury, temp, allergens
- Primary secretors of histamine (primary mediator associated with inflammation assoc w/ allergies)
RSHPL
Redness (rubor)
Swelling (tumor)
Heat (colour)
Pain (dolor)
Loss of function (functio laesa)
Signs of Swelling
Blood Tests in inflammation
Neutrophils
Lymphocytes
Eosinophils
C- Reactive Protein
Inflammation in Tissue Injury
Endothelium, tissues, and mast cells:
-release inflammatory mediators (histamine)
- Release pro-inflammatory mediators (cytokines etc)
Non-Sterodial Anti-Inflammatory Drugs (NSAIDS)
Selective COX Inhibitors:
- Target COX-2-MOA
- Analgesic, anti-inflam, and anti-pyretic actions typical of older NSAIDS
Non-Selective COX Inhibitors:
- First gen - block both COX 1&2
- Side effects of bleeding, gastric upset and reduced kidney function from blocking COX-1
- Eg ASA, Ibuprofen etc
Histamine
Primary mediator of inflammation assoc with allergic reaction
- Released upon mast cells’ contact with allergen… bind to H1 receptors
Histamine + H1 = Smooth muscle contraction, vasodilation & increased permeability, swelling and flare (redness), Increased sensitivity and pain and wakefulness
Anti-Histamines 1st & 2nd Gen
1st:
-block histamine
-receptors, very lipid soluble (causes drowsiness)
- Benadryl
2nd:
- Block H1 - histamine receptor
- Less lipophilic = decreased CNS distribution (non drowsy)
- Eg. Cetrizine (Reactine), Loratadine (Claritin)
Challenges in Drug Development
Local Response:
-Patient touches something
- localized hives, itching, no vital sign changes etc
Systemic: Patient comes to a friends house and a cat is present
- Watery eye, itchy eyes, runny nose, sneezing
Systemic Life-Threatening:
- The cat allergy worsens
- Itching, diffused urticaria throughout, difficulty breathing, tachy
- Anaphylaxis
Pancreas Types and Functions
ACINI:
- Secrete digestive juices into the duodenum
ISLETS OF LANGERHANS:
- Secrete hormones into the cell
- Composed of beta cells that secrete insulin, alpha cells that secrete glucagon and delta cells that secrete somatostatin
Endocrine Pancreas
Islets of Langerhans
Scattered in exocrine pancreas
Made up of 4 cell types
Distribution of cell type varies w/ region of pancreas
Pancreas Cell Composition
Alpha Cell = 10% and 0.5% (Glucagon) In response to low blood glucose and to activity of sympathetic nervous system
Beta Cell = 70-80% and 15-20% (Insulin, Amylin), In response to HIGH bl. glucose and activity of the parasymp. nervous system
Delta Cell = 3-5% and <1% (Somatostatin)
F Cell = <2% and 80-85% (Pancreatic polypeptide)
Pancreas Functions
- Located beneath LIVER and tucked into the curvature of the duodenum
- Has ENdocrine AND EXOcrine functions
EXOCRINE:
- Secretes enzymes into duodenum to support digestion of macromolecules
- Secretes bicarbonate into the duodenum to raise pH of chyme
ENDOCRINE:
- Islets of Langerhans includes Alpha and Beta cells to secrete hormones
3 Metabolic Processes That Ensure Glucose Supply for Body Fuel
1) GLYCOLYSIS = process through which glucose is broken down into water and CO2 w/ the release of energy
2) GLYCOGENOLYSIS = breakdown of stored glycogen (from liver or skeletal muscles)
- Controlled by 2 hormones = Epinephrine (Break down glycogen in muscle) and Glucagon (breaks down glycogen in the liver. Can be directly released into blood stream and used by nervous system)
3) GLUCONEOGENESIS = building of glucose from new sources
- Hormones that stimulate = Glucagon, Glucocorticoid hormones, Thyroid hormones
- Process usually occurs in the liver
Physiology of Serum Glucose Control
Glucose is preferred source of energy to produce ATP by cells of body
- Normal range for serum glucose = 3.3-5.5 mmol/L BUT body usually regulates between 4.4-5
Insulin:
- Promotes formation of glucose transporters that bring glucose from the blood into cells, lowering glucose
- Promotes conversion of monosaccharides, lipids, and amino acids into storage forms of polysaccharides, triglycerides and proteins
- Insulin secretion increases during fed state
Glucagon:
- Promotes conversion of glycogen, proteins and lipids into glucose and release glucose into blood
- Glucagon secretion increases during fasted state
Actions of Insulin on Glucose
- Increases glucose transport into skeletal muscle and adipose tissue
- Increases glycogen synthesis
- Decreases glyconeogenesis
Actions of Glucagon on Glucose
Promotes glycogen breakdown
Increases gluconeogenesis
Actions of Insulin on Fats and Proteins
- Anabolic in nature
- Promotes glucose uptake by target cells and provides for glucose storage as glycogen
- Prevents fat and glycogen breakdown
- Inhibits gluconeogenesis and increases protein synthesis
Actions of Glucagon on Fats and Protein
- Catabolic in nature
- Increases transport of amino acids into hepatic cells
- Increases breakdown of proteins into amino acids for use in gluconeogenesis
- Increases conversion of amino acids into glucose precursers
Other Hormones Affecting Blood Glucose
CATECHOLAMINES:
- Epinephrine and norepinephrine
- Help to maintain blood glucose levels during periods of STRESS
- Inhibiting insulin release and decreasing movement of glucose into cells
- Promoting glycogenolysis by converting muscle and liver glycogen to glucose
- Increasing lipid activity, conserving energy, Causes mobilization of fatty acids and conserves glucose
- Conversion of bl. glucose mediated by these actions is important in the homostatic effect
GH:
- Increases protein synthesis in all cells of the body
- Mobilizes fatty acids from adipose tissue and anatagonizes the effects of insulin
GLUCOCORTICOIDS:
- Critical to survival during periods of fasting and starvation
- Stimulate gluconeo. by the liver
Control of Insulin Release
Normally released in small increments when food is ingested
- Consists of 2 polypeptide chains
- Check amount a person is releasing by testing the C Peptide
- Rise in plasma insulin after a meal stimulates storage of glucose as glycogen in the liver and muscle
- Also inhibits gluconeo. and enhances fat deposition in adipose tissue
- Fall in insulin levels during the night when you’re eating facilitates the release of stored glucose from the liver, protein from the muscle and fat
Counter-Regulatory Hormones
Glucagons
Epinephrine
GH
Cortisol
Amylin
2nd Beta Cell Hormone
Effects:
- Amylin and insulin together suppress the secretion of glucagon by the liver
- Amylin slows the transfer of nutrients to the intestine
Glucagon
Produced in alpha cells
Transported via the portal veins to the liver
Acts in opposition to insulin
Stimulates breakdown of glycogen and fats to glucose and promotes gluconeo. from fats and proteins
Somatostatin
Produced in the pancreas by the delta cells
- Inhibits secretion of insulin, glucagon, GH
Diabetes Mellitus
Major disease affecting pancreas
Occurs when there is insufficient secretion of insulin from the pancreas or when target tissues do not respond to circulating insulin in the appropriate manner
Hyperglycemia is a symptom of underlying problem
Disorder of carb, protein, and fat metabolism (Results from an imbalance between insulin availability and insulin need)
Can represent:
- Absolute insulin deficiency
- Impaired release of insulin by the pancreatic beta cells
- Inadequate or defective insulin receptors
- Production of inactive insulin or insulin that is destroyed before it can carry out its action
Prediabetes
Impaired fasting plasma glucose and impaired glucose tolerance
Risk Factors and Causes of Diabetes
Family Hx.
Obesity esp. abdominal and visceral adiposity
BMI >27%
Race/ethnicity
GDM or babies >9lbs (mom is more at risk of developing if she has big babies)
HTN </= 140/90 mmHg
Triglycerides >200mg/dL
Prev. impaired glucose tolerance
Causes:
- Genetics
- Autoimmune
- Viral
- Environmental
3 Poly of Diabetes
Polyuria = Excessive urination
Polydipsia = Excessive thirst
Polyphagia = Excessive hunger
4 Types of Diabetes
Type 1 = Loss of Beta cell function, Absolute insulin deficiency
Type 2 = Impaired ability of the tissues to use insulin, relative lack of insulin or impaired release in relation to blood glucose levels
Gestational
Secondary
Type 1 DM
aka “Insulin-dependent DM (IDDM)
- Pancreas cannotproduce insulin
- Represents 5-10% of all cases of DM
- Usually underweight
- Treated w/ insulin replacement therapy
- Disease usually appears during childhood through early adulthood
- Rapid onset
Characteristics:
- Little to no C Peptide
- Autoimmune process
- Weak family history
- Obesity uncommon
- Diabetic Ketoacidosis (DKA) often present
- Insulin mandatory (Exercise and diet help)
S&S:
- Frequent urinations
- Unusual thirst
- Extreme hunger
- Unusual weight loss
- Extreme fatigue
- Irritability
- Ketoacidosis
Complications of Type 1 DM
Not treating it**
DKA:
- Extreme hyperglycemia, osmotic diuresis
- Body metabolizes lipids to ketone bodies to create source of energy for cells
- Ketone bodies reduce pH of blood causing metabolic acidosis
- Fruity breath (Due to presence of ketones)
- Treated w/ Insulin and fluid replacement
Type 2 DM
aka “Non-insulin dependent (NIDDM)”
Pancreas does not produce enough insulin to meet needs of body or receptors are not sensitive to insulin that is produced
Represents 90-95% of DM
Clients are usually overweight*
- Treated w/ appropriate diet and exercise, then w/ oral hyperglycemic drugs and then insulin if needed
- Usually appears in the middle adulthood though children w/ sedentary lifestyles are developing disease
- Gradual onset
Characteristics:
- Strong family history
- Obesity common
- DKA rare
- Insulin resistance
- Varying levels of insulin (hyperinsulinemia not uncommon)
S&S:
- Frequent infections
- Blurred vision
- Cuts/bruises slow to heal
- Tingling/numbness in hands and feet
- Recurring skin, gum or bladder infections
- Any of the type 1 signs
- Often no symptoms occur
Type 2 Risk Factors
Previously identified IFG (Impaired fasting glucose) or IGT (Impaired glucose tolerance)
(Aka “Prediabetes”)
- Hypertension (>/= 140/90)
- HDL cholesterol level >/=40 mg/dL
- History of GDM or delivery of babies over 9lbs
Subdivisions of Type 1 Diabetes
Type 1A = Immune-mediated diabetes
Type 1B = Idiopathic diabetes
Idiopathic Type 1B Diabetes
No evidence of autoimmunity is present
- Only a small number of people
- Usually African or Asian decent
- Strongly inherited
- Have episodic ketoacidosis due to varying degrees of insulin deficiency w/ periods of absolute insulin deficiency that may come and go
Metabolic Abnormalities Contributing to Hyperglycemia in Type 2 DM
Impaired beta cell function and insulin secretion
Peripheral insulin resistance
Increased hepatic glucose production
Causes of Beta Cell Dysfunction in Pts w/ DM
- Initial decrease in beta cell mass
- Increased beta cell apoptosis/decreased regeneration
- Long-standing insulin resistance leading to beta cell exhaustion
- Chronic hyperglycemia can induce beta cell desensitization (“glucotoxicity”)
- Chronic elevation of free fatty acids can cause toxicity to beta cells (“Lipotoxicity”)
- Amyloid deposition in beta cell can cause dysfunction
Metabolic Syndrome and Type 2 DM
Metabolic Syndrome:
- Triglycerides
- HDL
- Hypertension
- Systematic inflammation
- Fibrinolysis
- Abnormal function of the vascular endotheluim
- Macrovascular disease
- Obesity and insulin resistance
- Increased resistance to the action of insulin
- Impaired suppression of glucose production by the liver
- Hyperglycemia and hyperinsulinemia
Gestational Diabetes
Higher risk of C-section
Perinatal death
Neonatal complications
Risk of developing type 2 DM in 5-10yrs increased
Any degree of glucose intolerance during pregnancy
Hyperglycemia develops during pregnancy - secretion of placental hormones (Which causes insulin resistance)
-High risk women should be screened at 24-28weeks of gestation
-Need oral glucose tolerance test or glucose challenge
- 2hr Fasting level after 100mL glucose load of 155 would indicate GDM
Secondary Diabetes
Causes:
- Damage/injury/interference or destruction of pancreas
Conditions:
- Cushing’s
- Hyperthyroidism
- Recurrent pancreatitis
- Use of parenteral nutrition
Medications:
- Corticosteroids
- Thiazides
- Dilantin
- Atypical antipsychotics
*Resolves when treatment of underlying condition is treated
Chronic Conditions of DM
Macrovascular disease
Microvascular disease
Ocular disease
Neuropathy
Nephropathy
Other Symptoms of Hyperglycemia
Weight loss
Recurrent blurred vision
Fatigue
Paresthesias
Skin infections
Blood Tests for GLucose
- Fasting Blood glucose test
- Casual blood glucose test
- Capillary blood tests and self-monitoring of cap. blood glucose levels
- Glycated hemoglobin testing
Treatment Plans for DM
Nutrition therapy
Exercise
Anti-diabetic agents
Primary Control of DM
Diet
Exercise
Self-monitored blood glucose
Medications
Other monitoring/tests
Complication Control DM
Controlling complications and target organ damage:
- Bl. glucose/glycosylated hemoglobin
- BP
- Dyslipidemia
- Weight management
- Smoking
- Dental/foot/eye care
- Vaccinations
Oral Antidiabetic Agents
Sulfonylureas
Repaglinide and Nateglinide
Biguanides
α-Glucosidase Inhibitors
Thiazolidinediones
3 Principle Types of Insulin
RAPID-ACTING:
-Clear in appearance
Onset = 10-15min
Peak = 1-2hr
Duration = 3-5hr
Eg)
- Lispro (Humalog)
- Glulisine (Apidra)
- Aspart (NovoRapid)
INTERMEDIATE ACTING:
- Cloudy in appearance
Onset = 1-3hr
Peak 3-8hr
Duration = up to 18hrs
Eg)
NPH (Humulin-N, Novolin-NPH)
SLOW OR LONG ACTING:
- Clear in appearance
Onset = 90min
Peak = None
Duration = up to 24hrs
Eg)
Glargine (Lantus)
Detemir (Levemir)
Zinc
Acute Complications of DM
Diabetic Ketoacidosis
Hyperglycemia
Ketosis
Metabolic acidosis
Hyperosmolar hyperglycemic state
Hypoglycemia
Hypoglycemia Abnormally low bl. glucose level (<70)
Causes:
- Too much insulin or oral hypoglycemic agents
- Too little food or excessive exercise
- Delayed or skipped meals
Hypoglycemia
MILD = sympathetic nervous system is stimulated (Surge of epinephrine and norep.)
S&S = sweating, tremor, tachycardia, palpitations, nervousness, and hunger
MODERATE = Deprives the brain cells of needed fuel for functioning
S&S = inability to concentrate, headache, lightheadedness, confusion, memory lapse, numbness of lips and tongue, slurred speech, impaired coordination, emotional changes, irrational or combative behaviour, double vision and drowsiness
EMERGENCY MEASURES = for pts. who are unconsciousness or cannot swallow = Glucagon 1mg injection can be given IM
Hypoglycemia Unawareness
No warning S&S
Increase risk of dangerously low BS
Related to autonomic neuropathy
DKA
Caused by absence of markedly inadequate amounts of insulin and disorders in the metabolism of fats CHO and proteins
3 Main Clinical Features:
- Hyperglycemia
- Dehydration nad electrolyte loss
- Acidosis, Brunner & Suddath (Insulin deficiency leads to breakdown of fat (Lipolysis) into free fatty acids and glycerol and free fatty acids are converted into ketone bodies by the liver)
Diagnosis:
- Bl. glucose levels >250mg/dL
- Low bicarbonate (<15)
- Low pH (<7.3)
- Ketonemia (positive at 1:2 diluation)
- Moderate ketonuria
Ketoacidosis
S&S = Nausea & vomiting, rapid breathing, extreme tiredness and drowsiness, weakness, acidosis (Fruity breath, tachy, hypotension)
3 Main Causes of DKA and Treatment
1) Decreased or missed dose of insulin
2) Illness or infection
3) Undiagnosed or untreated diabetes
Treatment:
- IV fluid and electrolyte replacement
- Correct acidosis
- Provide adequate insulin
- Est. cause
- Can be mild or severe
Monitoring and Managing Potential Complications
Fluid Overload = administering fluids rapidly to treat DKA or HHNS
Hypokalemia = due to treatment of DKA loss of potassium
Cerebral Edema = cause unknown, may be rapid correction of hyperglycemia resulting in fluid shift
Hyperglycemia Hyperosmolar Nonketotic Syndrome (HHS)
- Serious condition - Bl. glucose 800-1000
- Ketosis usually minimal or absent
- Defect is usually lack of effective insulin (insulin resistance)
- Presistent hyperglycemia causes osmotic diuresis which results in losses of water and electrolytes
- To maintain osmotic equilibrium, water shifts from intracellular fluid space to extracellular fluid space
- With glycosurea and dehydration, hypernatremia and increase osmolarity occurs
- Usually occurs in older adults
Characteristics of HHS
Bl. Glucose = >600
Plasma osmolarity = >310
Dehydration
Absence of ketoacidosis
Depression of the senorium
Causes, S&S and Treatment of HHS
Acute illness
Medications that exacerbate hyperglycemia
Dialysis treatment
S&S:
- Hypotension
- Profound dehydration
- Tachy
- Variable neurological signs
- Morality rate 10-40%
Treatment:
- Fluid replacement and correct electrolytes
DKA vs HHS
DKA:
- More common in Type 1 DM**
- Lower mortality rate
- Onset = hours
- Treatment = fluid replacement, IV insulin, K replacement
HHS:
- More common in Type 2 DM**
- Higher mortality rate
- Onset = Days
- Treatment = NO INSULIN**, replace fluid/electrolyte
Chronic Complications of DM
Disorders of the microvasculature
- Neuropathies (impaired sensation or pain, carpal tunnel, slowed digestion), nephropathies (damage to small vessels that supply glomeruli of kidney. Leading cause of end-stage renal disease), retinopathies (leading cause of acquired blindness)
- Distal symmetric neuropathy and foot ulceration
Macrovascular complications:
- Diseases of large and medium sized vessels
- Atherosclerosis = from altered lipid met.
- Cerebral vascular
- Peripheral vascular disease
- Adults w/ DM = 2-4x increased risk
Heart disease and stroke account for majority of deaths in DM clients
Poor circulation
Pathologic Changes Observed w/ Diabetic Peripheral Neuropathies
Thickening of the walls of the nutrient vessels that supply the nerve
- Leading to the assumption that vessel ischemia plays a major role in the development of neural changes
Segmental demyelinization process that affects Schwann Cells
Accompanied by slowing of nerve conduction
Classification of Diabetic Peripheral Neuropathies
SOMATIC:
- Polyneuropathies (Bilateral sensory)
- Mononeuropathies
- Amyotrophy
AUTONOMIC:
- Impaired vasomotor function
- Imparied GI function
- Impaired GU function
- Cranial nerve involvement
Microvascular Diseases (+ 2 Areas Affected)
Unique to Diabetes
Capillary Basement membrane thickening
- Surrounds the endothelial cells of the cap
- Believed that increased bl. glucose levels react through series of biochemical responses to thicken basement membrane to several times its normal thickness
2 Areas Affected:
- Retina
- Kidneys
DM Retinopathy Proliferative Vs Non-Proliferative
Pro = Most SEVERE form
Non = Most COMMON form
Treatment of DM Nephropathy
Hypertension Control = Lower BP <120/80
Antihypertensive agents:
-ACE Inhibitors (“-pril”)= CaptoPRIL, EnalaPRIL, lisinopril, benazepril, fosinopril etc
- ARB (Angiotension Receptor Blocker) = CandesarTAN, cilexetil, irbesarTAN, losarTAN, potassium, telmisarTAN,
- Beta blockers
Glycemic control:
- Pre-prandial plasma glucose 90-130
- A1C <7.0%
- Peak postprandial plasma glucose <180
- Self-monitoring of Bl. Glu. (SMBG)
- Medical Nutrition Therapy
Restrict dietary protein to RDA of 0.8g/kg body weight per day
3 Primary Treatments of End-Stage Renal Disease (ESRD)
1) Hemodialysis
2) Peritoneal Dialysis
3) Kidney Transplant
Pathogenesis of DM Neuropathy
Metabolic Factors:
- High Bl. Glu.
- Advanced glycation end products
- Abnormal Bl. fat levels
Ischemia
Nerve fibre repair mechanisms
Autonomic Neuropathy
Affects the autonomic nerves controlling internal organs:
- Peripheral
- GU
- GI
- Cardiovascular
Is classified as clinical or sub-clinical on the presence or absence of symptoms
Hypoglycemic unawareness
Sudomotor neuropathy = absence of sweating of the extremities w/ compensatory increase in upper body sweating
Sexual dysfunction
Treatment of Foot Ulcers
Bed Rest
Antibiotics
Debridement
Good control of Bl. Glu.
*If pt has PVD, ulcers may not heal due to the decreased ability of O2 nutrients and antibodies to reach injured tissue
Acanthosis nigricans
Dark, course, thicken skin on the neck
Diabetic dermatopathy
Red-brown flat-topped papules
Granuloma Annulare
Type 1
Autoimmune
Partial rings of papules often in dorsal surface of hands and feet
Pharmacotherapy of Type 2 DM
Most common drugs promote release of insulin (secretagogues) OR increase receptor sensitivity to insulin
SECRETAGOGUES:
- Sulfonylureas (also decreases insulin resistance, can cause hypoglycemia, GI disturbances, rash, cross sensitivity w/ sulfa drugs and thiazide diuretics)
- Meglitinides (Administer slightly before meals, well tolerated)
SENSITIVITY INCREASE:
- Biguanides (Decreases production and release of glucose from liver, increase cellular uptake of glucose, lower lipid level, Risk of lactic acidosis, avoid alcohol, low risk of hypoglycemia)
- Thiazolidinediones (Increases insulin sensitivity to fat and muscle tissue, can cause fluid retention and worsening heart failure. Therapeutic effects take several days to develop. NO hypoglycemia)
ALPHA GLUCOSIDASE INHIBITORS:
- Reduce absorption of glucose by preventing digestion of carbs
- Hypoglycemia can occur if combined w/ another oral drug, insulin or sulfonylurea (treat w/ glucose NOT sucrose)
INCRETIN ENHANCERS:
- Reduce met. of insulin
- Decreases rate of digestion of carbs
- Well tolerated
- Minor nausea, vomiting, and diarrhea
- Some weight loss
- LOW risk hypoglycemia
Incretin Enhancers
GLP-1 acts rapidly to produce:
- Increased amount of insulin by pancreas
- Decreased amount of glucagon secreted by pancreas
- Delayed gastric emptying
- Decreased food intake
2 CLASSES:
- Activating GLP-1 receptor
- Inhibiting dipeptidyl peptidase 4 (DPP-4)
Sulfonylureas
- Divided into 1st and 2nd Gen. categories
- Stimulate release of insulin from pancreatic islet cells
- Increase sensitivity of insulin receptors on target cells
Diabetes Monitoring
Blood:
- Glucose
- Hemoglobin A1C
- Fructosamine
- Lipid Profile
- Creatinine
- BUN
Urine:
- Ketones (Type 1)
- Glucose
- Protein
Weight
BP
Problems Assoc. W/ Urine Glucose Testing
Not easily interpreted (some tests are qualitative instead of quantitative)
Potential false positive readings depending on test used
Lack of direct correlation between urine glucose and bl. glu. levels
Results are technique dependent
Frequency of Bl. Glu. Monitoring
Minimum Recommendation:
- Diet/exercise or oral meds = 2-3times/day to 2-3times/week
Fixed-dose Insulin:
- 3-4x/day to 3 days/week
Intensive Insulin Therapy:
- 3-4x/day everyday
- 3am measurement weekly
Additional measurements needed when:
- sick
- Change in exercise habits
- Travel
- Change in treatment plan
- Symptoms of hypo/hyperglycemia
Factors Affecting Accuracy of Bl. Glu. Tests
User variability
Hematocrit >60% or <25%
Defective strips (temp, moisture, time)
Very high TG and/or cholesterol
Extreme environmental temps
Hypoxia
Altitude
Uric acid
Ascorbic acid
Improper cleaning and maintenance
Glycosylated Hemoglobin (HbA1c)
Formed when glucose reacts w/ hemoglobin (concentration-dependent reaction)
Usually constitutes 4-6% of total hemoglobin
Level reflects ave. bl. glu. over 3 months
Level canbe drawn any time of day (regardless of meals)
Best indicator of overall degree of glycemic control
Monitoring Hemoglobin A1C
Gold Standard for monitoring long term
Should be performed every 3-6months
(3 = therapy has changed or goals not met)
(6 = if meeting goals)
Interpreting HbA1c Levels
> 8% = always warrants changes in therapy**
May experience hyperglycemia for 2-4 weeks before HbA1c will rise
Conditions Affecting Results
Anything affecting ave. life span of RBC can cause misleading HbA1c results:
- Bleeding
- Hemolysis
- Sickle cell anemia
DM & Dyslipidemia
Type 2 have a 2-4 increase risk of coronary Heart Disease
Most common pattern:
- Increased TGs + Decreased HDL
(While LDL seem to be similar to non diabetics)
Weight loss and exercise will DECREASE TGs and INCREASE HDL without need for drugs
Also decreased saturated fats in diet
Dm & HTN
HTN contributes to the development and progression of chronic complications of DM
Decreasing BP will slow the rate of progression of neuropathy, reduce CV disease and cerebrovascular complications
Goal BP = <140/90
ACE-1 or ARB first line = renal protective
Elements of the Hematopoietic System
All blood cells and their precursers
Bone marrow (where blood cells are born)
Lymphoid tissues (where some blood cells circulate as they develop and mature)
Composition of Blood
Fluid/Dissolved Components:
- Water
- Proteins
- Small molecular substances
Cellular Elements:
- RBCs
- Thrombocytes or platelets
- WBCs (lymphocytes and leukocytes)
Function of Plasma Components of Blood
Carry cells that transport gases
Aid in body defenses
Prevent blood loss
3 Plasma Proteins
ALBUMIN:
- 54% of plasma proteins
- Contributes to plasma osmostic pressure and maintenance of blood volume
- Serves as a carrier for certain substances
GLOBULINS:
- 38%
- Alpha globulins transport bilirubin and steroids
- Beta Globulins transport iron and copper
- Gamma “ constitute the antibodies of the immune system
FIBRINOGEN:
- 7%
- Converted to fibrin in the clotting process
Neutrophils (“first responders”)
50-60% of WBCs
Maintaining normal host defenses against invading substances
- 1st cells to arrive at the site of infection (first responder)
- Origins in myeloblasts (bone marrow)
- Move to the tissue for approx. 1-3 days (die in the tissue discharging phagocytic function OR die of senescence)
Eosinophils
1-3% of WBCs
Increase in number during allergic reactions and parasitic infections
- Assoc. w/ allergic reactions**
- In parasitic reactions, they use surface markers to attach themselves to the parasite and then release hydrolytic enzymes
Basophils
0.3-0.5% of total LEUKOCYTES
Involved in allergic reactions and hypersensitivity
- Consist of heparin (anticoagulant), histamine (vasodilator), and other mediators of INFLAMMATION**
Similar to mast cells
Lymphocytes
20-30% of LEUKOCYTES
Defend against microorganisms through IMMUNE RESPONSE
Function in the spleen or lymph nodes
3 Types:
1) B lymphocytes
2) T lymphocytes
3) NK Cells
Monocytes and Macrophages
3-8% total LEUKOCYTE
Important role in CHRONIC inflammation
Involved in IMMUNE RESPONSE:
- Activating lymphocytes**
- Presenting antigen to T cells
Cells survive for months to years in the tissues
Thrombocytes (Platelets)
Circulating cell fragments of the large megakaryocytes
Function to form platelet PLUG that helps CONTROL BLEEDING
8-9 days in circulation
Hematopoiesis
Blood cells originate from pluripotent stem cells in the bone marrow
Proliferation, differentiation, and functional abilities of various blood cells are controlled by cytokines (hormone-like growth factors)
Hemato. Growth Factors
- Increase peripheral stem cells for transplantation
- Accel. cell proliferation after bone marrow engraftment
Eg)
EPO
TPO
G-CSF
GM-CSF
Conditions Responding to Use of Hemato. Growth Factors
Bone marrow failure caused by chemotherapy or aplastic anemia
Anemia of kidney failure
Hemato. neoplasms
Infectious diseases such as AIDS
Congenital and myeloproliferative disorders
Some sold tumors
Complete Blood Count (aka CBC)
Provides info regarding the number of blood cells and their structural and functional characteristics
White cell differential count is the determination of the relative proportions (%’s) of individual white cell types
Ways to Obtain Blood Specimens
Skin puncture (capillary blood)
Venipuncture (Vein blood)
Arterial puncture (artery blood)
Bone marrow aspiration
Types of Diagnostic Tests for Blood
CBC
Erythrocyte sedimentation rate
Bone marrow aspiration and biopsy
Clinical Terms for Blood
Anemia = Low RBC
Polycythmia = High RBC
Leucopenia = Low WBC
Leucocytosis = High WBC
Thrombocytopenia = Low Platelets
Thrombocytosis = High Platelets
Anemia =
Blood loss (hemorrhage) = HEMORRHAGIC Anemia
Bone marrow failure (from radiation, toxin, tumor, fibrosis) = APLASTIC Anemia
Erythropoietin deficiency (secondary to renal disease, Iron, folic acid, Vit B12 deficiency) = NUTRITIONAL Anemia
Hemolysis (RBC destruction) = HEMOLYTIC Anemia
Polycythmia (High RBC)
Low O2 tension in blood (CHD, Cor pulmonale, pulmonary fibrosis)
Polycythemia rubra vera
Dehydration (from severe diarrhea)
Renal Disease w/ high erythro. production
Leucocytosis (High WBC)
Infectious diseases
Inflammatory Disease (Eg RA or allergy)
Leukemia
Severe emotional or physical stress
Tissue damage (Eg burns)
Low O2
Dehydration
Diarrhea
Leukopenia (Low WBC)
Bone marrow failure (Eg. b/c of infection, tumor or fibrosis)
Presence of cytotoxic substance
Autoimmune/collagen-vascular diseases (Eg. lupus erythematosus)
Diseases of liver or spleen
Radiation exposure
Thrombocytosis (High Platelet)
Chronic myeloid Leukemia
Thrombopenia (Low Platelet)
Aplastic anemia
Chemotherapy
Packed Cell Volume (PCV) Hematocrit
Ratio of volume of RBCs to volume of Blood
HIGH Hematocrit = Polycythemia
LOW Hematocrit = Anemic
5 Stages of Hemostasis
1) Vessel Spasm (Vascular Constriction)
2) Formation of platelet Plug
3) Blood coagulation or dev. of an insoluble fibrin dot
4) Clot retraction
5) Clot dissolution
2 Categories of Disorders of Hemostasis
THROMBOSIS:
- inappropriate formation of clots within vascular system
BLEEDING:
- Failure of blood to clot in response to appropriate stimulus
1) Vascular Constriction
Vessel spasm constricts the vessel and reduces blood flow (transient event lasting min-hr)
Vessel spasm is initiated by endothelial injury and caused by local and humoural mechanisms
2) Platelet Plug Formation
Adhesion and aggregation
1) Attracted to damaged vessel wall
2) Activation by subendothelial tissue
3) Changes from smooth disks to spiny spheres
4) Exposing glycoprotein receptors on their surfaces
3) Requirements for Blood Clotting Process
Presence of platelets produced in bone marrow
Von Willebrand factor generated by the vessel endothelium
Clotting factors synthesized in liver using Vit K
4) & 5) Clot Retraction/Dissolution
Interaction of substrates, enzymes, protein cofactors, and calcium ions that circulate in the blood or are released from platelet cells in the vessel wall
Intrinsic and Extrinsic Coagulation Pathways
Terminal steps in both pathways are the same:
- Calcium, factors X&V, platelet phospholipids combine to form prothrombin activator
- Prothrombin activator converts prothrombin to thrombin
- Causes conversion of fibrinogen in fibrin strands that create the insoluble blood clot
Thrombin System
Calcium ions must be present for the thrombin system to begin
Consists of several blood proteins that activate when bleeding occurs
Activated clotting proteins engage in a cascade of chemical reactions that finally produce a substance called “fibrin”
Fibrin strands stick to the exposed vessel wall, clumping together and forming a web-like complex of strands
RBCs become caught up in the web causing a clot
Regulation of Blood Coagulation
Antithrombin III inactivates coagulation factors and neutralizes thrombin
When antithrombin III is complexed w/ naturally occurring heparin, its action is accelerated and provides protection against uncontrolled thrombus formation on the endothelial surface
Protein C (plasma protein) acts as an anticoagulant by inactivating factors V and VIII
Protein S accelerates the action of Protein C
Plasmin breaks down fibrin into fibrin degradation products that act as anticoagulants
Conditions that Create Increased Platelet Function
Atherosclerosis
DM
Smoking
Elevated blood lipoid and cholesterol levels
Increased platelet levels
Conditions that Cause Accel. Activity of the Coagulatory System
Pregnancy and the puerperium
Use of oral contraceptives
Postsurgical state
Immobility
CHF
Malignant diseases
Hypercoagulability States
Increase risk of clot or thrombus formation in the arterial or venous circulations
Arterial thrombi are assoc. w/ conditions that produce turbulent blood flow and platelet adherence
Venous thrombi are assoc. w/ conditions that cause stasis of blood flow w/ increased concentrations of coagulation factors
Causes of Bleeding
Decrease in the # of Circulating Platelets:
- Depletion of platelets must be relatively severe before hemorrhagic tendencies of spontaneous bleeding occur
Impaired Platelet Function:
- Bleeding resulting from platelet deficiency commonly occurs in small vessels and is characterized by petechiae and purpura
Increased Platelet Function
Hypercoagulability due to increased platelet function results in platelet adhesion, formation of platelet clots and disruption of blood flow
Causes of increased platelet function are disturbances in flow, endothelial damage and increased sensitivity of platelets to factors that cause adhesiveness and aggregation
Atherosclerotic Plaques and Platelets
Plaques disturb blood flow, causing endothelial damage and promoting platelet adherence
Platelets that adhere to vessel wall release growth factors which cause proliferation of smooth muscle and thereby contribute to the development of atherosclerosi
Smoking, elevated blood lipids and cholesterol, hemodynamic stress, and DM predispose vessel damage, platelet adherence and eventual thrombosis
Platelet Defects
Thrombocytopenia:
- Low Platelets, increased sequestration of platelets in spleen or decreased platelet survival
Types:
- Drug-induced Thrombocytopenia:
- Idiopathic Thrombocytopenia purpura
- Thrombotic Thrombocytopenia purpura
Impaired Platelet Function
Manifestations of Thrombocytopenia
Bleeding:
- Mucus membranes (nose, mouth, GI tract and uterine cavity)
- Commonly occurs in small vessels (Petechiae = pinpoint purplish red dots & Purpura = purple areas of bruising)
Coagulation and Vit K
Vit K is an essential cofactor for synthesis of clotting factors
Fat-soluble vitamen synthesized by intestinal bacteria
In Vit K deficiency, the liver produces inactive clotting factor resulting in abnormal bleeding
Coagulation Defects
Deficiencies can arise b/c of defective synthesis, inherited disease, or increased consumption of the clotting factors
Eg) Hemophilia A
Hemophilia B
Von Willebrand Disease
Any genetic disruption of the production of the clotting factor
Vascular Disorders that Cause Bleeding
HEMORRHAGIC TELANGIECTASIA:
- Uncommon autosomal dominant disorder characterized by thin-walled, dilated capillaries and arterioles
VIT C DEFICIENCY:
- “Scurvy”
- Results in poor collagen synthesis and failure of the endothelial cells to be cemented together properly, causing fragile wall
CUSHING DISEASE:
- Causes protein wasting and loss of vessel tissue support because o the excess cortisol
SENILE PURPURA:
- Bruising in elderly persons
- Caused by the aging process
Conditions Assoc. W/ Disseminated Intravascular Coagulation
Obstetric conditions
Cancers
Infections
Shock
Trauma or surgery
Hematologic conditions
RBC Development
Continuously being formed from the pluripotent stem cells in bone marrow
Move through a series of divisions to develop into mature RBCs
Normoblast to reticulocyte, the RBC accumulates hemoglobin as the nucleus condenses and is lost
Red cell loses its mitochondria and ribosomes
Function of RBCs
Transportation of O2 to the tissues
Hemoglobin bind some CO2 and carry it from the tissues to the lungs
Hemoglobin molecule is comprised of two pairs of structurally different polypeptide chains
Each of the four polypeptide chains consists of globin (protein) and a heme unit (Which surrounds an atom of iron that binds to O2)
Each molecule of hemoglobin can carry 4 molecules of O2
The production of each type of globin chain is controlled by individual structural genes with 5 different gene loci
Mutations can occur anywhere in these 5 locations
Erythropoiesis
Red cells are produced in the red bone marrow after birth
Until Age 5, almost all bones produce Red cells to meet growth need
- After 5, bone marrow activity gradually declines
After 20yrs red cell production takes place mainly in the membranous bones of the vertebrae, sternum, ribs and pelvis
With this reduction in activity of red bone marrow is replaced with fatty yellow bone marrow
Hemoglobin Structure
Globin Chains = α & β
Heme = Iron & Porphyrin
O2 Binding
RBC Destruction
Lifespan = 120 days
- Broken down in the spleen
- Degradation products (Iron and amino acids) are recycled
Heme molecule is converted to bilirubin and transported to the liver:
- It is removed and rendered water soluble for elimination in the bile
Bilirubin
Heme unit is converted to bilirubin
Insoluble in plasma and attaches to plasma proteins for transport (unconjugated)
Removed from blood by liver and conjugated w/ glucuronide to render it water soluble (conjugated)
Jaundice
RBC Lab Tests
RBC Count:
- measures total # of RBC in 1mm3 of blood
% of Reticulocytes (normally 1%ish):
- Provides an index of the rate of Red cell production
Hemoglobin (grams per 100mL of blood):
- Measures the hemoglobin content in blood
Hemacrit:
- Measures volume of red cell mass in 100mL of plasma volume
Transfusion Therapy
Provides the means for replacement of RBCs and other blood components
4 Major ABO blood types are determined by the presence or absence of 2 red cell antigens (A & B)
The presence of D antigen = Rh-positive type
The absence of D antigen = Rh-negative type
RBC Components Used in Transfusion Therapy
Whole blood
RBCs
Leukocyte-reduced blood cells
Washed RBCs
Frozen RBCs
Immediate Hemolytic Transfusion Reaction
Intravascular lysis of transfused RBCs by complement, IgM
Causes:
- Transfusion of ABO-incompatible blood
- Transfusion of ABO-incompatible plasma
- Non-ABO antibodies
Clinical Manifestations:
- Fever (but most febrile reactions not hemolytic)
- Back pain
- Dark or red urine
- Bronchospasm
- Shock
- DIC
- Organ failure
- Death
S&S of Transfusion Reactions:
- Sensation of heat along vein where blood is being infused
- Flushing of face
- Urticaria (Hives)
- Headache, pain in lumbar
- Chills, fever, constricting pain in chest
- Cramping pain in abdomen
- Nausea and vomiting
- Tachy, hypotension and dyspnea
Treatment:
- Stop transfusion
- IV crystalloid or colloid
- Maintain BP, HR
- Maintain airway
- Diuresis (fluid, loop diuretic, mannitol may cause volume overload)
- Monitor renal and coagulation status
After Stopping Blood Transfusion
Check blood product/paperwork to ensure correct product given
Notify blood bank/transfusion service
Obtain blood and urine samples
- Plasma and urine hemoglobin
- Direct Coombs test
- Repeat crossmatch/antibody screen
- Repeat ABO/Rh typing
Delayed Hemolytic Transfusion Reaction
IgG-mediated lysis of transfused red cells (usually extravascular, non-ABO)
Usually begins 5-10 days after transfusion
Jaundice, falling Hct, positive direct Coombs test, fever
Not generally life-threatening
Febrile, Non-Hemolytic Transfusion Reaction
Cause:
- Cytokines released by leukocytes during storage, antibodies to HLA antigens on transfused or donor PMNS
Incidence:
- </= 0.5% of units transfused
More common in multiple transfused recipients
Fever, chills, res distress in severe reactions
Reduced incidence/severity w/ leukocyte-poor product
Transfusion Related Acute Lung Injury (TRALI)
Hypoxemia w/ bilateral pulmonary infiltrates
No increase in central venous or pulmonary artery pressures
Usually begins acutely within 6hrs of transfusion
Clinical = acute res distress, fever, chills
Pathophysiology:
- Underlying lung injury (Eg. sepsis, pneumonia) causes PMNs to adhere to pulmonary caps
- Mediators in transfused blood product (neutrophil antibodies, cytokines) activate PMNs w/ resistant cap injury
Risk = FFP > Platelets > RBC
Treatment:
- Stop transfusion
- O2
- Ventilatory support
- Pulse corticosteroids
G6PD
Hereditary deficiency of glucose-6-phosphate dehydrogenase predisposes to oxidative denaturation of hemoglobin, w/ resultant red cell injury lysis
Extravascular Hemolysis Vs Intravascular Hemolysis
Extravascular = When RBCs become LESS DEFORMABLE making it difficult for them to transverse the splenic sinosoids
Intravascular = Result of complement fixation in transfusion reactions, mechanical injury or toxic factors
Sickle Cell Disease
Inherited disorder in which an abnoraml hemoglobin (Hemoglobin S [HbS]) leads to the chronic hemolytic anemia, pain and organ failure
Thalassemias
Group of inherited disorders ofhemoglobins synthesis leading to the decreased synthesis of either the α- or β-globin chains of HbA
Iron Deficiency Anemia
Common worldwide cause of anemia affecting people of all ages
Results from dietary deficiency, loss of iron through bleeding or increased demands
B/C iron is a component of heme, a deficiency leads to a decreased hemoglobin synthesis and consequent impairment of O2 delivery
Vit B12 Deficiency
aka Megaloblastic Anemia
Red cells are produced abnormally large b/c of excess cytoplasmic growth and structural proteins
Primary vs Secondary Polycythemia
Primary = Proliferative disease of the bone marrow w/ an absolute increase in total RBC mass accompanied by elevated white cell and platelet counts
Secondary = results from increased erythropoietin levels caused by hypoxic conditions such as chronic heart and lung disease
Neonatal Blood
Hemoglobin concentrations at birth are high, reflecting the high synthetic activity in utero to provide adequate O2 delivery
HbF vs HbA = affinity of F vs A
Hyperbilirubinemia = Unconjugated vs conjugated, phototherapy
Hemolytic disease
Aging and RBCs
Age-Assoc. Decline in the hemto. reserve
- Reduction in hemato. progenitors
- Reduced production of hemato. growth factors
- Inhibition of erythro.
- Inflammatory cytokines interfere w/ erythro. interaction w/ its receptors
Anemia:
- Hb decreases
- RBC production decreases w/ age
- CBC = peripheral blood smear and reticulocyte count and index
- Studies rule out comorbid conditions such as malignancy, GI conditions that cause bleeding and pernicious anemia
Process of Hemostasis
“stopping blood flow”
Proceeds in a series of steps using clotting factors:
- Intrinsic and extrinsic pathways both lead to formation of prothrombinase
- Prothrombinase converts to prothrombin to thrombin
- Thrombin converts to fibrinogen to fibrin
- Fibrin strands trap RBCs forming clots
Cofactors = Ca+2 and Vit K are critical for synthesis of clotting factors
Fibrinolysis = Plasmin breaks down fibrin network
Pharmacotherapy focuses on manipulating these elements
Process of Fibrinolysis
“removal of blood clot, proceeds in cascading steps”
Initiated by release of enzyme ‘tissue plasminogen activator (tPa)’
- Converts inactive plasminogen enzyme in the clot to active form plasmin enzyme
Plasmin digests fibrin strands to remove clot
Diseases of Hemostatis
Thromboembolic disorders:
- Thrombus = stationary clot
- Embolus = clot that moves to another location
- Deep Venous Thrombosis (DVT) = venous clots often develop in the legs as a DVT but can migrate to lungs creating pulmonary embolism
- Clots migrating from left atrium can cause strokes
- Coronary artery clots cause MI
Platelet Disorders:
- Due to decreased production resulting in low Platelet counts
- Bone marrow suppression
- Folic acid and B12 deficiency
- Decreased thrombopoietin in liver failure
Hemophilia and von Willeband’s disease:
- Genetic conditions resulting in absence of clotting factors = difficulty clotting
Anticoagulants
Used to prolong bleeding time in order to prevent blood clots from forming
Eg) Heparin
- Enhances antithrombin III (AT-III) activity
- Decreases thrombin activity (active factor IIa)
- Decreases prothrombinase (Active factor Xa)
Low molecular weight heparin:
- Also enhances AT-III activity but more specific to prothrombinase (active factor X)
- Fewer adverse effects than heparin (Less risk of thrombocytopenia compared to heparin)
History of Anticoagulants
Warfarin has been the drug of choice for the prevention and treatment of arterial and venous thrombotic disorders for more than 40yrs
It was initially marketed as a pesticide against rats and mice and is still popular for this purpose
