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PHM143 Pathobiology > Midterm > Flashcards

Midterm Flashcards

1
Q

Causes of Cell Injury

A
  1. Oxygen deprivation
  2. Physical agents
  3. Chemical agents and drugs
  4. Infectious agents
  5. Immunologic reactions
  6. Genetic alterations
  7. Nutritional imbalances
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2
Q

Causes of Cell Injury: Oxygen Deprivation

A

-Hypoxia is a deficiency of oxygen
-Ischemia is a loss of blood supply from arterial flow or reduced venous drainage
+It occurs in highly perfused organs like the kidney, heart and brain

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3
Q

Causes of Cell Injury: Physical Agents

A
  • Mechanical trauma can occur due to injury from a blow, crush, cut or penetrating wound
  • Extremes of temperature
  • Radiation
  • Electric shock
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4
Q

Causes of Cell Injury: Chemical Agents and Drugs

A
  • Hypertonic salt concentrations - alteration of electrolyte homeostasis
  • Poisons such as arsenic, cyanide, and mercuric salts
  • Insecticides and herbicides
  • Air pollutants such as CO2
  • Alcohol and narcotics
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5
Q

Causes of Cell Injury: Infectious Agents

A
  • Parasites
  • Fungi
  • Bacteria
  • Viruses
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6
Q

Causes of Cell Injury: Immunologic Reactions

A
  • Anaphylactic reaction to foreign protein and drug

- Reactions to endogenous self-antigens (autoimmune response)

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7
Q

Causes of Cell Injury: Genetic Alterations

A
  • Congenital malformation
  • Decreased life of RBC
  • Inborn error of metabolism
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8
Q

Causes of Cell Injury: Nutritional Imbalances

A
  • Protein-calorie deficiencies
  • Vitamin deficiencies
  • Excesses of lipids (obesity, atherosclerosis)
  • Metabolic diseases (diabetes)
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9
Q

Mechanisms of Cell Injury

A
  1. Depletion of ATP
  2. Influx of Ca2+ and Loss of Ca2+ Homeostasis
    - Excess calcium in the cytosol leads to decrease in ATP and in phospholipids, leading to disruption of proteins and chromatic damage –> NECROSIS
  3. Mitochondrial Damage
    - Causes: Hypoxia, toxins, oxidative stress
  4. Accumulation of Oxygen-Derived Free Radical
    - Oxidative stress caused by superoxide anion, hydrogen peroxide
  5. Defects in Membrane Permeability
    - Causes: mitochondrial dysfunction, loss of membrane phospholipide
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10
Q

Mechanisms of Cell Injury: Depletion of ATP

A
  • Causes: Hypoxia, ischemia, chemical injury
  • Major consequence of dysfunctional sodium and calcium pumps because they result in increase influx of calcium, sodium and water –> swelling –> formation of BLEBS, which are small fragments of cell membrane that detach –> cell goes into anaerobic glycolysis and lactic acid increases –> pH more acidic

Ischemia leads to a decrease in oxidative phosphorylation and ATP, which leads…

  1. Decrease in sodium pump –> increase in sodium, calcium and water influx; increase in potassium efflux –> swelling and bleb formation
  2. Increase in anaerobic glycolysis –> decreased glycogen and pH –> clumping of nuclear chromatin
  3. Other: Ribosomes detach –> decrease protein synthesis –> lipid deposition
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11
Q

Types of Cell Death

A
  1. Necrosis

2. Apoptosis

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12
Q

Types of Cell Death: Necrosis

A

Necrosis is the premature death of cells caused by infection or the interruption of blood supply

  • Always pathologic as a result of irreversible injury
  • Types
    1. Coagulative necrosis
    2. Liquefactive necrosis
    3. Caseous necrosis
    4. Fat necrosis
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13
Q

Coagulative Necrosis

A
  • Dead tissue is preserved for a span of time so that the cells are dead but still present
  • Localized area of coagulative necrosis is called an infarct
  • Characterized by
    1. Intracellular acidosis
    2. Denaturation of proteins and enzymes
    3. Inhibition of proteolysis
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14
Q

Liquefactive Necrosis

A
  • Focal bacterial or fungal infections ingest cells
  • Characterized by
    1. Accumulation of inflammatory cells
    2. Digestion of dead cells
    3. Presence of pus
    4. Hypoxic death of cells with CNS
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15
Q

Caseous Necrosis

A
  • Characterized by
    1. Encounters gross appearance alteration (white and cheesy) in the area of necrosis
    2. Tissue structure completely obliterated
    3. Microscopic, granulomatous inflammation
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16
Q

Apoptosis

A
  • Naturally occurring, physiological form of cell death
  • Causes
    1. Physiological –> required for proper development
    2. Pathological –> destruction of cells that threaten an organisms integrity
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17
Q

Apoptosis vs. Necrosis: Mophologically

A

APOPTOSIS

  • Outset: Shrinkage of cytoplasm, condensation of nucleus
  • Plasma Membrane: Blebbing without loss of integrity
  • Chromatin: Aggregation at nuclear membrane
  • Organelles: Mitochondria become leaky due to pore formation
  • Vesicles: Formation of apoptopic bodies
  • Terminal: Fragmentation of cell into smaller bodies

NECROSIS

  • Outset: Swelling of cytoplasm and mitochondria
  • Plasma Membrane: Loss of integrity
  • Chromatin: NOTHAAANG
  • Organelles: Disintegration
  • Vesicles: No vesicle formation, complete lysis occurs
  • Terminal: Total lysis
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18
Q

Apoptosis vs. Necrosis: Biochemically

A

APOPTOSIS

  • Regulation: Tightly regulated process involving activation of enzymatic steps
  • Energy Input: ATP-dependent
  • DNA: Non-random mono- and oligonucleosomal fragmentation (ladder of agarose gel)
  • Timing: Prolytic DNA fragmentation
  • Biochemical Events: Release of factors (cyt c) into cytoplasm by mitochondria and activation of caspase cascade

NECROSIS

  • Regulation: Loss of regulation
  • Energy Input: None
  • DNA: Random digestion (smears of agarose gel)
  • Timing: Postlytic DNA fragmentation
  • Biochemical Events: NOTHAAANG
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19
Q

Apoptosis vs. Necrosis: Physiological Effect

A

APOPTOSIS

  • Extent: Localized effect that destroys individual cells
  • Induction: Induced by physiological stimuli (lack of growth factors changes in hormonal environment)
  • Phagocytosis: By adjacent cells or macrophages
  • Immune System: No inflammatory response

NECROSIS

  • Extent: Affects groups of contiguous cells
  • Induction: Non-physiological disturbances (viruses, hypothermia, hypoxia, ischemia, poison)
  • Phagocytosis: Macrophages
  • Immune System: Significant inflammatory response
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20
Q

Calcium

A
  • Atomic number is 20
  • Atomic weight is 40 g/mol
  • Valence is +2
  • 3.64% of Earth’s crust (5th most abundant element)
  • Sea water contains about 400 mg/L (10 mmol/L)
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21
Q

Calcium: Biological Importance

A
  1. Stabilizes biological membranes
    - Cations are linked to the negatively charged phosphoric part of the phospholipids that comprise the membrane, anchoring them and causing the cell membrane to be firmer and less permeable to other substances
  2. Subcellular signalling
  3. Key component of the structural material bone

Low calcium causes neurons to fire more readily because ion leakage increases need for active sodium transport, lowering the threshold voltage for firing

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22
Q

Hypocalcemia Testing

A
  1. Chvostek Sign

2. Trousseau Sign

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23
Q

Endocrine Control of Calcium

A

Decrease of calcium leads to
1. Decrease in calcitonin –> decrease in bone formation
2. Increase in PTH –> increase in bone resorption and renal calcium reabsorption
3. Increase in 1,25(OH)2D –> increase in calcium absorption
=> ALL of these lead to an increase in calcium to help get back to homeostasis (negative feedback loop)

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24
Q

The Human Skeleton

A
  1. Trabecular bone prevents vertical collapse
  2. Long bone prevents bending

-Bone is a structurally, self-engineering biomaterial

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25
Q

Bone-Density Through Life

A
  • Average for young women
  • This produces a t-score BMD reference point for older women
  • Adult bone is a dynamic tissue, in a subtle, negative equilibrium with environment
  • Approximately 1% of the human skeleton turns over every month
  • Osteoporosis < -2.5 t-score
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26
Q

z-score vs. t-score

A

z-score compares you to your group

t-score compares you to a different group

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27
Q

Osteoporosis

A
  • Diagnosis when bone density is 2 standard deviations below mean of healthy adults under age 35 (z-score of -2.5 if less than 35, t-score of -2.5 if over 35)
  • By 80, most people have osteoporosis (t<-2.5)
  • Once you are over 70, bone mineral density is a better predictor of life expectancy than blood pressure or cholesterol
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28
Q

Osteoporosis: Density Modalities

A
  • Bone Mineral Density using a dual-energy x-ray absorptiometry
  • Ultrasonography is predictive in post menopausal women of fracture risk, but threshold indices yet to be confirmed
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29
Q

Normal Bone Homeostasis

A
  • Bone constantly being turned over
  • Remodeling cycle lasts 120 days
  • Important to allow remodeling
  • Formation and resorption tightly coupled
  • Normally, adult bone mass does not increase
  • Involved cells: osteocytes, osteoclasts, osteoblasts
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30
Q

Bone Remodeling Process

A
  1. Initiation
  2. Resorption
  3. Reversal Phase
  4. Formation
  5. Remodeling Completed
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31
Q

Biochemistry Tests of Bone Markers

A

Formation Markers are released as collagen is made

  • Bone Specific Alkaline Phosphatase - reflects cellular activity of osteoblasts
  • Serum osteocalcin - a bone peptide that is not collagen, it reflects rate of bone protein synthesis by osteoblast
  • Amino and carboxy-terminal propeptides of collagen (PINP and PICP)

Resorption Markers are released as collagen is degraded to peptides

  • Incompletely digested peptide proteins - collagen crosslinks from the N or C terminals of mature bone collagen
  • Calcium - excreted into urine
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32
Q

Clinical Utility of Biochemical Bone Markers

A

-Bone density is like the odometer in a car
-Bone turnover marker is the speedometer
+High suggests rapid bone loss and risk of fracture
-Bone markers may provide useful adjunct in monitoring osteoporosis
-May be useful to predict fracture risk, rate of bone loss and response to therapy

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33
Q

Role in Diagnosis: Bone Density

A
  • Baseline markers higher in osteoporosis patients compared with healthy controls
  • BMD would be expected to be inversely related to bone marker level, but the substantial overlap between normal subjects and osteoporosis
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34
Q

Osteoporosis: Affects on Bone Markers

A

Age and Gender

  • Biochemical markers higher in children
  • In men, markers do not change with age
  • In women, markers increase at menopause, and remain elevated
  • Renal insufficiency may affect markers

Other

  • Markers increased with fractures, liver and kidney disease, bedrest
  • Markers decreased with heavy exercise
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35
Q

PK Features of Vitamin D Metabolites

A

Vitamin D3 –> 25(OH)D –> 1,25(OH)2D

  • Serum vitamin D rises and falls sharply after a dose of vit D3
  • Within 2-3 days, all of a given dose of vit D3 is either stopped in tissues, or converted to 25(OH)D
  • Serum 25(OH)D rises gradually over time and if supplies of vit D are removed
  • 1,25(OH)2D hormone control to increase calcium absorption and bone development; serum levels are not affected by vit D dose because its production is based on PTH and calcium need
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36
Q

Vitamin D: Autocrine/Paracrine Effects

A
  • Cell differentiation
  • Reduce replication
  • Immune function
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37
Q

Rickets and Osteomalacia

A

Rickets

  • Weak muscles
  • Infection prone
  • Vit D deficiency
  • Contracted pelvis

Osteomalacia
-Adult rickets

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38
Q

Vitamin D Fortification vs. Supplementation

A
  • Fortification

- Supplementation is overall more expensive (most for iron > iodine = vit A)

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39
Q

Drug vs. Nutrient Clinical Trial

A

DRUG

  • Recruit persons currently at high risk of disease event
  • Treat existing condition
  • High likelihood to show effect in individual
  • Dose-response is linearly related to a certain point

NUTRIENT

  • Recruit healthy persons at low risk
  • Prevent a currently non-existing future condition
  • Low likelihood to show effect in an individual
  • There are two graphs produced - one that is the index (classic effect of nutrient) and the other that represents a new, putative effect
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40
Q

Colour Blindness

A
  • Inability to perceive differences between some colours
  • Can be caused by mutations on 56 different genes on 19 different chromosomes
  • Most commonly inherited from results from mutations on the X chromosome (more common in men)
  • 3 Forms
    1. Monochromacy - can distinguish no colours
    2. Dichromacy - one colour cannot be seen; one cone type is missing
    3. Anomalous Trichromacy - one of the cone subtypes has an altered spectral sensitivity
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41
Q

Down Syndrome

A

-Caused by the presence of an extra copy of chromosome 21
-Life expectancy is not great and death is usually due to heart problems
-Tests can be done to test for this, but are not great
-Signs and symptoms
+Mental retardation
+Stunted growth
+Muscle impairment
+Others: Small teeth, flattened nose, short neck, eyelid crease, rounded ears, small genitals

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42
Q

Thalassemias

A
  • Hemoglobin is composed of alpha and beta protein subunits. Two genes of each are needed for proper hemoglobin production.
  • Thalassemia is a missing or defective gene that results in anemia
  • Symptoms: mild to severe anemia due to impaired erythrocyte production
  • Treatment: maintain healthy lifestyle, blood transfusions
  • At risk groups: Italian, Greek, Middle Eastern, Asian and African
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43
Q

Sickle Cell Disease

A
  • Results from two copies of the sickle cell hemoglobin gene being present
  • In homozygous individuals, low oxygen levels will cause the RBCs to deform “sickle”, which leads to circulation issues and lower oxygen levels
  • Repeated crisis leads to loss of spleen and reduced lifespan (42 in men, 48 in women)
  • Types of Crisis
    1. Vaso-occlusive Crisis - caused by cells blocking blood flow leading to necrosis, pain and ischemia; treat with morphine
    2. Splenic Sequestration Crisis - filtration function of the spleen is compromised, frequently resulting in splenectomy or death; treat by removing spleen leading to number of infections increasing
    3. Aplastic Crisis - Parvovirus B19 shuts down RBC production for 2-3 days which can be fatal due to pre-existing anemia; treat with repeated blood transfusions
    4. Hemolytic Crisis - rapid loss of RBCs, particularly in G6PD deficient people; treat with blood transfusions
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44
Q

Phenylketouria

A
  • Caused by the absence of the PAH enzyme which is required to metabolize phenylalanine to tyrosine
  • Excess phenylalanine leads to abnormal brain development, seizures, brain damage, and mental retardation
  • Elevated levels might protect fetuses from Ochratoxin A induced abortions; Ocrhatoxin A is a toxin produced by Aspergillus and Penicillium fungi in damp environments
  • Effects can be mitigated by a low phenylalanine diet
  • Screening: Prick newborn on heel and take blood sample –> mass spec for phenylalanine levels
  • Higher rates in Irish, West Scots, Slavs and Yemenite Jews
  • Two Forms
    1. PAH Enzyme Deficiency (98%)
  • Patient needs to severely restrict their intake, particularly in childhood
  • Biopterin-Deficient PKU (2%)
  • Life long supplementation with biopterin (cofactor) can be used and no dietary restrictions are necessary
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45
Q

Cystic Fibrosis

A
  • Results from mutations in cystic fibrosis transmembrane conductance receptors (CFTR). This gene is responsible for regulating the components of sweat, digestive juices and mucus.
  • Those with CF produce overly thick and sticky mucus, resulting in continuous lung infections, as well as sinus infections, poor growth, diarrhea, and poor digestion
  • Primary cause of death is respiratory failure, and you will die of this because medication is not forever

Treatment
-Medications to control infections and inflammation
+Mucolytics to loosen up lung mucus
+Bronchodilators to allow mucus to be coughed up
+Steroids to reduce damage due to chronic lung inflammation
+Antibiotics
-Nutrition
+Thicken mucus can prevent pancreatic excretion leading to poor digestion
+Diet should be high in fat, protein and calories due to poor absorption and energy demands
+Extra vitamins to compensate for poor fat uptake
-Double lung transplant

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46
Q

Muscular Dystrophy

A
  • Cause by group of genetic mutations that cause progressive weakness and wasting of voluntary muscles
  • Leads to muscle loss and fatty and connective tissue replacement
  • Many causes, but Duchenne muscular dystrophy is X linked

Duchenne

  • Leads to muscle degeneration –> loss of mobility, difficulty breathing –> death
  • 1/3000 males
  • Specific cause is dysfunctional dystrophin gene which codes for structural component of muscle tissue leading to fibrosis of muscle tissue
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47
Q

Neural Tube Disorders

A

-Patterning in an embryo is a complex process
-Neural tube should be formed at 3-4 weeks
-Problems can lead to
+Spina bifida –> spine stays open causing neonatal death or life-long paralysis
+Anencephaly –> brain does not form properly lading to miscarriage, still born or brief life
-Exposed spinal tissue in alpha feroprotein leaking into amniotic fluid. Alpha feroprotein also crosses into maternal circulation, so it can be screened for.
-Prevention
+Folic acid fortification

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48
Q

Eugenics

A

Applied science or the bio-social movement which advocates the use of practices aimed at improving the genetic composition of a population

BAD NEWS BEARS

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49
Q

Genetic Counseling

A
  • Can be used to identify carriers of many conditions
  • Can be used to determine if a fetus is a homozygote for a particular condition
  • Cost of gene sequencing is dropping rapidly
50
Q

Gene Therapy

A

-Use a vector to deliver a functional gene to target cells
-Issues to consider
+Is point of insertion random or targeted?
+Should vector be attenuated or capable of continued reproduction?
+Temporary or permanent?
+Should soma to germline transfer be allowed?

51
Q

Free H+

A

-Accumulation of CO2
-Production of metabolic acids
+Dietary proteins –> sulphuric acid
+Incomplete metabolism of carbs into lactic acid or fat into ketoacids
+Toxins such as methanol or ethylene glycol

52
Q

Bicarbonate Buffer System

A

-Increase removal rate of CO2 from hyperventilation
-Buffer with bicarbonate made from the kidney
-Filtered bicarbonate is reabsorbed
+In the cell, water and carbon dioxide makes H+ and HCO3-. H+ is secreted into proximal tubule in exchange for Na+. In lumen, H+ and HCO3- from carbonic acid, which is broken down by carbonic anhydrase when diffused back into the cell
-The kidney makes new bicarbonate by breaking down glutamine into ammonium and bicarb. The ammonium is then excreted in the urine.
-Bicarb can also be made by the metabolism of lactate or ketoacid anions
1. Glucose –> lactate- + H+ –> HCO3-

53
Q

Respiratory Acidosis

A

LOW pH, HIGH pCO2
-Increased level of [H+] due to accumulation of CO2
-Due to either increased production of CO2 and/or reduced rate of elimination
-Hypoventilation can be due to not breathing (sedatives) or not being able to breathe (problem with nerves or muscles of breathing, and/or chest wall; severe lung disease and patients get tired due to extra work of breathing)
-Consequences
+Proteins malfunction, especially cardiac and brain
+Reduced levels of oxygen in blood due to hypoventilation
+Body stimulates kidney to make more HCO3- to compensate for the low pH
-Treatment
+Treat the underlying cause
+Reduce work of breathing
+Assist breathing with a ventilator

54
Q

Respiratory Alkalosis

A

HIGH pH, LOW pCO2
-Reduced level of CO2 leads to reduced [H+]
-Usually due to hyperventilation, which can be triggered by lung disease, sepsis, cirrhosis, pregnancy, certain drugs (ASA, progesterone), brain legions, and anxiety
-Consequences
+Alkalemia causes change in proteins in CV system and CNS
+Twitchy - muscle spasms and risk of seizures/arrhytmias
+High pH inhibits kidney production of bicarb
-Treat underlying cause

55
Q

Metabolic Acidosis

A

LOW pH, LOW [HCO3-]
-Accumulation of H+ due to low [HCO3-]
-Low bicarb can be from loss from the body (diarrhea) or from being used up in buffering added acid
-Consequences
+Heart and brain dysfunction due to low pH
+Low pH stimulates increased ventilation, lowers pCO2 and thereby makes fall in pH less extreme (low bicarb causes H+ to increase –> low pH triggers hyperventilation –> H+ returns to normal)

56
Q

Lactic Acidosis

A
  • Metabolic Acidosis due to lactic acid build up
  • May be caused by hypoxia (TYPE A) or failure to metabolize normally produced lactic acid or greatly increased muscular work (TYPE B)
  • Treat underlying cause
57
Q

Ketoacidosis

A
  • Metabolic Acidosis due to ketoacid (acetoacetic acid/beta-hydroxybutyric acid) accumulation from the breakdown of triglycerides
  • Caused by insulin deficiency either due to type I diabetes mellitus (autoimmune destruction of pancreatic islet cells) or starvation (hypoglycemia)
  • Treat diabetes by replacing insulin
  • Treat starvation by correcting hypoglycemia and ECF volume depletion
58
Q

Metabolic Acidosis Due to Kidney Disease

A
  • Failure to reabsorb filtered bicarb leads to bicarb loss in urine (acetazolamide)
  • Treat by replacing bicarbonate with sodium bicarb
59
Q

Metabolic Acidosis Due to Salicylic Acid

A

-Acidosis only in overdose
-Consequences
+Acid-base disturbances
+Toxic to brain, lung, liver and heart cells
-Treat by alkalinizing plasma and urine by adding bicarbonate to keep the equilibrium shifted towards formation of salicylate anion, which is excreted in urine; hemodialysis if very severe

60
Q

Metabolic Alkalosis

A

HIGH pH, HIGH [HCO3-]

  • Reduced [H+] via increase in [HCO3-]
  • Consider where new source of bicarb is coming from and why it is not being excreted
  • Caused by vomiting or diuretics
  • Consequences - cardiac arrhythmias and neuromuscular twitchiness
  • Treat underlying cause and replace associated deficits such as sodium and potassium
61
Q

Body Fluid Compartments: Four Fundamental Rules

A
  1. Water, by osmosis goes where the particles are
  2. ECF volume is determined by sodium content
  3. Water crosses cell membranes rapidly to equalize osmolarity of ECF and ICF
  4. Volume of cells depends inversely on ECF osmolarity (mainly due to concentration of sodium)
62
Q

Sodium Content and ECF Volume

A

ADD SODIUM

  • Na+ stays in ECF
  • Water joins extra ECF Na+ by osmosis –> ECF volume increases
  • Water either comes from drinking or from ICF

LOSE SODIUM

  • Sodium came from ECF
  • Water is also lost from ECF volume
  • ECF volume shrinks
63
Q

Water and Osmolarity

A
  • Increase ECF osmolarity (HYPERNATREMIA) –> water exits cell –> cell shrinks until ICF and ECF osmolarities again equal
  • Reduce ECF osmolarity (HYPONATREMIA) –> water enters cell –> cell swells until ICF and ECF osmolarities again equal
64
Q

Nephron Action

A
  1. Fluid is ultra filtered from glomerulus into Bowman’s capsule, and then flows into proximal tubule
  2. Proximal tubule carries out bulk reabsorption of water, sodium, and other solutes
  3. Loop of Henle reabsorbs sodium without water in thick ascending limb
  4. Distal tubule reabsorbs NaCl without water
  5. Collecting duct fine tunes final urine composition, via reabsorption of water and salt, and secretion of potassium and H+

Sodium reabsorption is increased in the proximal tubule via action of SyNS and angiotensin II, and in the cortical collecting duct via action of aldosterone

65
Q

ECF Volume Depletion: Causes

A

Causes - Loss of sodium-containing fluid from…

  • Skin via excess sweating and burns
  • Gut via diarrhea and vomiting
  • Kidneys vis osmotic diuresis and pharmacological diuretics (which inhibit renal tubular Na+ reabsorption)
  • Internal Redistribution
  • Bleeding (external or internal)
66
Q

ECF Volume Depletion: Complications

A

Low ECF volume leads to…

  • Low blood volume
  • Reduced cardiac output
  • Reduced BP
  • Reduced perfusion of vital organs (SHOCK)
67
Q

ECF Volume Depletion: Response

A

Activate 3 hormonal systems via baroreceptors

  1. Sympathetic nervous system
  2. RAAS
  3. Antidiuretic hormone

Net Effect
-Circulation
+Increase CO, arteriolar and venous resistance, and arterial BP towards normal
-Kidney
+Reduce renal perfusion, GFR, and urinary flow rate and urinary excretion of sodium and water
+Increase renal tubular reabsorption

68
Q

ECF Volume Depletion: Manifestations

A 
-Changes in pulse and BP
\+BP falls
\+Pulse rises
\+Both changes more likely when patient stands
-Changes in organ function
\+Brain - confusion, depressed level of consciousness
\+Skin - cold, sweaty
\+Liver, gut and kidney dysfunction
-Reduced urine output
69
Q

ECF Volume Depletion: Treatment

A

-Treat underlying cause
-Replace lost NaCl and water
+Orally - eat and drink, oral rehydration (glucose, water, salt)
-IV - normal saline will not change the osmolarity of ECF (versus dextrose, D5W, which would dilutes ECF osmolarity and so water enters the cell, potentially dangerously)

70
Q

ECF Volume Excess: Causes

A

-Excess intake of sodium and water may contribute
-Major factor is inability of kidneys to excrete ingested sodium and water
-Impaired renal excretion due to
+Kidney disease
1. Renal Failure - GFR very significantly reduced, impairs excretion of all solutes and water
2. Nephrotic Syndrome - Excess filtration of proteins, including plasmin which directly stimulates distal tubule to reabsorb Na+
+Hormonal Signals which stimulate the kidney to increase reabsorption of water and filtered Na+
1. Congestive heart failure due to multiple MIs, valve disease, chronic untreated hypertension - low CO activates SyNS, RAAS and ADH
2. Liver cirrhosis due to alcohol, hep B or C

71
Q

ECF Volume Excess: Complications

A
  • Edema - Clinically detectable increased ISF volume
  • Most dangerous form of edema is pulmonary edema
  • Can also have accumulation of fluid in the pleural space (effusion) and peritoneal space (ascites)
72
Q

ECF Volume Excess: Treatment

A
  • Treat underlying cause
  • Reduce intake of Na+ and water
  • Diuretics - drugs which antagonize renal tubule’s reabsorption of Na+
73
Q

Diuretics

A
  1. Furosemide - Acts in ascending limb of the loop of Henle, by binding to the transporter for NKCC protein, which normally acts to reabsorb sodium, phosphate and chloride
  2. Hydrochlorothiazide - Acts in the distal convoluted tubule by binding to chloride site of transporter for the neutral NaCl transporter
  3. Spironolactone - Acts in the cortical collecting duct by binding to aldosterone receptor, inhibiting sodium reabsorption
74
Q

Water Physiology

A

-Regulated by balance of intake and excretion
-Level of thirst and ADH depend on action of osmoreceptor in the hypothalamus
+Shrinks when there is water deficit –> increases thirst and ADH levels
+Swells when there is water excess –> inhibits thirst and ADH levels

75
Q

Role of ADH

A
  • When ADH is not present, fluid passes through the kidney almost unchanged and so urine volume is high and concentration is dilute
  • When ADH is present, aquaporin channel causes water to get reabsorbed and added back to blood supply, therefore urine volume is small and concentration is high
76
Q

Water Excess: Causes

A

-Increased intake of water can be sole cause, and can always contribute
-Major cause is impaired renal excretion of water
+Severe reduction in GFR
+ADH acting when it should not be
1. A cancer of the lung makes ADH - Ectopic hormone production. Cell don’t give a shit. It just do what it want.
2. Severe Diarrhea - Loses water and NaCl, drinks only water, ADH is activated by low CO due to ECF volume depletion, and prevents kidney from excreting ingesting water
3. Congestive Heart Failure - Drinks water, ADH is activated by low CO output due to heart disease, and prevents kidney from excreting ingested water
4. Ecstasy at a Rave - Drug triggers ADH release, and dancing in the heat leads to loss of water and NaCl. Many ravers drink lots of water to prevent overheating and dehydration, which actually leads to severe water excess

77
Q

Water Excess: Complications

A
  • Excess water dilutes ECF [Na+] leading to HYPONATREMIA, which reduces ECF osmolarity, so some of the excess water enters cell
  • Most vulnerable cells are brain cells –> cerebral edema –> confusion, seizures, coma, death
78
Q

Water Excess: Treatment

A
  • Treat underlying cause
  • Restrict water intake
  • If severe, use high concentration IV NaCl to rapidly increase ECF osmolarity and suck water out of cells
79
Q

Water Deficits: Causes

A

-Reduced intake always contributes, especially common in infants and the elderly with dementia, strokes and who have difficulty swallowing
-Increased losses of water
+When fluid lost has lower [Na+] than ECF
+Skin - sweat, insensible skin losses
+Urine - osmotic diuresis and diabetes insipidus
+Gut - vomiting, diarrhea

80
Q

Diabetes Insipidus

A

-Dull, bland, tasteless
-Due to lack of ADH effect
1. Either ADH not being made
+Injury to hypothalamus, surgery, tumour…
+Can treat by giving ADH as DDAVP
2. ADH not working because of kidney problem
+Most common cause is kidney injury due to lithium

81
Q

Water Deficits: Complications

A
  • Water deficit leads to concentration of ECF [Na+] –> HYPERNATREMIA, causing water exit from cells and therefore cell shrinkage
  • Most vulnerable cells are brain cells –> confusion, reduced levels of consciousness, intracerebral bleeding (extreme)
82
Q

Water Deficits: Treatment

A
  • Treat underlying cause

- Give water, orally or IV (D5W)

83
Q

Hyperkalemia: Causes

A
  • Increased intake
  • Shift out of cells due to insulin deficiency, beta-blockers, or massive cell death
  • Decreased excretion from very low GFR and lack of aldosterone effect (adrenal gland disease, drug which inhibits its production (ACE inhibitors, angiotensin receptor blocker), drug which antagonizes aldosterone)
84
Q

Hyperkalemia: Consequences

A
  • Mostly on heart
  • Arrhythmias, particularly bradycardias
  • Extreme: Asystole or ventricular fibrillation
  • Due to increase in ratio of ECF to ICF [K+], which alters resting membrane potential of cell
85
Q

Hyperkalemia: Management Strategies

A
  • Protect the heart - calcium gluconate
  • Shift K+ inside cells - regular insulin + enough dextrose, beta 2 agonists, sodium bicarb (IV)
  • Enhance exit of K+ from body - via gut, urine, or hemodialysis
  • Correct underlying cause
  • Reduce K+ intake
86
Q

Hypokalemia: Causes

A

-Decreased intake
-Shifts into cells
+Insulin
+Beta 2 stimulation
+Sodium bicarb administartion
+Anabolism
-Increased loss
+Gut
+Urine - osmotic and pharmacological diuretics or hyperaldosteronism

87
Q

Hypokalemia: Consequences

A
  • Cardiac - arrhythmias, especially ventricular ones

- Skeletal Muscle - weakness and rhabdomyolysis

88
Q

Hypokalemia: Management

A
  • Correct underlying cause

- Consider prevention in future with ongoing K+ supplements

89
Q

Atherosclerosis

A
  • Chronic disease of elastic and large/medium sized arteries
  • Arterial Wall - Disease of the intima, with secondary damage to media (thickest layer), and almost no involvement of the adventitia (thickest layer)
  • Underlying cause of ischemic heart disease
  • Pathogenesis - respones to injury
  • Basis - focal, choric endothelial injury and dysfunction
90
Q

Atherosclerosis: Risk Factors

A
  • Age, gender, genetics, hyperlipidemia, hypertension, smoking, elevated homocysteine, etc.
  • Metabolic Syndrome
  • Name of a group of risk factors that raise the risk of stroke and other health problems, such as diabetes and heart disease
    1. Large waistline (abdominal obesity)
    2. High triglyceride level
    3. Low HDL cholesterol level
    4. High BP
    5. High blood sugar
  • Diagnosed if you have 3+
91
Q

Atherosclerosis: Endothelial Cells

A

-Endothelial cells are the powerhouse of the CV system and can initiate atherosclerosis if they are unhappy
-Almost anything can fuck up the cells and cause them to form thrombi making the surface uneven so blood vessels cannot flow properly –> turbulence
-Molecular/Gene Changes
+Adhesion molecules
+Cytokines/chemokines
+Growth factors
+Vasoactive peptides
+MHC molecules
+Coagulation factors
+Others

92
Q

Atherosclerosis: Lesions and plaques

A
  • Damage to inner linings of arterial wall
  • Insudation of lipoproteins
  • Adherence to platelets, microphages, etc.
  • Overgrowth of smooth muscle cells
  • Repeated injuries and excess cholesterol-blocked artery

Incidence or lesions - aorta, coronaries, popliteal, internal carotid, and circle of Willis

93
Q

Atherosclerosis: Complication of Plaques

A
  • Rupture and/or ulceration
  • Plaque hemorrhage
  • Thrombosis
  • Calcification
94
Q

Myocardial Infarction

A

-Pathology: Atherosclerosis, plaque changes and thrombosis
-Acute Myocardial Infarction - death of heart muscle due to prolonged reduction in the supply of oxygenated blood, relative to demand, in the region served by an occluded coronary artery
+Caused by disrupted atherosclerosis plaque with hemorrhage/thrombosis
+Morphology
1. Early - Cytoplasmic homogenization, hypereosinophilia, nuclear changes, wavy fibres, infiltration by WBCs
2. Gross (12-24 hours) - Discolouration, edema, softening
-Healing Stages - marked acute inflammation, granulation tissue, fibrosis
-Complications - arrhythmia, decreased perfusion, shock, death

95
Q

Myocardial Infarction: Treatment

A
  • Oxygen Therapy
  • Aspirin to thin blood and prevent further clotting
  • Nitroglycerin to reduce heart’s workload and improve blood flow through coronary arteries
  • Treatment for chest pain
  • Clot busters
  • Percutaneous coronary intervention
  • Beta blockers, ACE inhibitors, anticoagulants, anticlotting medicines
  • Procedure: CABG
96
Q

Heart Failure

A
  • Common, usually progressive condition, almost always the result of chronic or acute underlying cardiac disease
  • Poor prognosis
  • Clinical Features - Related to the heart being unable to pump enough blood and to meet the metabolic needs of the body tissues
  • Causes - Coronary/ischemic, primary myocardial or cardiomyopathies, valvular, congenital; other: thyroid disease, fluid overload, AC valve disease, mountain sickness
  • Most common causes are related to systolic dysfunction (failure of adequate/effective pump action)
97
Q

Heart Failure: Mechanisms

A
  1. Frank-Starling Mechanism
  2. Myocardial remodeling/adaptation with muscle fibre hypertrophy and chamber dilatation
    - Neuro-endocrine systems - norepinephrine, RAAS, ANF - are activated and only have a limited ability to cope and ultimately fail
98
Q

Heart Failure: Treatment

A
  • Treat underlying disease
  • Treat heart failure
  • Medical/Pharmacologic Therapy
  • Surgical - valve transplant or heart transplant
99
Q

Valvular Disease

A
  • Dysfunctions - stenosis (too tight), incompetence (too loose), combination of the mitral or aortic valves
  • Etiology - congenital vs. acquired
  • Rheumatic Heart Disease has focal scars on the myocardium and fibrosis of the valves
  • Complications - sequela, turbulent flow, infection, heart failure
100
Q

Common Liver Function Tests

A
  1. Markers of Liver Cell Damage
    - Aspartate/Alanine Aminotransferase (AST/ALT)
  2. Markers of Cholestasis (bile flow)
    - Alkaline Phosphatase - comes from bone
    - Bilirubin - comes from the breakodown of RBCs in the spleen, and that substance is further metabolized; elevated in someone who has gallstones and those who have pancreatic cancers that block bile duct
  3. Markers of Liver Synthetic Function
    - Albumin - someone with liver disease will not make albumin and so it will be low
    - Prothrombin Time (PT/INR) - time will be elevated with liver dysfunction
101
Q

Alcoholic Liver Disease

A

-Drinking about 80 g of alcohol for years (6 pack, mickey, bottle of wine)
-Leading cause of liver disease in NA
-Non-Alcohol Related Risk Factors
+Gender, ethnicity, genetics, iron storage, co-morbities
+Patients who make more TNF-alpha and PNPLA3 are more susceptible to liver damage because they get more inflammation due to alcohol intake

102
Q

Alcoholic Liver Disease: Pathogenic Pathways

A
  • Continuous alcohol intake leads to the translocation of lipopolysaccharide from the GI lumen to the portal vein, where it activates multiple cytokine genes with inflammatory cytokine production and decrease expression of STATs leading to reduced liver regeneration
  • Can also alter the intracellular balance of antioxidants with subsequent decrease in release of mitochondrial cyt c and expression of Fas, leading to hepatic apoptosis
  • Can lead to the formation of reactive oxidative species –> more liver damage
  • Can lead to leaky gut –> more liver inflammation
  • ACETALDEHYDE is crucial for a lot of the adverse effects
103
Q

Alcoholic Liver Disease: Stages

A
  1. Alcoholic Fatty Liver - Results from the redox imbalance generated by the metabolism of ethanol to acetate leading to increase in lipogenesis
    - May appear within days to weeks of heavy drink, but is reversible with abstinence
    - Almost no LFT abnormalities
  2. Alcoholic Hepatitis - Hepatocellular injury with elevated ALT/AST (AST > ALT) and bilirubin/PT
    - Usually improves with abstinence
    - Can be fatal
    - Prednisone can be used to improve outcome, especially if presenting with encephalopathy as well
104
Q

Cirrhosis

A
  • Diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules
  • Generally diagnosed with a biopsy, unless portal hypertension is present
  • Not completely reversible, fibrosis is present, but nodules are not
  • Prognosis - 5 year survival with 90%, but declines to 70% is they continue to drink
  • Inverse relationship between coffee consumption and risk of alcohol induced cirrhosis
  • Complications - Ascites, esophageal varices, and encephalopathy
105
Q

Cirrhosis: Stages

A
  1. Active Cirrhosis - Elevated ALT/AST, PT/INR and bilirubin; Low albumin
  2. Inactive Cirrhosis - No/minor LFT abnormalities
  3. Endstage Cirrhosis - Normal ALT/AST; Elevated PT and bilirubin; Increased sensitivity to many drugs; Renal failure
106
Q

Cirrhosis: Ascites

A
  • Chief contributing factor is splanchnic vasodilation due to nitric oxide accumulation
  • In its advanced form, there is fluid infection, breathing difficulties, and hepatorenal syndrome
  • Management - sodium restriction, paracentesis, diuretics (spironolactone, furosemide)
  • Treat spontaneous bacterial peritonitis (SBP) with norfloxacin or Septra
  • Patients should be evaluated for transplant as 5 yr survival is poor
107
Q

Cirrhosis: Esophageal Varices

A
  • Commonest bleeding site/complication of cirrhosis
  • Engorgement of veins in esophageal submucosa and stomach because of shunting blood away from liver
  • Accompanied by enlarged spleen –> thrombocytopenia
  • Endoscopic technique used to prevent or stop bleeding –> sclerosing or banding
  • Somatostatin or octreotide can produce some initial vasoconstriction and benefit
  • Prevent using beta-blockers (propranolol, nadolol)
108
Q

Cirrhosis: Hepatic Encephalopathy

A
  • Confusion –> coma
  • Due to accumulation of CNS toxins and increased sensitivity to GABA (main inhibitory NT)
  • Can be brought on by infection, upper GI bleeding, increased protein intake, constipation, and CNS depressants
  • Clinical Diagnosis - no blood test, imaging can detect
  • Managed by enemas, laxatives (lactulose), and dietary protein restriction
109
Q

Utility of Routine LFTs

A
  1. Bilirubin - Biliary function and biliary tract patency.
  2. Alkaline Phosphatase - Biliary tract patency; not liver specific
  3. Transaminases (ALT is more specific than AST) - Hepatocellular insult
  4. Gamma-glutamyltransferase (GGT) - elevated in all liver disorders, especially alcohol abuse
  5. Albumin - Liver synthesis (t50 = 3 weeks in blood); low levels reflect long-term, severe, sustained injury to hepatocytes and their ability to synthesize albumin
  6. Prothrombin Time (clotting time) - Liver synthesis (t50 = hours in blood)
110
Q

Utility of Speciality LFTs

A
  1. Ammonia - Metabolic Insufficiency - Formef from breakdown of amino acids, and generally excreted in the urine as urea. With liver dysfunction, ammonia builds up.
  2. Alpha-feroprotein - Hepatoma - Cancer causes reversion to this instead of albumin
  3. 5’-Nucleotidase - Cholestasis - Elevated if alk phos is from liver
  4. Lactate Dehydrogenase - Metastases, congestion
  5. Alpha1-Antitrypsin - Cirrhosis Etiology - Reduced levels can cause other proteases to run unchecked leading to cirrhosis
  6. Caeruloplasmin - Cirrhosis Etiology - Marker for Wilson’s Disease, which is characterized by an in ability to handle copper properly. Levels decrease with Wilson’s disease.
  7. Iron, TIBC, Ferritin - Cirrhosis Etiology - Marker for iron-storage disorders such as hemochromatosis, in which iron is absorbed in an unregulated fashion from the gut and is then hard to get rid of
  8. Viral Antigens and Antibodies - Hepatitis - Viruses invade the liver and lead to disruption of liver cells and so the antigens for these can be used to work out suspected disorder
  9. Immunoglobins - Chronic Disease - Elevated in liver disorders, can be used as adjunct to flesh out profile of auto immune liver disease
  10. Autoantibodies - Chronic Disease
  11. Acetaminophen - Dx/Px overdose
111
Q

Bilirubin

A
  • Breakdown of heme catabolism
  • Unconjugated bilirubin is transported via albumin to hepatocyte. It is then conjugated via glucoronidation (energy required) and then secreted out into the canaliculus.
  • Biliary tract is distal to hepatocyte in terms of blood flow, and so bilirubin is a maker for how well the liver can conjugate other entities.
  • Bilirubin the urine is only ever conjugated, and so if the liver is not functioning properly, it will not be seen in the liver, but unconjugated will build up in the blood
112
Q

Bilirubin: Handling and Transformation

A
  1. RBC broken down in spleen and unconjugated bilirubin is formed
  2. Unconjugated bilirubin is insoluble so it is bound to serum albumin
  3. Unconjugated bilirubin is transported to the liver where it is conjugated with two molecules of glucuronic acid
  4. Conjugated bilirubin is secreted into the small intestine in the bile where gut flora converts it to bilinogen
  5. Bilinogen can be excreted in the feces where it is then called stercobilinogen and gives feces its dark brown colour OR it can be reabsorbed into the bloodstream and excreted in urine as urobilinogen
113
Q

Biliary Tract Obstruction

A
  1. Extra-Hepatic Obstruction
    - There could be a stone lodged in the common bile duct which would prevent flow
    - Pancreatic cancer causes tumor growth in the lumen or pressing on the lumen from the outside
    - Post-surgical strictures/scar tissue can cause squeezing of common bile duct
  2. Intra-Hepatic Obstruction
    - All the little bile ductules can be impaired because the functioning of the cells lining the duct are impaired
    - Drug-induced
    - Metastasis of cancer from elsewhere to the liver
    - Autoimmune - Primary Biliary Cirrhosis - pyruvate dehydrogenase is fucked up or something
114
Q

Interpretation of Urine

A

Clinical Condition –> Bilirubin –> Urobilinogen

  1. Normal –> not detected –> not detected
  2. Increase hemolysis –> not detected –> increase
  3. Sick hepatocyte or partial cholestasis –> increase –> increase
    - Hepatocyte has impaired capacity that impacts failure to pick up bilinogen and so it spills over into urine
  4. Complete cholestasis –> increase –> not detected
    - Bilirubin is not flowing through the gut and so it is not converted into urobilinogen, but is instead excreted in the urine as conjugated bilirubin instead
115
Q

Diffuse Biliary Tract Obstruction

A
  • Concordance between markers and bilirubin - Majority of the tract is obstructed and marker enzymes rise (ALP, 5’-NTO, GGT) and bilirubin cannot get out of the tract as readily and so there is a rise
  • Acute - Hepatocyte will be normal, and no immune markers indicating chronic disorder will be present
  • Prolonged - Markers for leakage may start to rise
  • Chronic (Primary Biliary Cirrhosis) - Markers are present and there is eventual metabolic insufficiency; generally also associated with increase in IgM
116
Q

Focal Biliary Tract Obstruction

A
  • Metasteses (alpha-feroprotein present)

- Discordance - Bilirubin does not increase as much as in diffuse

117
Q

Hepatocellular Jaundice

A
  • Sick hepatocyte in end stage liver failure
  • Opposite discordance - Greater increase in bilirubin than cholestatic marker enzymes
  • Sick liver cannot conjugate bilirubin and so it builds up
  • Markers do not increase because cholestasis needs to occur for them to (and so you need healthy cell for that)
118
Q

Acute Viral Hepatitis

A
  • Hepatocellular insult
  • Increase AST/ALT (ALT > AST) due to apoptosis of virally infected cells, but not enough to differentiate virus type
  • Normal to increased bilirubin and markers
  • Viral serology can indicate a chronic vs acute condition
119
Q

Toxic Hepatitis

A
  • Halothane induced, metabolic idiosyncrancy
  • Increase in AST/ALT (AST > ALT)
  • Bilirubin is high, conjugated > unconjugated –> metabolic problem in liver
  • Normal IgG –> no long term chronic immune disorder or cirrhosis
  • Negative viral serology and antibodies –> toxic insult
120
Q

Chronic Viral Hepatitis

A
  • Waxing and waning phase
  • Progressive but has little spurts where it is worse and some where it is not as bad
  • Increase AST/ALT (AST > ALT)
  • Increase bilirubin and markers (IgG, anti-smooth muscle Ab, anti-mito Ab)
  • Slight decrease in albumin
  • Increase in prothrombin time
  • Late –> hepatoma –> increase alpha-feroprotein

PHM143 Pathobiology (2 decks)

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