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Glossary of Pathology pt 2

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Created by kwithers

Name 2 categories of diffuse lung disease
1. Obstructive disease
2. Restrictive disease
-these 2 categories are responsible for most of lung disease (some vascular but its a small %)
-both show common symptom: SOB


Define obstructive lung disease
=increased resistance to airflow due to obstruction of airway
Define restrictive lung disease
=decreased expansion of lung parenchyma accompanied by decreased total lung capacity
-airflow is NOT impaired
-fibrosis causes the decreased in total volume of air inspired

Name 4 causes of obstructive lung disease
Chronic disease
1. Emphysema
2. Chronic bronchitis
3. others (bronchiectastasis)

Episodic/reversible
1. Asthma





Describe the lung volume changes in obstructive lung disease.
Hallmark
1. Decreased FEV1
-decreased expiratory flow rate
-usu due to airway obstructive (anatomic narrowing-asthma, or loss of elastic recoil-emphysema)

Normal or increased
1. Total lung capaity
2. Forced vital capacity






Describe the fxnal volume changes in restrictive lung disease
1. FVC is reduced
2. FEV1 is normal or reduced proportionately
3. Ratio of FEV1 to FVC is near normal

Describe some of the causes of restrictive lung disease
=PAINT
Pleural
Alveolar
Interstitial
Neuromuscular
Traumatic cage




True or false: most chronic restrictive lung disease is due to idopathic pulmonary fibrosis
-true
True or false: acute respiratory distress syndrome is an example of an acute obstructive lung disease
-false
-example of acute restrictive lung disease
Name some key differences between chronic bronchitis and emphysema
-both are chronic obstructive lung diseases
-often tend to coexist (esp w/hx of heavy smoking)
1. Different definition emphases
-emphysema: morphologic definition
-chronic bronchitis: clinical features definition
2. Different anatomic distributions
-chronic bronchitis: affects both large and small airways
-emphysema: effects restricted to acinus






What's the difference between COPD and asthma?
-COPD involves IRREVERSIBLE airway obstruction whereas asthma involves REVERSIBLE airway obstruction
Define acinus
=clusters of alveoli ventilated from a common respiratory bronchiole
-basic until of resp
-repsiratory bronchiole is distal to terminal bronchiole
-this is main site of action in many chronic obstructive lung diseases, esp emphysema
-cluster of 3-5 acini=lobule



In chronic obstructive lung diseases, the major affected anatomic site is the _________.
=peripheral airways
Define emphysema
=main form of COPD
-enlargement of air spaces distal to the terminal bronchioles
-destruction of wall of peripheral airspaces w/o obvious fibrosis
-loss of elastic recoil
-different types of emphysema classified by anatomic distribution within lobule (cluster of 3-5 acini)



Name the 2 major types of emphysema.
1. Centriacinar
=centrilobar
-more common
2. Panacinar
=panlobar



Define Centriacinar emphysema
=most common type of emphysema
-central or proximal parts of acini (ie resp bronchioles) affected
-dilation of primary respiratory bronchioles
-distal alveoli spared
-tend to be more common and more severe in the upper lobes
-may have black pigments
-commonly seen with hx of smoking and NO alpha antitrypsin def





Define Panacinar emphysema
-acini are uniformly enlarged from respiratory bronchioles -> alveoli
-more common in lower lobes and lung and anterior part of lungs
-associated with alpha1-antitrypsin def

Define distal acinar (paraseptal) emphysema
-emphysema where proximal acinus is spared and distal acinus is dilated
-usually adjacent to areas of injury (fibrosis, scarring, atelactastasis)
-? association with pneumothorax

Define bullous emphysema
=any form of emphysema that produces large blebs or bullae (cystlike structures)
-associated with spontaneous pneumothorax
Describe the clinical features of COPD
1. Dyspnea
-insidious and progressive
2. Slow, forced expiration
3. Barrel chest
4. weight loss
-if chronic bronchitis
1. cough
2. wheezing
-show reduced FEV1







Contrast pink puffers and blue bloaters.
Pink puffers
-prominent dyspnea -> strong respir. drive
-but oxygenation of HgB NOT impaired

Blue bloaters
-less prominent dyspnea
-retain CO2
-become hypoxic and cyanotic
-tend to be obese

-both types develop secondary pulmonary hypertension









Name the 2 imbalances in the pathogenesis of emphysema.
1. Protease-antiprotease imbalance
2. oxidant-antioxidant imbalance
-cigarette smoke contains ROS that deplete supply of antioxidants in lung tissue -> tissue injury
-both balances tend to coexist
-additive effects of both imbalances



Define alpha1-antitrypsin
-antiprotease -major inhibitor of proteases secreted from neutrophils during inflammation
-normally in serum, tissue fluid, macrophages
-people with alpha1-antitrypsin definiciency have increased incidence of early onset, aggressive emphysema (often compounded by smoking)
-emphysema results from unchecked elastic tissue destruction by proteases


How does cigarette smoke play a role in development of emphysema?
1. Inflammation
-neutrophils and mphage accumulate in alveoli of smokers -> release proteases
-mphage elastase is not inhibited by alpha1 antitrypsin (so still getting tissue destruction even w/out alpha1 antitrypsin def)
2. Cigarette smoke contains ROS that use up anti-oxidants -> oxidative tissue injury


Describe histopathologic changes in emphysema
1. Thinning and destruction of alveolar walls
2. Loss of elastic tissue
-> reduced radial traction -> alveoli collapse during expiration

Define mediastinal emphysema
-condition related to emphysema
-air enters connective tissue of lung, mediastinum, subcutaneous tissue
-Sudden increase in intraalveolar pressure-> alveolar tear -> dissection of air into interstitum -> swelling of head and neck with crackling crepitation all over chest
-air resorbed spontaneously when site of air entry is sealed


Define Chronic bronchitis
-clinical definition
1. Persistent productive cough
2. cough for at least 3 months
3. Cough at least 2 consecutive years
-seen in habitual smokers
-if emphysema is associated the extent of bronchitis can NOT be determined during life




Define the histopathologic changes in chronic bronchitis
Hallmark=hypersecretion of mucus glands
-hypertrophy in tracheal mucus glands
-more goblet cells in smaller airways

Obstruction to airflow due to damage to small airways ->luminal narrowing ->obstruction
1. goblet metaplasia and mucus plugging
2. inflammation
3. bronchiolar wall fibrosis
-coexistent emphysema oten develops







Define bronchiectasis
=permanent dilation of bronci and bronchioles -> secretions accumulate in airspaces
-dilation from:
1. destruction of muscle
2. destruction of elastic tissue
-secondary obstructive lung disease (infections or other causes)
-Hallmark: coughing up copious, purulent, smelly! sputum




Name some major causes of bronchiectasis.
1. Bronchial obstruction
-tumors, foreign bodies, impation of mucus
-bronchiectasis localized to obstructed segment

2. Congenital/ hereditary conditions
-CF, Kartagener syndrome, immunodef (complication of Ab def b/c repeated bacterial infections)

3. Infections
-necrotizing pneumonia (S. aureus, Klebsiella)







Describe the pathogenesis of bronchiectasis
2 intertwined processes:
1. Obstruction
2. Chronic persistent infection
-either process can come first
-if obstruction first -> hampered by obstruction -> secondary infection develops

-if persistent infection -> damage to bronchial walls -> weakness and dilation





Define Kartagener syndrome
-syndrome associated with bronchiectasis
-genetic disorder that mutation that results in microtubular disorgationzation -> defective cilia
1. Impaired clearance of cilia
-stasis of cilia
-leads of accumulation of secretion
-causes bronchiectasis
2. Impaired motility of sperm-> infertility
-Also see:
1. sinusitis
-due to impaired cilia
2. situs inversus (major visceral organs in mirrored positions from normal anatomic location)









Define Cystic fibrosis
-most common genetic lethal disease among whites
-defect in CFTR gene on chromosome 7
-characterized by malfxn of exocrine glands ->
1. increased viscosity of mucus
2. increased Cl- [] in sweat
-Manifestations in:
1. lung
-chronic lung disease with chronic bronchitis and bronchiectasis
2. Pancreatic insufficiency
-def in pancreatic enzymes
3. Sweat
-see finger clubbing










Describe the pathogenesis of restrictive lung diseases
-diffuse fibrosis of parenchyma -> stiff lung
-hallmark is reduced compliance of the lung
-also see reduced:
1. expansion lung parenchyma
2. total lung capacity
3. O2 diffusing capacity -> hypoxia
-due to damage of alveolar epithelium and intersitial vessels





Name some causes of chronic restrictive lung diseases
-many heterogeneous causes lead to common end pt of a stiff lung
1. Unknown
-idiopathic: 65% of all cases
-post-ARDS
2. Environmental
3. Drug and tx related
-some chemo drugs
-ionizing radiation
4. Immunologic disorders
-hypersensitivity pneumonia
-Sarcoidosis
-Wegener's
-allograft rejection











Describe the histopathological changes with restrictive lung disease
-type I cells are injured and type II cells proliferate (hyperplasia) and repair/replace injured lining
-proliferation of fibrosis
-recruitment and activation of neutrophils and macrophages, lymphocytes
-interstitum accumulates inflam cells and fibroblasts or noncellular material (ex ECM)
-formation of honeycombing
-thickened wall from fibrosis pulls airspaces wider




Define Wegener's granulomatosis
-unknown etiology
-necrotizing granulomatous vasculitis of small-medium sized vessels of respiratory tract, kidneys
-respir tract symptoms (esp paranasal sinuses)
-can see necrotizing glumerulonephritis
-fibrinoid necosis of small arteries and veins
-granuloma formation
-associated with antineutrophil cytoplasmic antibodies (C-ANCAs)





Contrast ventilation and respiration
ventilation
=movement of gas into and out of the lungs; the mechanical aspect

Respiration
=what happens to gas when it gets into the lungs
-gas exchange between organism and environment




Why can young people do so much damage to their lungs and not have symptoms?
-b/c of lung reserve
-in general, have to lose half your lung fxn before you have symptoms
-symptoms here are defined as ability to perform daily activities
-tests of lung performance used to detect disease may not correspond with symptoms pt reports


True or false: in order to get air into the lungs, you have to create a pressure gradient
-true
-to get air into the lungs, you have to have a higher pressure at airway opening than in the lungs


The flow of gases in the lungs depends on:
1. driving pressure
2. how fast the air can flow
-this is affected by resistance
-if an airway is narrowed, you will either have to generate more pressure or have slower flow


How do we create the driving pressure for ventilation
=need to generate a negative pressure in lungs
-negative pressure created by muscles of inspiration (diaphragm) contracting -> flattens and moves down
-you suck air into your chest
-the way you normally expire is to stop inspiring and recoil in lungs creates passive positive pressure for air to leave
-vs with forced expiration, you have to contract your abdominal muscles to create positive driving pressure



How do we use lung fxn tests to evaluate disease?
-mostly used to distinguish between obstructive and restrictive lung diseases
-obstructive lung disease= something obstructs airflow into or out of lungs; narrowed airways, you have to do more work
-pressure-flow problem
-restrictive= lungs wind up too small
-pressure-volume problem



True or false: vascular lung diseases can be effectively evaluated with lung fxn tests
-false
How is spirometry used?
-measure volume and flow of gas
-noseclip, tube in mouth
-get a volume-time tracing
-can use spirometry to measure:
1. FEV1
2. FVC




Define FEV1
-forced expiration for 1 sec
-how much air comes out in first second when you blow as hard and as fast as you can
-most air comes out of lung in 2-3 sec
-volume or flow problems will reduce FEV1


Define FVC
=forced vital capacity
-how much air can you get into and out of your lungs through you much
-volume measurement, not time dependent



What does FEV1/FVC tell you?
-tells you the percent of total volume you can get out in the first second
-obstructive lung disease: FEV1 reduced more than FVC -> ratio decreased
-the proportion of FVC that comes out in the first second is reduced
-in restrictive lung disease, both FEV1 and FVC are reduced -> ratio is normal or increased


Name the 4 important lung volumes
1. TLC
-maximum lung volume
2. FRC
-resting, end-tidal volume
3. RV
-minimum lung volume
4. VC
-max volume you can exhale (or inhale) through your mouth






Name 3 techniques used to measure absolute lung volumes (including RV)
1. Helium dilution/nitrogen washout
-measures gas volume "communicating" with the airways
2. Body plethymograph
-measures "compressible" thoracic gas volume
-most accurate
3. Radiograph
-measures thoracic cage volume from standard chest xray

-usually volumes from all 3 are same, but can see some differences when pt has lung disease







How do lungs compensate for obstruction and decreased flow rates in COPD?
-hyperinflates (raises its lung volumes)
-FRC, RV and sometimes TLC are elevated


Name 2 lung volumes that are affected in restrictive lung disease
-in restrictive lung disease, volumes are reduced
1. VC
-always reduced in restrictive lung
-can also be reduced in obstructive lung
2. TLC
-only lowered in restrictive lung disease

-when both VC and TLC are lowered -> evidence of restrictive lung disease






How do things affecting the pleural space cause restrictive lung disease
=if you fill the pleural space up with stuff -> lungs get smaller
-air, fluid, inflamm exudate, fibrinous material, infection
Interstitial tissue in the lung refers to the space between the _____ and the _______.
-air
-blood
-in restrictive lung disease you can have interstitial space fill up with edema, inflammation, fibrous tissue -> lung gets stiffer

How do neuromusclular changes cause restrictive lung disease?
-by affecting your ability to inhale or exhale
-weakended muscles -> reduced respiratory excursion (amplitude)
True or false: lungs volumes can be altered in restrictive lung disease without lung itself being altered in restrictive lung disease
-true!
-abnormalities in thoracic cage (lung is normal, but volumes are reduced)
Name 2 tests of respiratory fxn (not involving lung volumes)
-not evaluating ventilation
1. Arterial blood gases (PaO2, PaCO2)
2. Diffusing capacity (DLCO)



Name the 3 determinants of arterial oxygen transport
1. Lungs (P02: driving pressure to load hemoglobin)
-affected by ventilation, perfusion, and diffusion
2. Blood (hemoglobin)
-affected by affinity for O2, quantity
3. Cardiovascular
-affected by CO, distribution




Why do we care about alveolar-arterial oxygen gradient?
-assess for arterial hypoxemia (efficiency of lungs in oxygenating mixed venous blood) -gradient increased with age -normal is less than
Name some causes of hypoxemia for normal and elevated alveolar-arterial oxygen gradient
hypoxemia=low PaO2
Normal gradient (no problem with lung)
1. Altitude
2. Alveolar hypoventilation
-drug overdose

Elevated gradient
1. Low V/Q due to lung disease
-responds to supplemental O2
2. Right to left shunt due to lung or heart disease
-no response to supplemental O2
3. Low diffusion










True or false: PaCO2 reflects adequacy of alveolar ventilation
-true
-PaCO2 can be increased by:
1. increased CO2 production
2. decreased ventilation
3. increased dead space



Name some causes of hypercapnia for normal lungs and for lung disease.
Normal lung
-reduced ventilation
1. Depression of respiratory center
-drug overdose, CNS injury
2. Neuromuscular disease involving respiratory muscles,
-MG, Guillan Barre, SCI

Lung disease
1. Increased ventilation
-high V/Q
2. Decreased ventilatory reserve
-limits ability to increase ventilation to excrete CO2










Describe DLCO
=diffusing capacity
-noninvasive
-evaluate adequacy of alveolar-capillary surface in gas transfer
-if disease process that thickens barrier between air and blood -> diffusion can be blocked
-DLCO can be affected by many factors
-when reduced, nonspecific indicator of lung disease
-DLCO can be increased in states of pulmonary pleothora (CHF, hemorrhage, asthma)





True or false: aging mimics emphysema
-true
Changes in lung _____ cause you to lose flow with age.
parenchyma
-airways affected as well b/c they are embedded in the parenchyma
-loss of elastic recoil
-increase in Type III collagen (makes lung more floppy)
-b/c of loss of recoil, lung becomes more compliant and can hold increased volume
-as a result, lower FEV1 with age
-vital capacity also lowered in aging





True or false: exercise can prevent the regression of lung fxn with age
-false
-even with exercise, you still see regression
-you do improve your VO2 max with age

Why are old people more likely to get infections such as pneumonia?
-b/c mucociliary escalator fxn declines with age -> increased propensity for infections
Name 5 factor of airway resistance
Dynamic
1. Mucosal thickness
2. Mucus gland secretion
3. airway SM tone

Static
1. Airway size
2. lung elastic recoil






Who secretes surfactant?
-type II alveolar cells
-decreases air-water surface tension
Name 4 effects of surfactant

-decreases air-water surface tension which:
1. increases lung compliance -> decreased work of lung
2. creates hysteresis in pressure-volume curve of lung b/c modulates surface tension in volume-dependent manner
3. prevent atalectasis (prevent smaller radius alveoli from overfilling larger alveoli)
4. helps prevent pulmonary edema by preventing surface tension from decreasing interstitial pressure



Name 5 important metabolic products produced by the lung
1. surfactant
-by type II pneumocytes
2. Prostaglandins
3. HM
4. ACE (angiotensin converting enzyme)
-converts AngI-AngII
-inactivates BK
5. Kallikrein
-activates BK







A right shift of the oxygen dissociation curve means....
-decreased affinity of Hb for O2
-this facilitates unloading of O2 to tissue
-Factors causing Right shift:
Increased
1. metaoblic needs
2. H+ ions
(but DECREASED pH)
3. PCO2
4. Temperature
5. 2,3 DPG (high altitude)








Name 5 kinds of drugs that can be used to tx asthma
1. Beta 2 agonists
-albuterol, salmeterol
-bronchodilators
2. Methylxanthines
-theophylline
-bronchodilation
-narrow TI
3. Ipratropium
-muscarinic antagonists ->prevents bronchoconstriction
4. Cromolyn
-prevents mast cell degranulation
5. Antileukotrienes
-Zileuton: LIPOX inhibitor
-Zafirlukast, motelukast: block LT R; good for ASA-induced asthma












Define Goodpasture syndrome
-disease caused by antiglomerular basement membrane antibodies directed against Ag in glomerular and pulmonary alveolar BM
-Clinical manifestations:
1. Nephritic syndrome
2. Pneumonitis with hemoptysis
3. peak incidence in men in mid 20s
4. RPGN crescentric morphology
-linear immunofluorescence shown with IgG antibody studies
-can cause restrictive lung disease






How can a pneumothorax be classified as a form of restrictive lung disease?
-b/c you lose negative intrapleural pressure that normally keeps the lung opposed to the chest wall to allow inflation for breathing
Name 7 structural pathological hallmarks of restrictive lung disease
1. thick strands of collagen in interstitum
2. loss of alveolar wall capillaries
3. chronic inflammatory infiltrate (mononuclear cells and fibroblasts)
4. distortion of normal alveolar structure
5. loss of alveolar gas space (gas volume) and of entire alveoli
6. Airways pulled open even more because as collagen fibers shrink -> increased radial traction
7. heterogenity (some areas of lung affected more than others)





Why are lung volumes reduced in restrictive lung disease?
-b/c of:
1. loss of alveoli
2. encroachment by collagen -> stiffer lung that can't expand as well (reduced compliance)
-all lung volumes reduced to same degree (TLC, FRC, VC, RV)


True or false: restrictive disease lungs show less dynamic compression than normal healthy lungs
-true
-greater radial traction from increased collagen fibers decreases ability of airways to collapse
-also see greater expiratory flow rates b/c of increased radial traction

Name 4 causes of hypoxemia
=low PO2 in arterial blood
1. hypoventilation
2. V/Q mismatching
3. Shunting
4. Diffusion limitation



Why do people with restrictive lung disease have low DLCO?
-DLCO=carbon monoxide diffusing capacity
1. fewer capallaries -> less gas exchange surface area
2. fer capillaries -> less capillary blood volume
3. longer diffusion pathways from alveolar gas to RBC due to interstitial fibrosis
4. non-uniform distribution of CO inhaled during test -> reduced CO uptake -> reduced DLCO
-b/c of uneven distribution of fibrous tissue
-but diffusion limitation is not a cuase of hypoxemia in most cases at rest (b/c need at least 3x decrease in DLCO)





How does restrictive lung disease result in shunting?
-cause of hypoxemia in restrictive lung diseases
-2 ways:
1. collagen build-up in alveolar walls -> alveolus collapse -> loss of ventilation
2. capillaries embedded deeply in fibrous interstitial tissue -> prevents diffusion of O2 into capillaries


Of the 4 causes of hypoxemia, _________ is the major cause in restrictive lung disease (fibrosis).
=V/Q mismatch
-low V/Q in some parts of lung and uneven V/Q ratio distribution throughout lung
1. fibrosis -> decreased compliance -> decrease ventilation (V)
2. Destruction of capillaries and replacement by collagen -> decreased Q


What effect does the mixed venous PO2 have on hypoxemia?
-it worsens it!
-In areas of lung with shunts or low V/Q, blood will be poorly oxygenated (remain close to mixed venous PO2) -> when mixes with normal oxygenated arterial blood in pulmonary veins -> lower arterial PO2
-peripheral tissues continue to extract normal amounts of O2, and this makes mixed venous O2 even lower

True or false: pulmonary HTN is common with fibrotic restrictive lung disease
true
HTN due to increased pulmonary vascular resistance
1. destruction of pulmonary capillaries
2. distortion by pushing and pulling of lung tissue by collagen fibers in random directions
3. hypoxic pulmonary vasconstriction

-physical exam sign: P2 louder than A2 due to pulm HTN
-pulmonary HTN can result in RV hyptertrophy and if HTN for long enough, RHF
-HTN made worsen with exercise







Is pulmonary fibrosis associated with hypercapnia or hypocapnia?
-hypocapnia
-distortion of alveolar walls -> activate alveolar J (juxtacapillary) Rs -> stimulate respiratory centers in brain -> hyperventilation -> breath off CO2 -> lower PCO2
How is gas exchange exacerbated during exercise in pulmonary fibrosis?
-basically, all the 1.abnormalities in pulmonary fibrosis at rest made worse with exercise
Additional factors
2. diffusion limitation from exercise causes hypoxemia
3. CO may not rise as much as in normals
4. because of capillary destruction, not able to recruit unperfused capillaries during exercise, can only distend -> increased pressure b/c of increased CO -> high afterload -> worsens RV hypertrophy



Name 3 anatomic locations that can result in increased resistance to airflow
1. inside the lumen
-excessive secretions
-pulmonary edema
-foreign body
2. in wall of airway
-contraction of broncial SM
-hypertrophy of mucus galdns
-inflammation and edema of airway wall
3. outside the airway (peribronchial region)
-destruction of lung parenchyma -> loss radial traction -> airway narrowing
-compression of airway by enlarged lymph node, neoplasm
-peribronchial edema










Describe the lung fxn characteristics in COPD
-chronic cough
-poor exercise tolerance
-evidence of airway obstruction
-overinflated lungs
-impaired gas exchange



A normal alveolar-arterial gradient is less than ____.
=25 mmHg
use A-a gradient to evaluate cause of hypoxemia
-hypoxemia but normal gradient -> problem is not in the lung (esp CNS depressed vent drive, etc)
-Increased A-a gradient and hypoxemia -> the problem is in the lung (diffusion defect, V/Q defect, R-> L shunt)


Contrast hypoxemia and hypoxia
-hypoxemia= decreased arterial PO2

-hypoxia=decreased O2 delivery to tissues
-O2 delivery= CO x O2 content of blood
-can be decreased by:
1. decreased CO
2. decreased O2 binding capacity to Hb
3. Decreased arterial PO2






Define pulmonary hypoxic vasoconstriction
=response by pulmonary blood vessels to hypoxia
-increases pulmonary vascular resistance
-redirects blood away from poorly ventilated areas of lung toward well-ventilated regions

True or false: changes to ventilatory drive is mediated by changes in PC02 in central (CNS) mechanisms only
-false -also PCO2 peripheral Rs in carotid and aortic bodies -also PO2 Rs (but have to get PO2 < 60 mmHg before get hyperventilation), H+ peripheral Rs
Define ARDS
=acute respiratory distress disorder
-acute restrictive lung disease
-main site of disease action: alveolar wall (diffuse injury to alveolar wall-> alveolar capillary and epithelial damage)
-characterized by breakdown of normal barrier (alveolar wall)-> leakage of protein-rich fluids from pulmonary capillaries into interstitum and alveolar spaces
-can be due to pulmonary or systemic causes
-impaired gas exchange -> hypoxia
-fatal in over 50% of cases





Name some pulmonary causes of ARDS
1. Diffuse pulmonary infections
2. Inhalation
(oxygen, smoke, other irritant fumes)
3. Aspiration of gastric fluid
4. Near drowning
5. Irradiation
6. Chemical toxicity
7. Massive embolism
(air, fat, or amniotic fluid)







Name some systemic causes of ARDS
1. Sepsis
2. Shock associated with trauma/hemorrhage
3. Acute pancreatitis
4. DIC
5. Extracorporeal circulation for major surgery



Describe the major early/acute tissue pathology associated with ARDS
-capillary/ alveolar epithelial injury
-edema
-congestion
-inflammation (inflammatory exudate in alveolar wall)
-hyaline membrane
-Injury NOT evenly distributed
-alveolar wall thickened -> impaired gas exchange





Describe the physiological changes due to structural derangements of ARDS
-stiff tissue
-decreased compliance
-decreased blood-gas exchange
-V/Q mismatch




Name 4 symptoms/signs associated with ARDS
Show rapid onset, severe respiratory insufficiency
1. Dyspnea
2. Cyanosis
3. Arterial hypoxemia
-poorly responsive to oxygen Rx
4. Respiratory acidosis
-may progress to multiorgan failure
-high mortality rate (greater than 50%)
-if survive, may progress to chronic interstitial fibrosis







Describe the later cellular/tissue changes in ARDS
1. Resorption of alveolar and intersitial edema
2. Clearing of injurious debris
3. Repair of alveolar lining
-with proliferation of type II cells
4. Gradual resolution or fibrosis
-fibrosis due to collagen deposition in the walls




Name 4 categories of extrapulmonary causes of restrictive lung disease
1. Neuromuscular
2. Respiratory Muscle disorders
3. Chest wall deformity and impaired movement
4. Pleura diseases


All of the following are neuromuscular causes of restrictive lung disease EXCEPT
a. Guillan-Barre
b. ALS
c. Myasthenia gravis
d. polymyositis



=polymyositis
(autoimmune disease of SKM that can affect muscles of respiration and lead to restrictive lung disease)
-do NOT confused with poliomyelitis

Give some examples of pleural diseases that can cause restrictive lung disease
1. Primary pleural disease
-neoplasm: mesothelioma
-bacterial infection in intra-pleural space
2. Secondary pleural disease
-pleural effusion (fluid)
-pneumothorax (air)




Define malignant meothelioma
=tumor of the pleura
-causes primary pleural disease -> can cause restrictive lung disease
-tumor arises from mesothelial cells of pleura (but could also arise in peritoneum, pericardium)
-exposure to asbestos responsible for approx 50% (shows long latency period)
-pathogenesis unknown





True or false: smoking and asbestos exposure have a synergistic carcinogenic effect on mesothelioma
-false
-but they do increase risk of develop bronchogenic cancer (a synergistic effect)
Define pleural effusion
=increased accumulation of fluid ( > 15mL) in pleural space
-can be due to a variety of mechanisms/associated diseases
-Fluid composition varies (inflammatory, non-inflammatory)
-secondary pleural disease that can result in restrictive lung disease


Name 4 mechanisms of pleural effusions and give examples of diseases that cause it.
1. Increased hydrostatic pressure
-CHF
2. Increased vascular permeability
-pneumonia
3. Decreased oncotic pressure
-nephrotic syndrome
4. Decreased lymphatic drainage
-medistinal malignancies






Give examples of inflammatory and non-inflammatory pleural effusions
-fluid composition can vary depending on cause of effusion

Inflammatory
1. Serofibrinous -inflamm. in adjacent lung
2. Suppurative (pus)
-suppurative infection
3. Bloody
-tumor

Non-inflammatory
1. Transudate
-CHF
2. Blood
-trauma
3. Chyle
-tumor obstruction of lymphatics














Define pneumothorax
=when air/gas gets into the pleural space
-as air enters -> lung collapses and rib cage springs out
-2 types
1. Spontaneous
2. Tension



Define Spontaneous pneumothorax
-pneumothorax caused by break in pleura due to: 1. Trauma 2. Rupture -emphysematous bulla -cyst of honey-combed lung -destructive pneumonia 3. Air via needle or catheter 4. No known cause -air usually gets resorbed gradually b/c partial pressure pulm cap < atm pressure
Describe the clinical presentation of pneumothorax
-sudden 1-sided pain
-dyspnea
-decreased breath sounds
-xray diagnostic (side w/collapsed lung will look darker)


Define tension pneumothorax
-collapse of lung caused by air entering, but not leaving the pleural space
-as amt of air in pleural space increases -> pressure builds up in chest ( IPP > atm pressure)-> interferes with venous return to thorax
-lung collapses and can push mediastinal structures toward other side of chest -> shift can cause other lung to be compressed
-Sx: dyspnea, tachycardia
-can be medical emergency
-X ray shows pneumothorax + mediastinal shift
-relieve pressure by inserting tube into chest wall and connect to underwater seal





How does ARDS develop?
-imbalance of pro and anti-inflammatory mediators causeing acute inflammatory injury to alveolar epithelium and capillary endothelium -> increased vascular permeability and flooding
-injury to type II pneumocytes ->surfactant abnormalities
-infiltration with neutrophils -> release products that cause further alveolar damage and sustain inflammation
-presence of hyaline membranes
-gross appearance of lung is dark red, firm, airless, and heavy



The characteristic microscopic finding of ARDS is ________.
=hyaline membrane
-hyaline=pink
-membrane made up of fibrin-rich (coag molecular found in clots) edema fluid mixed with remnants of necrotic epithelial cells



Describe the sequelae associated with various pleural effusions
Resobed without residual effects if cause is controlled or remits
1. transudates
2. serous exudates

Fibrous organization -> adhesions or fibrous pleural thickening, sometimes calicifications
1. fibrinous
2. hemorrhagic
3. suppurative






Define pulmonary edema
=abnormal accumulation of fluid in extravascular spaces and tissues of the lung
-impt complicattion of many heart and lung diseases
-may be life threatening

Compare the interstitum on either side of the pulmonary capillary
1. Thin side
-fused basement membranes of alveolar epithelium and capillary endothelium
-impt for gas exchange

2. Thich side
-2 fused BM + type I collagen fibers
-impt for fluid exchange





True or false: alveolar epithelium are highly permeable to ions
-false
-they are relatively impermeable, compared with the pulmonary capillary
The net flow of fluid out of a capillary is described by the ______ eqn. ________ forces tend to move fluid out of the capillary while ______ forces tend to keep fluid in the capillary.
-starling eqn
-hydrostatic forces
-osmotic forces

What's the significance of the perivascular and peribronchial spaces in the lung?
=thin sheath of tissue around pulm art, veins and bronchi
-this is where fluid goes when it leaves the capillaries
-contains lymphatics
-when there is interstitial edema, these spaces become engorged (cuffing)


Name 2 factors that reduce fluid outflow during excessive capillary leakage
1. increased hydrostatic pressure in interstitial space
2. decreased colloid osmotic pressure in capillary space (increased fluid dilutes the proteins)
Name the 2 stages of pulmonary edema
1. Interstitial edema
-increased lymph flow from lung
-perivascular and peribronchial cuffin
-septal lines on chest radiograph
-little effect on pulm fxn

2. Alveolar edema
=fluid in alveoli (they shrink)
-often severe dyspnea and orthopnea
-pt may cough up pink, frothy fluid (contains RBCs, proteins)
-marked opacification on radiograph
-often severe hypoxia










Name 6 mechanisms that result in pulmonary edema
1. Increased capillary hydrostatic pressure
2. Increased capillary permeability
3. Reduced lymph drainage
4. Decreased interstitial pressure
5. Decreased colloid osmotic pressure
6. Unknown




Name some causes of increased capillary hydrostatic pressure that result in pulmonary edema
-usu result of heart disease
1. acute MI
2. HTN LV failure
3. mitral valve disease
-development of pulmonary edema depends on rate of raise of edema (if chronic, lymphatics can accomodate edema)
4. transfusion overload
5. pulmonary veno-occlusive disease
-depending on amount of increased pressure, can get low permeability edema (mostly fluid) to high permeability edema (disruption of cap endothelium -> edema fluid contains proteins, cells)






Name some causes of increased capillary permeability that result in pulmonary edema
1. Inhaled toxins (chlorine, etc)
2. Circulating endotoxins
3. Radiation (ex. breast cancer tx)
4. oxygen toxicity
5. ARDS
-edema fluid has high protein concentration and many blood cells




Name some causes of reduced lymphatic drainage that can result in pulmonary edema
-Increased central venous pressure
1. ARDS, HF, overtransfusion

-obstruction of lymphatics
1. tumor
2. lymphangitis
3. silicosis (silica ingest by mphage kills the cells --> they jam up the lymphatics)





Name some causes of decreased interstitial pressure that results in pulmonary edema
1. rapid removal of pleural effusion or pneumothorax
2. Rapid expansion of collapsed lung
3. hyperinflation of lung

Name some causes of decreased colloid osmotic pressure that can result in pulmonary edema
-not sufficient to cause pulm edema but can exacerbate
1. saline overtransfusion
2. hypoproteinemia (liver disease, renal disease)

Name some causes of pulmonary edema due to unknown mechanisms
1. High altitude in normal lung
-due to uneven arterial hypoxic vasoconstriction -> increased pressure on some capillary beds
2. Neurogenic pulm edema (CNS injuries(
3. overinflation of lung
4. Heroin overdose



Describe the clinical features of pulmonary edema
1. Dyspnea, orthopnea, paroxysmal nocturnal dyspnea
-often rapid, shallow breathing
2. Cough, may be pink frothy sputum
3. Crepitations on auscultaton at base of lungs
4. Radiograph
-septal lines (interstitial edema)
-blotchy shadowing
(severe edema); "butterfly wing"






Describe the effects of pulmonary edema on lung fxn
Mechanics
-reduced distensibility
-Decreased lung volumes
-increased airway resistance

Gas exchange
-not affected w/interstitial edema
-impaired in alveolar edema

Control of ventilation
-rapid shallow breathing due to stimulation of J Rs on alveolar walls (vagal afferents)

Pulmonary circulation
-PVR increases
-can see higher blood flow at apex vs base (reversal of normal, cardiogenic pulm edema only)















Name 7 predisposing factors for venous thrombosis in legs
-impt b/c source of 95% of PE
1. prolonged bedrest
2. surgery
3. severe trauma
4. CHF
5. women in period around parturition or who take birth control pills with high estrogen content
6. disseminated cancer
7. primary disorder of hypercoaguability (factor V Leiden)






What happens if you block a major branch of the pulmonary artery in PE?
-acute right heart failure
-increase pulm arterial pressure
-decreased cardiac output

Describe the pathophysiology that arises from PE
Pulm arterial occlusion ->
1. increased arterial pressure upstream
2. ischemia of pulmonary parenchyma downstream -> alveolar collapse

Hypoxemia results from
1. V/Q mismatch
-perfusion of lung zones that have become atelectatic
-pulm infarction is impossible but rare






Why are the lungs less likely to infarct?
1. because of dual blood supply (pulmonary artery and bronchial arteries)
-if one is compromised, other able to compensate a little bit
2. also, lung has lower metabolic needs versus the brain or heart

-thus, infarct is rare complication of PE



Name 2 factors influencing the severity of consequences from a PE
1. size of the emboli
-one big emboli in large artery or multiple smaller embolisms can cause sudden death, acute RHF, CV collapse
2. general state of circulation
-compromised CV status -> can get infarction
-infarction usu hemorrhagic and usu in lower lobes



True or false: patients who have had one PE are at increased risk of developing another
-true
-people at high risk may need anticoagulation
True or false: the majority of PE are clinically silent
-true
Name 3 longterm consequences of PE.
1. Dissolution of the clot (lysis)
2. Post-phlebitic syndrome
-veins chronically blocked -> leg edema
3. Chronic thromboembolic pulmonary HTN
-clot in pulm artery replaced by fibrous tissue ->turns into big scar -> causes HTN



Define embolism and name some things that can embolize
=any material that travels through venous circulation to lodge in distal vessel (ex pulm circulation)
-things that can embolize
1. iatrogenic (bone, etc)
2. fat
3. tissue cells
4. drugs and drug carriers
5. micro-organisms
6. venous thromboembolism (clot)








Name 2 mechanisms that result in pulmonary HTN
1. decrease in cross-sectional area of the pulmonary arteries
2. increased pressure in pulmonary arteries
-pulm HTN usu due to secondary causes that affect these 2 mechanisms

Contrast compensation and decompensation in pulmonary HTN
Compensation: RV hypertrophies to maintain flow
-usu asymptomatic

Decompensation: RV unable to maintain output -> dyspnea/dizziness during exertion
-can lead to RV failure and death if untreated



Name 4 categories of causes of pulm arterial HTN
1. Idiopathic
-primary
2. Familial
3. Secondary to other diseases
-chronic obstructive or interstitial lung disease
-recurrent pulm emboli
-antecedent heart disease (mitral valve, congential left->right shunt)
4. pulm HTN due to venous or capillary involvement






Describe the pathology of pulm HTN in small arteries
-note: pulm HTN can cause changes to all levels of the arterial tree

small arteries
1. vasoconstriction (reversible vasospasm)
2. arterial wall hypertrophy (SM hypertrophy)
3. vascular lumen obstruction




Describe clinical presentation of primary pulmonary HTN
-often idiopathic
-young persons
-women
-fatigue
-syncope (esp w/excercise)
-dyspnea on exertion
-complications:
1. respiratory insufficiency and cyanosis
2. RHF
-need a lung transplant








Define tuberculosis
=communicable chronic granulomatous disease caused by Mycobacterium tuberculosis
-usu involves lungs but can affect any tissue in body
-granulomas undergo caseating necrosis
-clinical disease is result of previous infection with M. tuberculosis


Name some epidemiological factors that cause TB to flourish
1. Poverty
2. Crowding
3. Chronic debilitating illness/immunosuppression
-high rates in people with HIV/AIDs

-elderly susceptible b/c weakened immune defenses
-children under 2 years susceptible for infection progressing to disease





Contrast TB infection and TB disease
-Need TB infection to get disease
-BUT NOT everyone with TB infection gets disease

-Infection=seeding of a focus of tissue with organisms
-usu asymptomatic, often self-limited infection
-5% risk of progressing to develop TB disease unless immunosuppressed, etc

-disease associated with significant tissue damage








How is TB spread
-person to person transmission via airborne respiratory droplets from person with active TB
Why is TB able to reactivate?
-b/c via organisms can remain
Name some anatomic requirements for ventilation and give example of diseases that can disrupt ventilation
Bellows
1. central drive
-drugs, stroke, trauma
2. intact brainstem
-stroke, trauma, tumor
3. SC
-trauma (C2-C5), tumors, transverse myelitis, MS
4. anterior horn cells
-poliomyelitis, ALS
5. Peripheral nerves
-critical illness polyneuropathy, Guillan-Barre
6. NMJ
-Myasthenia gravis, Eaton-Lambert, botulism
7. Intact thoracic cage
-kyphoscoliosis, pectus excavatum
8. Respiratory muscles
-fatigue, muscular dystrophy, polymyositis

Lungs
-primary lung diseases


















Define respiratory failure
-failure of respiratory system to maintain adequate gas exchange (pH, PCO2, PO2) at a reasonable metabolic cost

-respiratory system here defined as lungs AND brain, SC, peripheral nerves, thoracic cage, respiratory muscles

Define ventilation
=moving air into and out of the lungs
-reflected by PCO2
-alveolar ventilation can be found by subtracting dead space from the exhaled ventilation

As alveolar ventilation decreases, alveolar PaCO2 ______.
-increases
-hypercapnia
-PaCO2= VCO2/VA
-level of CO2 related to its production and ventilation




What is a normal Alveolar -arterial gradient?
-20 or less than 1/3 of age
-A-a gradient impt to establish cause of respiratory failure
-if respiratory failure with NORMAL A-a gradient -> hypoventilation WITHOUT lung problem
-look in the bellows

-respiratory failure with ABNORMAL A-a gradient -> primary lung problem




Define hypercapnia
=high PCO2
-respiratory cause due to decreased ventilation
-causes respiratory acidosis
-can be compensated by kidneys
-can cause confusion, headache, papilledema, coma
-can result in pulmonary arterial vasoconstriction




True or false; chronic hypercapnia can lead to decrease responsiveness to ventilation stimulatory effects of CO2.
true
Name the 4 mechanisms of hypoxemia and give examples of conditions that can that cause these
-can produce hypoxemia with normal PCO2 levels
1. Impaired diffusion
-pulm fibrosis, profound anemia, hemoglobinopathy
2. Shunt
-congenital heart disease, pulmonary atreriovenous
malformation
-will NOT respond to 100% O2
3. Inadequate inspired partial pressure of O2
-altitude
4. Ventilation-Perfusion Mismatch
-almost anything can cause this!
-most common cause of hypoxemia
-pneumonia, pulmonary edema, emphysema
-will respond to 100% O2
-PO2 decreases b/c blood perfusing some areas that are not well ventilated













Name the 4 diagnostic criteria for ARDS
1. bilateral pulmonary infiltrates
-assuming pt has 2 lungs
2. hypoxemia
3. normal left atrial pressure
-allows to rule out pulmonary edema from left heart failure
4. acute onset




Name 6 major causes of ARDS
1. Trauma
-esp if under 30 yrs
2. Infection
3. Pancreatitis
-result of immense activation of immune system
-often get noncardiogenic pulm edema
4. Aspiration lung injury
5. Blood transfusions
-TRALI
6. Drug Rxns
-ASA, opiods (heroin overdose)









Describe the main pathophysiological findings of ARDS
1. Decreased compliance
-requires high pressures to inflate the lungs
-> decreased ventilation -> hypoxemia
2. Impaired gas exchange
-b/c of alveolar infiltrate (fluid, proteins cells) + hyaline membranes
-> hypoxemia
3. Altered pulmonary hemodynamics
-b/c of hypoxic vasoconstriction and obstruction due to vascular microthrombi

-patchy involvement of the lung
-initially most hypoxemia b/c V/Q mismatch but later shunt impt too









Static compliance of the lung reflects the ____ pressure
-alveolar pressure
-vs dynamic compliance reflects pressure of entire resp system
-static compliance decreased in ARDS

How do we treat ARDS?
1. Supportive measures
-ventilation but try to limit O2 toxicity/trauma to lungs
2. Treat underlying cause

True or false: granulomatous disease predisposes to hypercalcemia
-true
Define non-bacterial thrombotic endocarditis
-associated with cancer
Name 4 defense mechanisms of the nasopharynx
1. nasal hairs
2. turbinates
3. mucociliary apparatus
4. IgA secretion


Name 4 defense mechanisms of the oropharynx
1. saliva
2. sloughing of epithelial cells
3. local complement production
4. interference from resident flora


Name 4 defense mechanisms of the conducting airways
=trachea and bronchi
1. Cough, epiglottic reflexes
2. sharp angled branching airways
3. mucociliary appartus
-sweep up toward oropharynx
4. Ig production (IgM, IgA, IgG)




Name 5 defense mechanisms of the lower respiratory tract
=terminal airways and alveoli
1. alveolar lining fluid (surfactant, complement, Ig, fibronectin)
2. cytokines
3. alveolar macrophages
4. PMN leukocytes
5. cell-mediated immunity




When do you get pneumonia?
-when pulmonary defense mechanisms are overwhelmed
1. immunosuppressed, immunodeficiencies
2. Interference with clearing mechanisms
-ex smoking interferes with mucuociliary apparatus and bactericidal actions of mphages
-also accumulation of fluid or secretions in alveoli -> makes a broth for bacteria, etc to get comfy in



Alcohol can interfere with all of the following respiratory defense mechanisms EXCEPT:
1. loss/suppression of cough or epiglottic reflex
2. injury to mucociliary appraratus
3. Interference w/ phagocytic or bactericidal action of alveolar mphages
4. in



-mucociliary apparatus (affected by smoking)
True or false: most community acquired pneumonias are bacterial in origin.
-true
Describe the symptoms of a community acquired pneumonia
-abrupt onset
1. high fever
2. shaking chills
3. pleuritic chest pain
4. productive purulent cough
5. +/- hemoptysis

-infection may follow a URI






Name 6 bacteria most likely to cause community acquired pneumonia
1. S. pneumoniae
2. Haemophilis influenzae
3. Moraxella catarrhalis
4. Staph aureus
5. Klebsiella pneumoniae
6. Legionella pneumophilia




Name 3 groups of people who frequently develop pneumonia from S. pneumoniae.
1. Chronic underlying disease (CHF, COPD, diabetes)
2. Congenital or acquired Ig defects
3. Asplenic (splenectomy or sickle cell)

Typical community acquired pneumonia shows a _______pathologic pattern of infection while atypical community acquired shows a _______ pattern.
-typical: inta-alveolar
-atypical: interstitial
Name 2 gross patterns of distribution with intra-alveolar pneuomnia.
=typical community acquired pneumonia
1. Lobar pneumonia
2. Bronchopneumnia

-patterns frequently overlap and bronchopneumonia can develop into lobar



Define Lobar Pneumonia
=gross pattern for an intra-alveolar pneumonia (typical community acquired)
-seen w/ S. pneumoniae infecitons
-large portion of one lobe or complete lobe involved
-4 stages
1.congestion
2. red hepatization
3. gray hepatization
4. resolution






Name the 4 stages of lobar pneumonia
1. Congestion (24 hrs)
-gross: heavy,boggy, red
-micro: vascular congestion, intra-alveolar fluid (edema), few PMNs
2. Red Hepatization (2-4 days)
-gross: firm, dry, red, airless
-micro: alveoli filled with exudate of RBCs, PMNs, fibrin
3. Gray hepatization
(days 4-7)
-gross: gray, dry
-micro: RBCs disintegrate, LOTS of fibrin, PMNs, necrotic debris
4. Resolution (8-10days)
-gross: normal or septal thickening and adhestions
-micro: exudate digested and resorbed











Define Bronchopneumonia
=gross pattern of intra-alveolar pneumonia (typical community acquired)
-patchy distribution
-frequently multilobar
-can be bilateral and basally located
-Bacteria: H. influenzae, Legionella
-gross, well-developed 3-4 cm lesions (gray/red -yellow)
-lesions may become confluent and mimic lobar pneumonia





Describe the pathology seen with bronchopneumonia
1. Patchy distribution
2.PMN rich exudate in bronchi, bronchioles, alveoli
3. large areas of lung between lesions that are normal

Define atypical community acquired pneumonia
-shows interstitial pattern of involvement
-atypical b/c:
1. ONLY moderate sputum production
2. No physical findings of consolidation
3. only moderate elevation of WBC
4. Lack of alveolar exudate
-usu due to organisms that need cells to replicate





Name some organisms that cause atypical community acquired pneumonias
-need host cells to replicate
1. Mycoplasma pneumoniae
Viruses
1. Influenzae A and B
2. Resp Synctial virus



Describe the pathology of atypical pneumonia
=interstitial
-alveolar septum are widened and filled with inflammatory cells
-more lymphocytes that PMNs
-NOT in the alveolar sac
-patchy or lobes bilaterally or unilaterally
-usu alveoli free of exudate but can contain proteinaceous material (ARDS)




Describe pathogenesis of interstitial pneumonia
1. Organism attaches to resp epithelium -> necrosis and inflammation
2. inflammation in airways -> interstitial edema
3. Damage due and denudation of respir epithelium inhibits mucociliary clearance and predisposes to 2ndary bacterial infections
-fluid may leak into alveolar spaces so that on chest xray it may mimic bacterial pneumonia


Define nosocomial pneumonia
=hospital acquired pneumonia
-esp common in hospitalizaed pts w/
1. severe underlying disease
2. immune suppression
3. prolonged antibiotic therapy
4. on ventilators

Offending organisms:
1. gram negative rods
2. S. aureus








Define aspiration pneumonia
-pneumonia caused by aspiration of:
1. infective material (from oral cavitiy, infected tonsils, sinuses)
2. Gastric contents
(usu accompanied by organisms from oral pharynx)
-pneumonia is partly chemical (gastric acid) and partly bacterial (oral pharynx normal bacteria; aerobic and anaerobic)
-often necrotizing pneumonia w/ abscess formation
-part of lung affected varies





What determines that part of the lung affected in aspiration pneumonia?
=the patient's position
1. Upright pt
-right middle and lower lobes
-b/c more vertical orientation of R mainstem bronchus
2. Lying down
-right upper lobe




Define Lung abscess
=localized area of suppurative necrosis within pulmonary parenchyma
-results in formation of one or more cavities
-similar process seen in necrotizing pneumonia
-Organisms that like to form lung abscesses:
1. Normal flora of oral cavity
2. aerobic and anaerobic strep
3. S. aureus
4. gram negative organisms






Name 5 causes of lung abscesses:
1. Aspiration of infective material from oral pharynx, gastric contents
2. Complication of necrotizing pneumonia
3. Bronchial obstruction
4. Septic emboli
5. Hematogenous spread of pyogenic bacteria
-esp Staph bacteremia




Describe the morphology of a lung abscess
-cavity containing pus
-walled off by fibrin, leukocytes, granulation tissue
True or false: aspiration pneumonia is usually due to a single organisms
-false
-usu due to a couple
-aspirate infective material from oral cavity or gastric contents + normal oral flora
-bacteria can be aerobic and anaerobic


__________ is a form of chronic pneumonia
-tuberculosis
-most often localized lesion in immunocompetent person
-typically due to:
1. M. tb
2. fungi



Name the 3 pathologic stages of tuberculosis due to Mycobacterium
1. Primary
-in a previously unexposed person
2. Secondary
-in a previously exposed person
-occurs when host defenses are weakened
3. Miliary
-either primary or secondary TB
-result of hematogenous or lymphatic spread -> M. tb seeds in other organs
-get tiny granulomas in other organs







Define Primary Stage of tuberculosis due to Mycobacterium
-in previously unexposed person
-usu asymptomatic
-affects:
1. lower pt upper lobe
2. upper pt lower lobe
-Characterized by Ghon complex




Define Ghon complex
-characteristic of primary stage of tuberculosis
-1-1.5 cm caeseating granuloma and lymph node
Define Secondary stage of tuberculosis due to mycobacterium
-in a previously exposed person
-occurs when host defenses are weakened
-Sx:
1. low grade fever
2. night sweats
3. hemoptysis
4. Pleuritic chest pain
-caesating granulomas in apex of lungs






How is pneumonia different in the immunocompromised host?
-includes HIV, organ transplants
-due to opportunistic organisms (rarely cause disease in healthy people)
-higher mortality
-can be local or diffuse depending on infecting organisms


How does CD4 T cell count influence risk of infection with pneumonia in HIV patients?
-more likely to get infected with pneumonia from different organisms depending on CD 4 T cell count 1. CD 4> 200 -common bacterial pathogens 2. CD 4< 200 -Pneumocystis jiroveci 3. CD 4 < 50 -CMV -Mycobacterium avium
Define Cytomegalovirus
-member of human herpes family
-Infects:
1. intra-alveolar macrophages
2. endothelial cells
3. epithelial cells
-Affected cells become enlarged
1. basophilic inclusions in nuclei and cytoplasm
-can cause pneumonia in pts with HIV and CD 4 T cell count less than 50
-causes interstitial mononuclear with foci or necrosis







Define Pneumocystis jiroveci
=pneumocystis carnii -yeast -causes pneumonia in HIV pts with CD 4 T cell count < 200 -transmitted through resp droplets -ground glass opacities on chest xray -causes pneumonia with intra-alveolar exudate -look like flattened ping pong balls
Who gets bronchiectastasis?
-associated with chronic necrotizing infections (ex Aspergillus-mold)
1. CF
2. immunodeficiency states
3. primary ciliary dyskinesia
4. post-infection
5. obstruction




Name some symptoms of bronchiectastis
1. Severe persistent productive cough
2. sputum is foul smelling and sometimes bloody
3. dyspnea
4. orthopnea

-sx result of inflammation and damage to airways (necrosis of mucosa, SM, elastic tissue) and results in permanent dilation of bronchioles




Describe the pathology associated with bronchiectastasis
Gross:
-can trace bronchioles all the way to pleural surface (permanent dilation of bronchioles)

Micro:
-inflamm infiltrate in walls of bronchioles
-ulceration of mucosa
-chronic -> fibrosis of bronchioles





Name 2 examples of occupation/environmental lung diseases
=diseases due to inhalation of dust or chemicals
1. Pneumoconiosus
2. Hypersensitivity pneumonitis

-diagnosis NOT based on pathologic findings (clinical, radiological, etc) -> need careful hx of exposures
-development of environmental lung disease depends on amount of dust in lungs




Define Pneumoconiosis
=occupational/environmental lung disease
-due to presence of environmental "dust" in lungs and the patholgoic effects/lungs' response
-typically due to inorganic mineral (dusts), sometimes chemical fumes and vapors

Define hypersensitivity pneumonitis
=extrinsic allergic alveolitis
-occupational/environmental lung disease
-complex syndrome usu caused by ORGANIC Ag
=immunologically mediated interstitial lung disease caused by exposure to ORGANIC dusts and other occupational Ag
-involves both type III (immune complexes) and type IV (T cell mediated) hypersensitivities



Why are 1-5 micron dust particles the most dangerous in terms of causing environmental lung disease?
-b/c they can reach the terminal airways and lodge there

-exception is asbestos: fibers can be as long as 10 microns and get down into terminal airways
-straight more dangerous than curly shaped particles


Name 3 factors that development of environmental lung disease depends on:

1. Amount of dust inhaled
-duration of exposure, concentration in air
2. Size and shape of dust particle
3. Solubility of dust particles
4. ? additive effects w/ smoking



True or false: soluble vs insoluble inhaled particles cause different types of lung injury
-true

Soluble paritcles
-able to dissolve and reach toxic levels in blood (ex toxic gases)
-tend to cause acute lung injuries

Non-soluble particles
-lead to inflammation and fibrosis






Name some mechanisms to protect against dust and/or clear it from the lungs
1. tortuous pathways of upper tract
2. bronchoconstriction
3. entrapment in mucus blanked
4. mucociliary elevator
5. phagocytosis by mphage





Environmental/occupational lung diseases tend to lead to lung _________.
-fibrosis
-how fibrosis develops depends on infective agent
-some inhaled particles cause direct damage that leads to wound healing and fibrosis
-other particles activate mphages -> activate fibroblasts
-will have some fxnal consequences as restrictive lung disease due to fibrosis



Define Coal workers pneumocosis
-occupational lung disease due to pathologic effects of inhaling and retaining coal dust in lungs
=black lung
-Coal dust contains lots of stuff and some combinations in coal dust more likely to cause disease
-see range of disease
1. asymptomatic anthracosis
2. simple coal workers pneumoconiosis
3. complicated coal workers pneumoconiosis/progressive massive fibrosis





Define anthracosis
-disease on spectrum of coal workers pneumoconiosis
-asymptomatic
-also seen in urban dwellers and smokers
-carbon pigments taken up in mphages -> mphages can accumulate in lymphatics and lymph nodes


Define simple coal workers pneumoconiosus
-occupational lung disease due to pathologic effects of inhaling and retaining coal dust in lungs
-usu asymptomatic
-some chronic productive cough w/black-tinged sputum
-tends to affect upper lobes and upper zones lower lobes
-consists of coal macules and coal nodules in walls of respiratory bronchioles
-may develop centrilobal emphysema




Define coal macule and coal nodule
-seen in walls of respiratory bronchioles in simple coal workers pneumoconiosis

-macules= small, carbon laden mphages
-nodule = less than 1cm, have collage and mphages


Define complicated coal workers pneumoconiosis

-occupational lung disease from pathologic effects of inhaling and retaining coal dust in lung
-develops in background of simple CWP
-Sx: dyspnea, cough, sputum production
-may develop RHF
-coal nodules > 1cm
-nodules can have dense collagen and center of necrosis + carbon mphages
-associated with progressive massive fibrosis







True or false: complicated coal workers pneumoconiosis can progress even after exposure to coal dust is stopped
-true
Define Silicosis

-environmental lung disease
-most prevalent pneumoconiosis
-seen in sandblasters and coal miners
-caused by inhalation of silicon dioxide
-associated with increased susceptibility to tuberculosis



Describe pathogenesis of silicosis
-crystalline and amorphous forms
-inhaled silica is toxic to mphages
-also get activation of mphages -> release cytokines -> fibrosis
-lesions in upper portions of lungs
-initially nodular (no sx) -> fibrosis





Describe lung pathology of silicosis
gross: hard, collagenous scars

Micro: concentric layers of hyalinized collagen surrounded by more collagen
-silica particles are birefrigent under polarized light


Describe the pathogensis of asbestosis
-amphobiles (straight, stiff fibers) are less prevalent than curly but more pathogenic
-asbestos crystals activate mphages -> stimulate prod of ROS and cytokines
-> fibroblast and mesothelial prolif
-correlate w/mesothelioma
-pathological hallmark= ferruginous bodies



Define ferruginous body
=asbestos body
-pathological hallmark of asbestosis
-result of mphages trying to phagocytose asbestos particles
-golden brown beaded rods w/clear core
-iron stain positive (prussian blue)
-seen in lung parenchyma > pleural plaques or mesothelioma




Name 4 lesions of chronic asbestos exposure
1. Benign asbestos pleural effusions (asbestos pleurisy)
2. Focal or diffuse interstitial pulm fibrosis
-lower lobes
-around resp bronchioles first then extend to alveoli
-same destruction to lung tissue as other fibrosis
3. parietal pleura plaques
4. mesothelioma





Pleural plaques are characteristic of what disease?
=asbestosis
-found on parietal pleura (pleura on chest wall)
-Do NOT contain ferruginous bodies
-caused by chronic irritation of the mesothelial cells
-can calcify



Define Malignant Mesothelioma
-rare cancer of pleural lining of thorax
-risk factors: asbestos, radiation, chronic inflammation
-associated w/ exposure to asbestos but long latency period
-No increase in risk for asbestos workers who smoke
-Sx: chest pain, dyspnea, pleural effusion



True or false: malignant mesothelioma is the most frequent malignancy in people exposed to asbestos
-false
-actually lung carcinoma
-b/c risk of lung carcinoma is greatly increased in asbestos workers who smoke

Describe pathogensis of malignant mesolthelioma
-asbestos fibers cause chronic irritation of mesothelial cells of pleurla cavity
-asbestos fibers may generate ROS -> DNA damage -> oncogenic mutations
-mesothelioma can eventually encase the lung by filling the pleural space
-will see multiple gray-white nodules in diffusely thickened pleura


True or false: histologic types in malignant mesothelioma does NOT predict prognosis
-true
-types:
1. epithelial
2. sarcomatoid
(spindle cells)
3. mixed




Describe pathogenesis of hypersensitivity pneumonitis
=lung attempts to form granulomatous response but mounts a dysfxnal granulomatous response that causes widespread fibrosis
-T cells -> activate mphages -> activate fibroblasts -> fibrosis
-can see some non-caeseating granulomas

Describe the clinical features of hypersensitivity pneumonitis
-pts have heightened response to offending agent
-Acute attacks:
1.fever
2. cough
3. dyspnea
4. Leukocytosis
-acute attacks via type III hypersensitivity

May also see restriction of lung fxn with pulm fxn tests
-chronic damage mediated by type IV hypersensitivity (T cells)








Name the 4 diagnostic criteria for hypersensitivity pneumonitis
1. known exposure to offending agent
2. compatible clinical and radiological findings
3. BAL w/ T lymphocytosis (CD8 > CD4)
4. positive inhalation test


Describe the lung pathology of hypersensitivity pneumonitis

1. Diffuse mononuclear cell interstitial cell infiltrates w/ peribronchial accentuation
2. poorly formed peribronchial non-caseating granulomas
3. interstitial fibrosis in advanced cases

Describe tx and prognosis of hypersensitivity pneumonitis
Tx
1. remove offending agent
2. corticosteroids

Prognosis
1. good unless chronic exposure has caused irreversible fibrosis




Name some drugs (iatrogenic agents) that can cause lung disease
Cytotoxic drugs (chemo)
1. bleomycin
2. methotrexate
Others
3. amiodarone
4. aspirin
5. beta antagonists
6. nitrofuratonin






True or false: radiation exposure can cause hypersensitivity pneumonitis
-true
-can lead to pulmonary fibrosis
(ex. if doing breast cancer tx)

Name 2 types of hypersensitivity pneumonitis
1. farmer's lung
-caused by thermophillic actinomyces that grow on hay
2. Byssinosis
-caused by cotton, linen, or hemp exposure


Describe the pathogenesis of silicosis
-silca dust in lungs is ingested by alveolar macrophages -> mphages damaged -> release of mphage lysosomal enzymes and production of Fibroblast growth factor (FGF) -> form collagenous fibrotic nodules of silica deposits
True or false: the lung is more often affected by metastatic tumors than it is by primary neoplasms.
-true
True or false: bronchogenic carcinoma is the most frequently diagnosed major cancer worldwide and most frequent cause of cancer mortality worldwide.
-true
-at time of diagnosis, 50% already have distant metastases
-5 year survival is 15% with all stages combined

Name some risk factors for bronchogenic carcinoma
1. tobacco smoke
2. air pollution
3. industrial hazards
-asbestos
-ionizing radiation
4. genetic predisposition
-polymorphisms in p450 gene





Polycyclic aromatic hydrocarbons in tobacco smoke are _______ that cause irreversible DNA damage, while phenol derviatives are ________.
polycyclic aromatic hydrocarbons = initiators

phenol derivatives = promoters
-enhance proliferation of initiated cells (DNA damaged cells)

-tobacco smoking is most commonly associated with squamous cell and small cell carcinoma




Describe the signs and symptoms of lung cancer
-5-20% are clinically occult
-Systemic symptoms
1. Weight loss
2. loss of appetite
3. malaise
4. fever

-Local/direct effects
1. cough, dyspnea, wheeze, stridor, hemoptysis
2. chest or back pain
3. obstructive pneumonia +/- abscess formation
4. pleural effusion

-Extension into mediastinal structures












Name some signs and symptoms associated with lung cancer extending into mediastinal structures
1. Hoarseness
-recurrent laryngeal nerve
2. Dysphagia
-esophageal invasion
3. SVC syndrome
-SVC compressed by tumor
4. Horner Syndrome
-Sympathetic ganglia invasion
5. Pericardial effusion or tamponade







Name 5 types of paraneoplastic syndromes associated with lung cancer
1. Myasthenic syndromes
-Lambert-Eaton
2. Peripheral neuropathy
3. Hypertrophic pulmonary osteoarthropathy
-associated w/clubbing of fingers
4. Hematologic manifestations
-migratory thrombophlebitis
-non-bacterial endocarditis
-DIC

5. Effects due to hormone-producing tumors









Name 6 hormones and their effects that can be produced by lung tumors
1. ADH
-> hyponatriemia
2. ACTH
-> Cushing's syndrome
3. PTHrp
-> hypercalcemia
4. CT
-> hypocalcemia
5. Gonadotropins
->gynocomastia
6. Serotonin
-associated with carcinoid syndrome










Describe the origin and spread of bronchogenic carcinomas
Origin
-hilar regions of lung

Spread
1. Nodes
tracheal, bronchial, mediastinal
2. Organs (mets)
-liver, adrenals, other lung, brain, BM






Lung cancer can be classified as _________ or __________ cancer
1. Small cell cancer
2. Non-small cell cancer
-NSCC can be subdivided
1. squamous
2. adenocarcinoma
3. large cell carcinoma
4. mixed

-subdivided this way b/c small cell not curable by surgery (b/c most have mets at time of diagnosis) but more responsive to rad and chemo







Define squamous cell carcinoma
=non-small cell lung cancer
-tend to arise in major bronchi (centrally)
-cancer preceded by squamous metaplasia
-sx when tumor obstructs lumen of bronchus
-tends to metastasize late
-seen in men, smokers




Describe pathological findings of squamous cell carcinoma
-preceded by metaplasia (respir columnar epithelium replaced w/squamous epithelium)
-central lesion
-can see central cavitation or necrosis
-keratin pearls
-intercellular bridges



Define adenocarcinoma of lung
-non-small cell carcinoma
-can see in women who are non-smokers (as well as smokers)
-metastasize earlier than squamous carcinoma
-usu peripheral lesion
-can involve visceral pleura-puckered appearance
-acinar(glandular), papillary, or solid differentiation w/intercellular mucin production




Adenocarcinomas of lung seen in Asian, non-smoking women tend to be associated with activating mutations in _______.
=epidermal growth factor receptor
-if give patient tyrosine kinase inhibitors against EGFR, high response rate
Define Bronchoalveolar carcinoma
=histologic subtype of adenocarcinoma (non-small cell lung cancer)
-shows PURE bronchioalveolar growth pattern with NO INVASION of pleura, stroma, or vascular spaces
-develops in periphery of lung w/ multiple nodules
-associated with smoking
-better prognosis than invasive adenocarcinomas



Define Large cell lung cancer
=undifferentiated non-small cell cancer
-cancer cells lack features of squamous or adenocarcinoma cells
-most pts are smokers
-large, peripheral mass




Define small cell carcinoma
-high grade neuroendocrine lung carcinoma
-central lesions
-seen in heavy smokers
=oat cell carcinoma
-older pts male> female
-tend to metastasize early and have poor prognosis
-paraneoplastic syndromes due to ectoptic hormone production common







Describe the pathologic features of small cell carcinoma
-central lesions
-small cell w/little cytoplasm and usu neurosecretory granules
-nuclear molding
-high mitotic rate
-frequent necrosis



Define carcinoid tumors of the lung
-5% of all lung tumors
-low grade malignancy that arise from Kulchitsky (neuroendocrine) cells
-benign neuroendocrine lung tumors (vs small cell carcinoma)
-50% pts no sx
-can get carcinoid syndrome



Who gets carcinoid tumors of the lung?
-non-smokers -younger (usu < 40 years) -kids can get them =benign neuroendocrine tumors of lung
Define carcinoid syndrome
-associated with carcinoid tumors of lung (benign neuroendocrine tumors)
Intermitten attacks
1. Diarrhea
2. flushing
3. cyanosis



Describe carcinoid tumor pathology in the lung
-gross: polyp masses that project into bronchial lumen, usu limited to main stem bronchi

micro:
-salt and pepper nuclei
-few mitotic figures (vs small cell)
-no necrosis (vs small cell)






Coin lesion on a chest xray usu refers to a ___________.
=hamartoma
-benging neoplasm in lung
-well-circumscribed nodule
-usu incidental finding on chest xray
-usu found in the periphery of lung



Name 2 histologic features of a hamartoma
1. composed predominantly of mature hyaline cartilage
2. cellular elements of the neoplasm do NOT reproduce the normal architecture of the surrounding tissue
What is the most common cause of hyperpituitarism?
-anterior lobe pituitary adenoma
Define pituitary adenoma
-benign neoplasm of the anterior pituitary
-Can be classified as:
1. Microadenoma (less than 1 cm) or Macroadenoma (greater than 1 cm)
2. Functional (produce excess hormone and clinical effects of excess) or silent or hormone negative
-usu isolated lesion but can be associated with MEN-1
-freq associated w/ activating mutation in Gs alpha
-most common cause of hyperpituitarism
-can cause hypopituitarism if the encroach on and destroy adjacent anterior pituitary parenchyma






The most common type of hyperfxning pituitary ademonas are the __________.
=prolactinomas
-hyperprolactinemia can cause:
1. amenorrhea
2. galactorrhea
3. loss of libido
4. infertility
-easiest to diagnose in pre-menopausal women
-need to rule out other causes of hyperprolactinemia (pregancy, high disease estrogen therapy, renal failure, DA-inhibiting drugs, etc)






Many of the manifestations of hypersecretion of growth hormone are mediated through ______ in addition to direct effects of growth hormone.
-insulin-like growth factor
-hypersecretion of GH stimulates hepatic secretion of IGF-1
What are the sx and signs of hypersecretion of growth hormone
-if before puberty/ epiphyseal closure
1. gigantism

-if after epiphyseal closure
1. Acromegaly



Describe the sx and signs of acromegaly
-result of growth hormone excess in adults (post-closure of epiphyseal plates)
1. enlargement of jaw and nose -> coarsening of facial features
2. big fingers and feet
3. enlargement of visceral organs

-complications
1. abnormal glucose tolerance/DM
2. generalized muscle weakness
3. HTN
4. arthritis
5. osteoporsis
6. CHF










True or false: ACTH-producing pituitary adenoma is just one of the causes of Cushing syndrome
-true
-results in hypercortisolism and hyperpigmentation
Name some mechanisms of cause of hypopituitarism
1. Non-fxning pituitary adenoma that comnpresses the tissue
2. ischemic necrosis of anterior pit.
-ex. Sheenan syndrome (postpartum infarct)
3. hypothalamic dysfxn
4. iatrogenic (ablation of pit by surgery or radiation)
5.Inflammatory lesions (TB, sarcoidsosis)
6. trauma
7. metastatic neoplasms






Name the 2 hormones released by the posterior pituitary
=neruohyphophysis
-hormones are produced in hypothalamus and stored and released from post pit
1. ADH
2. oxytocin


Describe the actions of ADH
-peptide hormone produced in hypothalamus and released from post pit
-acts on collecting tubules of kidneys to promote resportion of free water
-ADH def = Diabetes insipidous
-ADH excess= SIADH


Define diabetes insipidous
=ADH definiciency
-inability of kidney to properly resorb water from urine
-sx: making lots of dilute uring, hypernatriemia, increased serum osmolality, thirst
-lots of causes
1. central
-damage to hypothalamus or pit
2. nephrogenic
-result of renal tubular unresponsiveness to circulating ADH






Define SIADH
=syndrome of inappropritate ADH
-ADH excess -> resorption of excessive amounts free water -> hyponatriemia
-causes:
1. ectopic ADH by malignant neoplasms
-small cell carcinoma of lung
2. non-neoplastic lung diseases
3. injury to hypothalamus and/or neurohypophysis
-Sx: hyponatriemia, cerebral edema, neurologic dysfxn






Name 3 mechanisms of pituitary disease.
1. Pituitary masses and mass effects
-sx: headaches, visual field defects (compress CN II), oculomotor palsies
2. Hypersecretion of pituitary hormones and its effects
Ant pit: Growth hormone oversecretion -> acromegaly
Prolactinoma
-Post Pit: SIADH
3. Hyposecretion of hormones and its effects
Ant Pit: various causes of hypopituitarism
Post Pit: Diabetes insipidus







Name some types of pituitary tumors and parasellar masses that can cause mass effects
1. Ant. Pituitary tumors
2. Macroadenoma
3. Craniopharyngioma
4. Rathke's cyst
5. Meniningioma
6. Dysgerminoma
7. Mestasis





Define macroadenoma
=pituitary adenoma that is greater than 10mm
-usu not hormonally active
-usu derived of gonadotrophy or prolactinotroph cells
-can cause mass effects and if big enough compress ant pit tissue and cause hypopituitarism


Define craniopharyngioma
=cranial tumor derived from Rathke's pouch
-can be intrasellar or hypothalamic in location
-very aggressive
-can cause mass effects


Define a Rathke's cyst
=mass in the sellar compartment when Rathke's pouch (embryonic origin of ant pituitary) failed to obliterate
-seen in 20% of people at autopsy
-often no sx

True or false: 25% of all pituitaries harbor microadenomas
-true
-but since so small usu do not cause mass effects -> no sx


Name 3 types of mutations associated with pituitary adenomas
=benign neoplasms of the anterior pituitary
-99% of adenomas monoclonal
-3 mutations
1. Mutations of G proteins
-GHRH Receptor (GPRC)
-Gsalpha activating mutation
2. Mutations of tumor suppressor genes
3. enhancement of growth factor activity






How pituitary adenomas of polyclonal origing develop?
-ie not due to 1 mutation in one cell that then proliferates
-Mechanisms:
1. Excess stimulation by hypothalamic hormone
-ex chest or abdominal tumor that produces ectopic CRH or GHRH
2. Inhibition of negative feedback
-ex primary hypothyroidism -> unrestrained prolif of thyrotroph




Name 2 genetic syndromes associated with pituitary adenomas
1. MEN-1
=multiple endocrine neoplasia
2. McCune Albright Syndrome

What cranial structures and what effects would you evaluate for if you suspected a pituitary mass causing mass effects?
1. Pituitary
-look for hypopituitarism, secondary hypoadrenalism, hypothyroidism, hypogonadism
2. Optic chiasm
-check for visual field defects (bitemporal hemianopsia), loss of red perception, blindness
3. Cavernous sinus
-check for opthalmoplegia, CN palsy (III, IV, VI), CSF leak
4. Brain
-check for headache, hydrocephalus, personality disorder






How do you diagnose a pituitary mass cause mass effects?
1. Evaluate for signs and sx of mass and its effects
2. Imaging studies
-CT and MRI
3. Opthalmologic eval
-check for visual field defects
4. Lab tests
-Pit hormones: increased prolactin, alpha subunit, decreased TSH, FSH, LH
-usu decreased end-organ hormones (free T4, Testosterone, etc)






Why would prolactin be high in a pituitary tumor?
-prolactin secretion is usu inhibited by DA
-if pituitary stalk is compressed b/c of pit mass -> loss of DA inhibition -> increased prolactin levels
Name the top 3 sx of pituitary tumors
1. Visual field defects
-ex bitemporal hemianopsia
2. Headaches
3. Acromegaly


How do we tx pituitary tumrors?
-goal is reversal of mass effects
1. Trans-sphenoidal surgery
2. Adjunct radiation
3. Hormone replacement (cortisol, thyroxin, estrogen, testosterone, growth hormone)


How do we get CSF leak with pituitary tumors?
-b/c of mass effects by compression of the cavernous sinus
Define MEN
=multiple endocrine neoplasia syndrome
-results from inactivation of MENIN
-can result in:
1. pituitary adenomas
2. parathyroid adenomas
3. pancreatic islet tumors




Name 3 main mechanisms of hypopituitarism
1. Structural (acquired)
-destruction of pituitary tissue
2. Functional
-decreased function of the pituitary cells
3. Pituitary deficiency



Name some causes of destruction of pituitary tissue
1. neoplasia
-pressure on the head and death of pit secretory cells
2. Trauma
-head injury, surgery, radiation
3. Infiltrative
-ex sarcoidosis
4. vascular
-pit infarction (Sheenan syndrome)
5. Infections
-TB, pneumocystis carnii-HIV
6. Empty sella syndrome









Name some causes of fxnal hypopituitarism
=result in decreased fxn of pituitary cells
1. Hypothalamic deficiency
2. Neurogenic/metabolic
-anorexia nervosa (GnRH)
-Critical illness
-malnutrition




Name 3 types of pituitary deficiency
1. Combined deficiency
-loss ant pit hormones
-due to Pit1 mutation
2. Isolated deficiency
3. Kallman syndrome
-GnRH deficiency associated with anosmia




Hypopituitarism can clinically present as _____ or as a __________.
1. Panhypopituitarism
-all hormones decreased and resulting effects
2. Isolated hormone deficiency
-ex. TSH def (=sec hypothyroidism)
-will see both low T4 and low TSH



Define panhypopituitarism
=one of the presentations of hypopituitarism where all pit hormones decreased
-Effects:
1. Decreased cortisol
-lethargy, hypotension, low Na, high K
2. Decreased Thyroxin
-sx of hypothyroidism
3. low growth hormone
-short stature (early onset), decreased muscle mass, muscle weakness
4. Decreased estrogen
-amenorrhea
5. Decreased testosterone
-decreased libido, muscle weakness










What accounts for the variation in clinical presentation of hypopituitarism
-it depends on:
1.cause of hypopituitarism
-if tumor may also see mass effects
2. end organs affected

-when tissue destruction caused by pituitary being compressed by a mass, hormones dropout in characteristic fashion: growth hormone, prolactin, FSH, LH, TSH, ACTH (last)




How do we treat hypopituitarism?
1. if due to a tumor, reverse mass effects
2. otherwise hormone replacement of end organ hormones (ex cortisol, thyroxin,etc)
What are the pathophysiological effects of hypothalamic tumors
-ex. craniopharyngioma
-get disruption of normal fxn
1. abnormal food intake
2. abnormal thirst regulation
3. abnormal temp regulation (ex spiking fevers w/no infectious cause)
4. abnormal endocrine fxn (production of ADH, oxytoxcin, disruption of ant pit fxn with prod of TRH, GHRH, etc)
5. abnormal sleep-wake cycles
6. memory and behavioral abnormalities






Define Empty sella syndrome
-form of hypopituitarism
-hole in diaphragm of sella -> pressure of CSF transmitted against sella -> remnant of pituitary pressed flat against bony sella -> pit def
-more likely in females
-assoicated signs and sx


Name the 3 most common types of pituitary adenomas causing hypersecretion.
1. Prolactinoma
2. GH tumor
-> gigantism (before epiphyseal closure)
-> acromegaly (after epiphyseal closure)
3. ACTH
-Cushing's disease




Name 5 actions of growth hormone
1. increased bone and cartilage growth
2. increased synthesis of protein, RNA, DNA
3. anti-insulin effects
-increased gluconeogenesis
4. serum phosphorous increased
5. increased somatomedin (IGF-1) produced in liver

-these get exacerbated in acromegaly (hypersecretion of growth hormone)






Name some causes of acromegaly
1. Monoclonal GH producing tumors
-Gsalpha activating mutation
2. Somatotrope adenoma

Describe the clinical presentation of acromegaly
Sx and signs
1. growth of the acral pts of body (fingers and toes)
2. visceromegaly
3. coarsening of facial features (jaw enlargement, large nose)
4. evidence of pituitary tumor



Many of the effects of growth hormone are mediated by ________ in addition to direct effects of growth hormone on tissues.
=IGF-1
-insulin-like growth factor 1
-growth hormone stimulates its production in the liver

How do we diagnosed acromegaly?
1. Sx and signs
-acral enlargement
-pit tumor signs
2. Lab values
-increased IGF-1 (above normal range for age)
3. Glucose tolerance test
-glucose usu suppresses GH secretion





How do we treat acromegaly?
1. Trans-sphenoidal surgery
-60% successful w/ macroadenoma removal
2. Radiation
3. Medical therapy
-bromocriptine
-somatostatin analogues (somatostatin normally inhibits GH secretion)
4. GH anatagonists





Describe the prognosis of acromegaly
-decreased life expectancy if untreated
-Mortality related to:
1. Cardiovascular disease
-60%
-cardiomyopathy, heart failure
2. Pulmonary disease
-sleep apnea
3. HTN
4. DM
5. GI malignancy
-colon cancer









What are the effects of prolactin?
1. Inhibits GnRH secretion
2. Interferes with LH and FSH on Gonads
What are some causes of hyperprolactinemia?
-hypersecretion of prolactin
-can be due to:
1. Hypothalamic origin
-impaired DA secretion or transmission due to tissue destruction or drugs (reserpine)
-increased neurogenic impulses
2. Pituitary origin
-prolactinomas
2. Mixed somatotroph and prolactin adenoma
3. estrogen (birth control)
4. hypothyroidism








Describe the symptoms and sx of hyperprolactinemia
-result from inhibition of GnRH secretion and interfering w/ LH and FSH effects
Women
1. amenorrhea
2. galactorrhea
3. infertility
4. tumor signs

Men
1. gynecomastia
2. decreased libido
3. infertility
4. tumor signs










How do we diagnose hyperprolactinemia?
1.signs and sx
-note: diff for men vs women
2. Lab values
-increased prolactin (over 100)
-decreased testosterone, gonadotropin



How do we treat prolactinoma?
1. Bromocriptine
-DA agonist
-able to shrink tumor size
-even give first for macroadenoma, then do surgery if doesn't shrink enough


Describe the factors regulating the release of ADH
-ADH produced in hypothalamus and released by post pituitary
-Major factors:
1. Increased plasma tonicity
2. Decreased filling volume
-sensed by atrial stretch R
Other factors:
1. pain
2. emotion/stress

-ADH acts on collecting duct of renal tubules to increase H20 resorption from urine








Describe the symptoms of diabetes insipidus
1. Polyuria
-making lots of dilute urine
2. Polydipsia
3. Thirst
4. Dehydration
5. Hypernatremia
6. Hyperosmolarity
7. coma






Name some causes of diabetes insipidus
1. Central diabetes
-due to absent or decreased secretion of ADH from Pit (ADH def)
-can be due to: neoplasm, infiltrative lesions, surgery/trauma
-50% idiopathic
2. Nephrogenic
-mutations in V2 R so ADH note able to exert its effects
-ADH resistance

3. Primary polydipsia
-psych patients

4. Gestational DI












How do we diagnose and treat diabetes insipidus?
Dx
1. Water deprivation test
2. determine ADH levels w/radioimmunoassay
3. hypertonic saline infusion test

Tx:
1. adequate water
2. desmopressin
-recombinant ADH







How do we diagnose and tx SIADH?
Dx
1. Serum hyponatriemia w/ high urine osmolarity
2. no dehydration, edema, or orthostatic hypotension

Tx
1. Fluid restriction
2. Democlocycline
-inhibits ADH action






Define renal osteodystrophy
=complex skeletal disease of chronic renal failure
-several components
1. Osteitis Fibrosa Cystica
-disease of PTH excess
2. Osteomalacia
-disease of Vit D def
3. Extraskeletal ossification and calcification
-disorder of abnormal calcium and phosphorous metabolism due to renal failure
4. Adynamic bone disease
-due to hormone suppression

-if young pt, also see growth retardation










Name some hormones associated with Ca homeostasis
1. Vit D
2. PTH
3. CT
4. PTHrp
5. Gonadal steroids
-women: estrogens
-men: androgens
6. Steroids/glucorticoids
-bad for bones







Name some disease associated with abnormal calcium levels
Most common
1. Hypercalcemia of malignancy
2. Hyperparathyroidism

Others
2. Rickett's/osteomalacia
3. Osteoporosis
4. Paget's
5. Hypoparathyroidism
6. Vit D def
7. Osteitis Fibrosis Cystica









Name the actions of PTH and how is it regulated?
-PTH produced by parathyroid gland
PTH increases serum Ca
1. increased bone resoprtion of calcium and phosphate
-stimulates both osteoclasts and osteoblasts
2. Increased kidney resorption of calcium in distal convuluted tubule
3. stimulates increased production of 1,25OH VitD by kidney

Gets rid of phosphate
1. decreased kidney resorption of phosphate

PTH stimulated by decreased free serum Ca









Name the 3 major actions of active Vit D
=active= 1,25OH Vit D
1. increased absorption of dietary Ca
2. Increased absorption of dietary phosphate
3. increased resorption of Ca and PO4


Describe the pathogenesis of renal osteodystrophy
=complex skeletal disease due to renal failure
-decreased renal mass ->
1. decreased phosphorous excretion -> increased serum levels
-results in secondary hyperparathyroidism and osteitis fibrosa cytstica
2. decreased production of 1,25OH Vit D (active form)
-causes hypocalcemia and osteomalacia




Describe the role of increased serum phosphorous in renal osteodystrophy
-renal failure -> decreased excretion -> increased serum phosphorous -> binds serum Ca and can precipitate -> lower serum free Ca -> increased compensatory PTH secretion -> increased serum calcium and decreased phosphorous
-but compensation will not be complete with kidney dysfxn
-chronic stimulation of PTH b/c hypocalcemia still not compensated -> secondary hyperparathyroidism -> high levels of PTH
-PTH excess causes osteitis fibrosa cystica


How do you get tertiary hyperparathyroidism?
-ex in renal osteodystrophy, you get secondary hyperparathyroidism in attempt to compensate for hypocalcemia
-if the hyperplastic partathyroid glands -> monoclonal expansion of abnormal parathyroid cells -> no longer under secretory control by calcium (loss of feedback inhibition) -> tertiary hyperparathyroidism
-to dx, need to rule out hypercalcemia due to other causes (ie take off supplemental Ca and Vit D); if PTH levels still high, then tertiary
-can tx w/ surgery to remove a parathyroid gland


Describe the extraskeletal calcification in renal osteodystrophy
-renal failure -> decreased phosphorous excretion -> increased serum phosphorous -> binds calcium -> calcium phosphate precipitates
-Sites of precipitation:
1. Medium sized arteries
2. articular joints
3. visceral calcification (kidney, heart, lungs)



Describe the sx and signs of renal osteodystrophy
1. bone pain and tenderness
2. pathologic fractures
3. muscle weakness
4. effects of extraskeletal calcification
-digital gangrene
-uremia pruritis (itchiness)
-calciphylaxis (skin necrosis and non-healing wounds)







How do you diagnose renal osteodystrophy
1. Renal failure
2. Lab tests
-low serum ca
-increased serum phosphorous
-increased serum phosphatase
-decreased 1,25 VitD
3. Xray
-signs of osteomalacia, extraskeletal calcification
-skeletal deformity
-if young see growth retardation
4. Extraskeletal complications
-calciphylaxis
-pruritis











How do you treat renal osteodystrophy?
-goal is to lower serum phosphorous to suppress PTH excretion, but also supplement for hypocalcemia due to decreased 1,25OH VitD
1. Vit D
2. Oral Calcium
3. dietary phosphate restriction
4. Calcimimetics
-bind to Ca sensing R on parathyroid gland -> suppress PTH secretion

-calcitriol (mimics active Vit D) is drug of choice
-calcitriol suppresses PTH secretion w/out hypercalcemia







Describe the manifestations of hyperthyroidism/thyrotoxicosis
1. Heat intolerance, flushing, sweating
2. increased metabolism, wt loss
3. periorbital puffiness (opthalmologic sign)
4. nervousness, irritable
5. hyperactive state
6. hypermotility in GI, diarrhea
7. high output heart failure
8. carbohydrate intolerance, increased insulin requirement
9. amenorrhea, infertility







What are the most frequent: a)sx and b)signs of hyperthyroidism
Sx
1. nervousness
2. sweating
3. heat intolerance
4. palpitations

Signs
1. goiter
2. tachycardia
3. skin changes
4. tremor









How do we diagnose hyperthyroidism
1. Sx and signs
2. Lab tests
-decreased TSH
-increased free T4
-increased T3



Describe pathogenesis of Grave's disease
-part of TSH R serves as autoantigen
-fragments of TSH R found on MHC complexes on T cell
-develop population of T cells that respond to the TSH R -> production of autoantibodies that stimulate TSH R

-genetic and environmental factors mediate increased propensity to develop Graves disease



Describe the sx and signs of Graves disease
1. Sx due to thyroid hormone overproduction
2. Sx due to autoimmunity
-goiter
-opthalmopathy (lid lag, retraction upper lid, proptosis, periorbital edema, stare)
-dermopathy (thickened edematous nodules or placques on lower extremities)
-acropachy (clubbing of fingers and toes with soft tissue swelling)

-can also see increased incidence of mitral valve prolapse






How do you treat Grave's disease?
Reduce thyroid hormone synthesis
1. Inhibit thyroid hormone formation
-antithyroid drugs (propylthiouracil, methimazole)
2.reduce amt of thyroid tissue
-radioactive iodine
-surgery

Inhibit beta sympathetic activity
1. Propranolol
2. Vitamin replacement (A, D, E, K)










Name some "other" causes of hyperthyroidism
1. Toxic multinodular goiter
2. solitary toxic adenoma
3. thyroiditis
increased release of T3/T4
4. TSH producing pituitary tumor
5. Thyroid storm






Define ACTH
=peptide hormone produced by corticotrophs in anterior pituitary
-stimulates adrenal cortex to produce its hormones
-only slight effect on aldosterone secretion
-stimulates converstion of cholesterol to pregnanolone (first step in making steroid hormones of adrenal cortex)


List the major effects of glucocorticoids
-endogenous=cortisol
-produced by zona fasiculata of adrenal cortex
-prod stimulated by ACTH

Metabolic
1. Promote gluconeogenesis
2. make cells less sensitive to insulin and more sensitive to glucagon
3. increase protein breakdown and lipolysis
Anti-inflammatory
4. Block phospholipase A2 -> inhibit synthesis PG and LT
5. Inhibit mast cell degranulation/HM release
6. Inhibit IL-2 prod












Name 3 things that can stimulate aldosterone secretion.
Aldosterone=minerlocorticoid produced by zona glomerulosa of adrenal cortex
2 major stimulators:
1. RAAS
-Ang II stimulates adrenal cortical cells
2. increased K+
-direct effect

Minor effect
1. ACTH









Name the major actions of aldosterone
1. promote renal Na+ retention
2. Promote K+ renal excretion
3. Promote H+ renal excretion

If ADH also present
1. Promote water retention




Name the 2 enzymes that degrade catecholamines
catecholamines= epi and NE
enzymes:
1. COMT
2. MAO


Define Cushing syndrome and name its 4 major causes
=syndrome of cortisol excess
-causes:
1. Pituitary Cushing
2. Adrenal Cushing
-adrenal adenoma
3. Ectopic Cushing
-ACTH secreting tumor (bronchogenic carcinoma)
4. Iatrogenic Cushing
-too much exogenous glucocorticoids or ACTH







A 30 year old woman who presents with HTN, abnormal glucose tolerance, truncal obesity, muscle wasting, moon facies, buffalo hump, and striae would be characteristic of...
-Cushing syndrome
-4 different causes
-Use ACTH levels and dexamethosone suppression test to distinguish

Define Pituitary Cushing syndrome
=syndrome of cortisol excess
-in this case, due to basophilic pituitary adenoma
-characterized by:
1. high serum ACTH
2. bilateral adrenal hyperplasia
-Dx with dexamethasone suppression test (will see suppression of ACTH levels)




Define Conn Syndrome
=syndrome of aldosterone excess
-primary hyperaldo (b/c problem w/adrenals)
-usu caused by adrenal adenoma secreting aldo but can have other causes
-sodium retention, hypokalemia, metabolic alkalosis
-low renin levels distinguish from secondary hyperaldo



21 hydroxylase deficiency is the most common form of __________.
=congenital adrenal hyperplasia
-due to congenital deficiency in one of the enzyme needed to produce steroid hormones of the adrenal cortex
-21 hydroxylase def shows cortisol def but normal aldosterone fxn
-sx of virilism (male secondary sex characteristics in a female due to increased production of adrenal androgens)


Name some causes of acute adrenal insufficiency
Primary causes (affect adrenal fxn)
1. Rapid withdrawl of exogenous glucocorticoids
2. Stress (trauma, surgery, infection)
3. Addison disease
4. Adrenal apoplexy (Waterhouse-Friderichsen syndrome)

Secondary effects
-various causes affecting the hypothalamic-pituitary axis
-see decreased ACTH levels







A syndrome characterized by weakness, weight loss, anorexia, nausea and vomiting, hypotension, skin pigmentation, inability to tolerate stress, abdominal pain, hypoglycemia w/ prolonged fasting is charactersitic of......
=Addison disease
-chronic primary adrenal insufficiency
-sx result of lack of cortisol and aldosterone
-high serum ACTH
-bilateral atrophy of adrenal glands



To produce clinical adrenal insufficiency _______% of the adrenal gland must be nonfxnal.
=90%
Name some causes of Addison's disease
=chronic primary adrenal insufficiency
-> def cortisol and aldosterone
-causes:
1. TB
2. idiopathic (autoimmune)
3. infections
4. iatrogenic
5. mestastases
6. adrenal hemorrhage







Define Waterhouse-Friderichsen syndrome
=massive sudden adrenal hemorrhage usu associated w/ meningococcal septicemia
-results in adrenal insufficiency -> loss of cortisol and aldosterone
Name the 4 major types of adrenal neoplasms
1. Adrenal adenomas
2. Adrenal carcinomas
-rare, very malignant
3. Pheochromocytoma
4. Neuroblastoma



Define Pheochromocytoma
=neoplasm of neural-crest derived chromaffin cells of adrenal gland
-neoplasm secretes catecholamines
-Characterized by:
1. paroxysmal HTN
2. elevates urinary catecholamines and metabolites (HVA and VMA)
-can be seen w/ genetic syndromes (MEN IIa, III; NFT; von Hippel-Lindau)




Describe the rule of 10%s for pheochromocytoma
=chromaffin cell neoplasm that secretes catecholamines
1. 10% extra-adrenal
2. 10% bilateral
3. 10% malignant
4. 10% affect children
5. 10% familial (associated w/genetic syndromes)




Define neuroblastoma
=most common malignant extracranial solid tumor of CHILDHOOD
-tumor of neural crest derivative tissue (usu adrenal gland but could be sympathethic chain ganglia)
-amplification of N-myc oncogene
-rapid growing tumor
-metastasizes widely
-elevated urinary catcholamines




Toxic multinodular goiter is a form of _________.
=hyperthyroidism
-AKA Plummer's disease
-goiter with areas or autonomous overproduction of T3/T4
-iodine exposure can be inducing event
-can be seen in elderly pts with hyperthyroid sx
-can be apathetic hyperthyroidism (only 1 sx of hyperthyroidism)
-Dx based on labs (low TSH, high T3) and radioactive iodine scan showing multiple areas of increased uptake







How does radioactive iodine tx toxic multinodular goiter
-only toxic nodules will take up the radioactive iodine in increased amounts -> these areas of increased T3/T4 production are eliminated
-rest of thyroid is ok

-if going to do surgery, must make sure euthymic before start


Name 2 severe syndromes associated w/ hypothyroidism
1. Myxedema
-periorbital puffiness, pale doughy skin, sparse hair, cardiac enlargement, cardiomyopathy, pleural effusions, anemia
2. Cretinism
-severe hypothyroidism in children
-arrested physical and mental development



True or false: primary hypothyroidism accounts for 98% of all hypothyroidism
-true
-characterized by thyroid failure, decreased production of T3/T4 by thyroid gland

-secondary hypothyroidism=1%
-due to pituitary failure, low TSH

-rarely see thyroid hormone resistance due to mutations in T3 R in periphery
-see elevated T3/T4 AND TSH






Describe some mechanisms resulting in primary hypothyroidism
-characterized by low T4/T3 but elevated TSH
1. Destruction of fxnal thyroid tissue
-Autoimmune (Hashimoto's, end-stage Graves)
-Iatrogenic (radiiodine, surgery)
-Infiltrative (Riedel's, sarcoidosis, lymphoma)

2. Decreased hormone synthesis
-iodine def
-goiterogens
-antithyroid drugs
-dysmorphogenesis (enzyme defects for T4 formation)









Delayed ankle reflexes are characteristic of __________.
-hypothyroidism
How do we treat hypothyroidism?
-thyroxine (thyroid hormone replacement)
Define sick euthyroid syndrome
=severe illness inducing low T3 in absence of thyroid disease
-no clinical sx/signs of hypothyroidism
-no need to tx hypothyroidism, just tx underlying disease

Define thyroiditis
=inflammatory state of thyroid gland caused by infectious or autoimmune process
Name some causes of thyroiditis
1. Autoimmune
-Hashimoto (chronic)
-postpartum (subacute, lymphocytic)
2. Infectious
-de Quervains (subacute granulomatous thyroiditis following viral infection)
-can also get from bacteria or fungus
3. Sclerosing
-Riedel's thyroiditis
4. Radiation induced
-post tx for Graves disease








Define Hashimoto thyroiditis
=chronic form of hypothyroidism
-T-cell mediated autoimmune destruction of thyroid -> hypothyroid sx and goiter
-elevated antithyroglobulin, antiperoxidase antibodies
-usu seen in middle aged women
-associated w/increased risk of lymphoma



Describe pathology of Hashimoto thyroiditis
=hypothyroidism
1. exuberant lymphocytic rxn surrounding surviving thyroid follices
-can even see germinal centers in thyroid

Describe some complications of Hashimoto thyroiditis
1. can get concurrent disease with Graves
2. encephalopathy
-autoimmunity to CNS proteins
-confusion, seizures, coma
-steroid responsive



Describe post-partum thyroiditis
=subacute, lymphocytic thyroiditis
-usu painless and silent
-seen in 5-15% of women a few months after deliver
-early hyperthyroidism then hypothyroidism
-Dx: increased TPO antibodies, decreased radioactive iodine uptake
-80% will recover normal thyroid fxn
-25% will be permanently hypothyroid
-rule out postpartum graves disease during hyperthyroid phase






Define goiter
=enlargement of the thyroid gland
-endemic goiter=more than 10% of children in a population have a goiter
-pt can be hyperthyroid, euthyroid, or hypothyroid
-concerns: compressive sx (dyspnea, dysphagia), malignancy, hyper or hypothyroidism


Name the major causes of goiter
1. Endemic
-iodine def
-goiterogens
-genetic factors
2. Sporadic goiter
-also enzyme def
-special circumstances (puberty, pregnancy, acromegaly)
-antibodies stimulating thyroid growth
3. w/fxnal abnormalities
-hypothyroidism
-hyperthyroidism









Name some molecular factors associated with goiter.
1. TSH
-iodine def
-iodine excess
-goiterogens
2. Thyroid growth immunoglobulin
3. GH, IGF-1
-puberty and acromegaly
4. thyroid cell clones w/increased replication rate






Name some sx and signs of compression by a goiter

1.Pressure on trachea
-dyspnea
-inspiratory stridor
2. larynx/recurent laryngeal nerve
-hoarseness
3. Esophagus
-difficulty swallowing
4. Return of venous blood
-Pemberton sign (can't hold hands above head for long)

-would need to treat even though non-toxic if getting compressive sx









How do we treat non-toxic goiter?
1. T4 suppression trial
2. surgery (ex if obstructing trachea)
3. radiiodine therapy

True or false: non-toxic thyroid nodules are the result of iodine deficiency
-false
-iodine def results in diffuse enlargement (goiter)
-non-toxic nodules due to clonal expansion of thyroid line

Define granulomatous subacture thyroiditis
=most common cause of thyroid pain
-due to rupture of follicles -> inflammation and granuloma formation
-thyroid enlarges
-usu post-viral (coxsackie, mumps, measels, adenovirus)
-self-limited
-hyperthyroidism followed by hypothyroidism




Define Riedel's thyroiditis
=thyroid disease characterized by connective tissue proliferation -> destruction of thyroid gland
-gland completely replaced by fibrous tissue (giving firm, nodular gross appearance)
-unknown etiology
-less than 50% of pts are hypothyroid
-may present w/sx of compression or painless lump



What characteristics of a solitary thyroid nodule would make you think neoplasm?
-usu solitary nodules are benign
-things that suggest neoplasm:
1. solitary > multiple nodules
2. younger > older pts
3. males > females
-need fine needle aspiration biopsy to make definitive diagnosis




________ adenocarcinoma is the most common type of thyroid cancer
=papillary
-other types
1. follicular
-more malignant than papilary
-hematogenous metasis
2. medullary
-neuroendocrine tumor
-associated w/ MEN IIa and III
-secrete CT
3. anaplastic
-aggressive thyroid cancer (death in 2 yrs)
-undifferentiated cells










Describe papillary adenocarcinoma of the thyroid
=most common type of thyroid cancer
-neoplasia of follicular cells
-risk factors: radiation, genetic
-can be seen at any age (ex under 40 yrs)
-affects females more than males
-good survival
-morphology:
1. papillary pattern due to exuberant growth
2. ground glass nuclei (orphan Annie eyes)
3. Psammoma bodies








What is the usual course of tx for thyroid cancer
Goal is to eliminate for all thyroid tissue in body
1. Surgery
-thyroidectomy
-removal palpable lymph nodes
2. Ablation w/radioactive iodine
-NO radiation for medullary cancer
-can cause BM suppression
3. Thyroxine replacement
-keep TSH low/normal

Chemo and rad as adjunct if metastasis or certain cancers (medullary, anaplastic)









________ is marker used to follow patients with thyroid cancer
=thyroglobulin
-want low levels (below 0.5 ng/mL)
What are the clinical uses of thyrogen?
=recombinant human TSH
-uses
1. Dx of thyroid cancer remnant
2. Thyroid remnant ablation


Contrast Diabetes type I and Diabetes Type II
DM I
1. early onset
2. pts have normal wt
3. decreased blood insulin
4. islet cell antibodies present
5. prone to ketoacidosis

DM II
1. Later onset
2. often overwt/obese
3. normal or increased insulin
4. NO islet cell antibodies
5. ketoacidosis is rare











The MHC hapylotype associated with diabetes is ________.
=HLA-DR4
Describe the pancreatic tissue pathology in diabetes
1. reduced number of islets (endocrine units)
2. replacement of functional tissue w/fibrous scarring
3. Inflammatory infiltrates (T lymmphocytes)
4. Islet cell antibodies (90% have w/in first year of diagnosis; seen in type I DM)
5. amyloid deposits



Diabetes induces what kinds of changes in small blood vessels?
1. basal lamina thickening
2. endothelial proliferation
-can contribute to complications in the kidneys, eyes, and peripheral nerves

Large blood vessels have accelerated rates of atherosclerosis



How do we diagnose diabetes
1. Fasting blood sugar
-Normal: less than 100
-Prediabetes (impaired glucose tolerance): 100-125
-Diabetes: 126 or greater
-need 2 times with fasting blood glucose > 126 to dx diabetes
2. Oral glucose tolerance test
-normal: less than 140
-prediabetes: 140-200
-diabetes: 200 or greater
-usu don't need to repeat OGTT








What are the blood sugar control goals for diabetics?
1. Before meals (FBG) between 80-140 -normal:
What does hemoglobin HbA1C tell you?
-tells you their 2-3 month control of their blood sugar

-RBCs typically last about 2-3 months
-glucose sticks to RBCs -> forms glycosylated hemoglobin
-so if lots of excess glucose in blood, more will stick to RBCs -> increased HBA1C



Contrast the cause of diabetes type I vs type II
Diabetes type I
-Due to autoimmune destruction of islets of pancreas
-mediated by autoantibodies against beta cells
-more likely to have another autoimmune disease as well
-you can get type I at any age too; if dx as adult may be slower rate of islet destruction

Type II
-due to insulin resistance
-intracellular defect in glucose metabolism







True or false: genetics do not contribute to the development of type II diabetes
-false!
-90% of people with type II diabetes have a family member w/it as well
Define LADA
=Latent Autoimmune Diabetes in Adults
-late-onset type I diabetes
-show slower destruction of pancreatic islets
-also positive for GAD antibodies


Describe the development of type II diabetes
-develop insulin resistance (SKM and adipose tissue)
-pancreatic beta cells secrete more insulin to maintain blood glucose at given level (compensated BG but hyperinsulinemia)
-eventually pancreas fails and blood sugars go up (decompensation)
-insulin levels drop
-increased hepatic glucose production (normally suppressed by insulin)
-blood glucose levels rise further -> diabetes
-process takes about 10-15 years





What is the incretin effect?
Incretins=hormones produced by L cells of SI (GIP, GLP-1)
-stimulate insulin release and inhibit hepatic glucose production
-also circulate in brain to control appetite
-net effect is weight loss

-now there is a drug (Exenatide) that is an incretin to help tx diabetics by helping them lose weight




Who gets metabolic syndrome?
-people w/type II diabetes
1. diabetes
2. dyslipidemia
3. HTN

-> heart disease and stokes




What are the ABCs of diabetes management?
1. hbA1c
2. Blood pressure
3. Cholesterol/lipids

-get people on aspirin



True or false: insulin is only needed to tx type I diabetes
-false
-if have trouble keeping pts HbA1C under 7% with oral agents, diet and exercise, may need to add insulin

-not all type II patients will need insulin but eventually a lot of them do


Define gestational diabetes
=diabetes that develops during pregnancy (not diabetic before pregnancy)
-many hormones increased during pregnancy -> insulin resistance
-associated w/genetic predisposition
-may need insulin through third trimester


How does type 1 diabetes develop
-need genetic predisposition
-trigger: viral, environmental, stress
-develop autoimmune disease with circulating autoantibodies against beta pancreatic cells
-when less than 20% beta cells left, insulin production down, and blood sugar levels go up
-tx with insulin to prevent diabetic ketoacidosis



What do diabetics have to think about when calculating insulin doses
-blood sugar at the moment
-blood sugar levels over the preceding hours
- prior exercise
-anticipated exercise
-what they've eaten
-what they're going to eat
-whether they are sick





Why are people with type II diabetes less likely to go into ketoacidosis?
-because they still have some insulin around (vs type I w/virtually no insulin left)
Name 3 mechanisms that result in the chronic manifestations of diabetes
1. Nonenymatic glycosylation
-small vessel -> thickening of basement membrane -> retinopathy, nephropathy)
-large vessel -> atherosclerosis

2. Osmotic damage
-neuropathy
-cataracts (sorbitol accumulation)





What are the physiological effects of insulin deficiency?
1. Decreased glucose uptake -> hyperglycemia
2. increased protein catabolism
3. increased lipolysis
->increased plasma FFAs, ketone body formation
4. Unopposed effects of glucagon, growth hormone, and epinephrine -> exacerbate hyperglycemia

-lead to acute manifestations: polydipsia, polyuria, polyphagia, weight loss, DKA (type I), hyperosmolar coma (type II)





Define DKA
=diabetic ketoacidosis
-common complication of type I diabetes (can be seen rarely with type II)
-usu due to an increase in insulin requirements b/c increase in stress (ex infection)
-excess fat breakdown and increase in ketogenesis -> form ketone bodies
-results in dehydration and acidosis
-can have life-threatening complications
-tx: fluids, insulin, potassium





A pt presents to the ER with dehydration, nausea and vomiting, abdominal pain, confusion, and rapid,deep breathing. Their breath has a fruity odor. What do they have?
-diabetic ketoacidosis
-frequent complication of type I diabetes
Describe the lab values you would expect for a person in DKA
1. hyperglycemia
2. increased H+, decraesed HCO3- (leading to increased anion gap)
3. increased blood ketone levels
4. leukocytosis
5. hyperkalemia



Name 5 complications associated with DKA
1. Life threatening mucormycosis
=fungal infection that occurs in sinuses, brain, or lungs of people w/immune disorders
2. Rhizopus infection
3. cerebral edema
4. cardiac arrhythmias
5. heart failure




How do sulfonylureas work?
=pancreatic secretalogues
-stimulate release of endogenous insulin
-tx type II diabetes
-useless in type I b/c no islet fxn
-close K+ channels in beta cell membrane -> cell depolarizes -> Ca influx -> stimulate release of insulin



How does metformin work?
-inhibits hepatic gluconeogenesis
-exact mechanism is unknown
-can be used in both type I and type II treatment

How do Rosiglitazone and pioglitazone work?
-used to tx type II diabetes
-insulin sensitizers that increase target cell response to insulin

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