Exam 1 Flashcards
cardiac hypertrophy or cardiomegaly
any increases in size or particularly in increases in masses
Left ventricular hypertrophy
A nything that should exceed that, so say more than 15mm, (normal is 13-15)
a cellular, structural response to a variety of insults.
consequences of both pumping against increased pressure and you also reduce the cardiac output because of reduced stroke volume
right ventricular hypertrophy
anything above that 5mm threshold (normal is 3-5mm)
cor pulmonale: primary pulmonary hypertension will lead to right sided changes in the heart.
Pulmonary arteries hypertrophy, constrict, and sclerose
Persistent elevations in pressure result in right to left shunt (Eisenmenger syndrome)
After birth, blood flow from right to left results in hypoxemia and cyanosis
Bypasses the pulmonary circulation
Emboli from veins to the systemic circulation (paradoxical emboli)
Cardiac dilation or dilatation
increase chamber size often related to disease state
Microscopic consequence of systemic hypertension
increased production of sarcolemma proteins and markedly enlarged, what we call boxed car nuclei, with thickened myofibrils
Three major coronary arteries
Left anterior descending (breaks into diagonal branches)
Left circumflex (Marginal branches)
Right Coronary
Pathologic changes of the valves
Damage to collagen that weakens the leaflets
Nodular calcification
Fibrotic thickening
Secondary changes:
Ventricular dilation
Tendinous cord rupture
Papillary muscle dysfunction
Left to right shunts
result in an increase in pulmonary blood flow
Elevate both volume and pressure in the low-pressure, low- resistance pulmonary circulation
Most common congenital heart disease
Symptoms vary from asymptomatic to fulminant heart failure
Ventricular septal defects
o incomplete closures of the ventricular septum, allowing free communication of blood between the left and right ventricles
o most common form of congenital heart disease
o 90% occur in the region of the membranous interventricular septum (membranous VSD)
o 10% occur below the pulmonary valve (infundibular VSD)
o Functional consequences of a VSD depend on the size of the defect and associated right-sided malformations
o Lead to early right ventricular hypertrophy and pulmonary hypertension
o Irreversible pulmonary vascular disease, shunt reversal, and death
o 50% CLOSE SPONTAEOUSLY
Atrial septal defects
o Abnormal, fixed openings in the atrial septum caused by incomplete tissue formation
o Usually asymptomatic until adulthood
o left to right shunts, increased pulmonary blood flow, and murmurs
o Pulmonary hypertension is unusual
o Secundum ASD (90%) results from a deficient septum secundum formation
o Primum anomalies or sinus venosus defects (10%) occur adjacent to the AV valves or the entrance of the SVC
Patent Ductus Arteriosus
o The ductus arteriosus arises from the pulmonary artery and joins the aorta just distal to the origin of the left subclavian artery
o PDAs cause a characteristic continuous harsh “machinery-like” murmur
o Large defects can lead to volume and pressure overloads in the small pulmonary arteries, reversal, and associated consequences
o May be life saving for infants with other congenital abnormalities that obstruct pulmonary or systemic outflow tracts (TOF)
Tetralogy of Fallot
o RIGHT TO LEFT SHUNT*
o Four features
VSD
Obstruction of the right ventricular outflow tract (pulmonary stenosis)
Overriding aorta
Right ventricular hypertrophy
o Boot shaped heart
o Severity = based on the ability of the right heart to pump blood and adequate amount of blood into the pulmonary circulation
pink tetralogy: you may only have a left-to-right shunt because you haven’t built up pressures sufficiently to cause the right to left; mild and may not require surgery
most infants are symptomatic at birth and will require immediate surgery right after birth.
Transition Of The Great Arteries
o produces ventriculoarterial discordance
o Aorta arises from the right ventricle/ Pulmonary artery arises from the left ventricle
o Atrium-to-ventricle connections are normal
o Early survival depends on accompanying shunting defects
Obstructive Lesions
o Congenital obstruction can occur at the level of the heart valves, within a great vessel, or within a chamber
Aortic or pulmonary valve stenosis or atresia
Outflow obstruction in TOF
Coarctation of the aorta
• constricting or narrowing of the aortic arch
• Infantile
o Often symptomatic in early childhood with tubular hypoplasia of the aorta arch proximal to the ductus
• Adult
o Discrete, ridge-like infolding of the aorta just opposite of the closed ductus
• with PDA usually manifests early in life due to the delivery of unsaturated blood through the lower part of body
• without PDA often goes unrecognized until adulthood
o Hypertension of the upper extremities
o Hypotension of the lower extremities
o Development of collateral circulation
Six principal mechanisms of Cardiac Dysfunction
- Pump failure
- Flow obstruction
- Regurgitant flow
- Shunted flow
- Disorders of cardiac conduction
- Rupture of the heart or a major vessel
Congestive heart failure
occurs when the heart is unable to pump blood at a rate sufficient to meet the metabolic demands of the body tissues
Malignant hypertension
o a rapidly rising blood pressure that if left untreated will die within 1 -2 years
o Systolic BP above 200 mm Hg/Diastolic BP above 120 mm Hg
o Renal failure/ Retinal hemorrhages
Arteriosclerosis
hardening of the arteries
Hyaline Arteriolosclerosis
Pink hyaline thickening with associated luminal narrowing
Plasma protein leakage across injured endothelial cells leading to increased smooth muscle matrix synthesis
Hyperplastic Arteriolosclerosis
Concentric, laminated, onion- skinning thickening of the walls with luminal narrowing
Consists of smooth muscle cells with thickened, reduplicated basement membranes
May lead to necrotizing arteriolitis in malignant hypertension, particularly in the kidneys
Atherosclerosis
o form of arteriosclerosis caused by the build up of fatty plaques within the arterial walls
o underlying pathology of coronary artery, cerebral, and peripheral vascular disease (the main driver for end organ damage within the cardiovascular system)
a chronic inflammatory and healing response of the arterial wall to endothelial injury
Lesion progression occurs due to complex interactions of lipoproteins, macrophages, T- cells, and smooth muscle cells
Modifiable Risk Factors for Atherosclerosis
Diabetes mellitus Unhealthy diet Inactivity Obesity Alcohol use Smoking Hyperlipidemia Low-density lipoproteins Systemic inflammation Hyperhomocystinemia Metabolic syndrome Insulin resistance, hypertension, dyslipidemia, hypercoagulability, and a proinflammatory state
Pathophysiology of Atherosclerosis
Endothelial injury or dysfunction
Accumulation of lipoproteins
Monocyte adhesion to the endothelium
Platelet adhesion
Factor release
Smooth muscle cell proliferation
Lipid accumulation
What percent decrease in luminal diameter is needed to reach critical stenosis in the coronary arteries?
70% decrease in the luminal diameter for critical stenosis and subsequent tissue ischemia
Angina pectoris
“chest pain” in response to reaching the point of critical stenosis and the vessels are not able to respond in times of increased demand
FANCY ANSWER: paroxysmal and usually recurrent attacks of substernal or precordial chest discomfort caused by transient myocardial ischemia that is insufficient to induce myocyte necrosis
Stable angina
“Chest pain with exertion”
A stable plaque that’s 70-80% occluded, so, when your heart requires, because of the activity, more oxygen delivered – increased contractility – your vessel cannot respond to that by delivering increased amount of blood and oxygen causing pain
Unstable angina
“Chest pain at rest”
You’re probably well above the 70% mark, approaching 80-90%. Even at base line contractility of the heart, the coronary arteries are not able to deliver as much oxygen as necessary.
plaque disruption can then result in thrombosis and vasoconstriction without total occlusion, so you can develop a thrombus in that area as a response to plaque disruption.
A person can go from unstable to stable
Plaque Disruption
Plaques erode or rupture when they are unable to withstand mechanical stresses generated by vascular shear forces
Plaque rupture results in the release of the necrotic lipid core, and rapid recruitment of platelets
Plaque rupture is typically promptly followed by partial or complete vascular thrombosis
Myocardial Infarction
heart attack
Death of cardiac muscle due to prolonged and severe ischemia
The incidence of MI strongly correlates with genetic and behavioral predispositions to atherosclerosis
most common cause of death in older women
Ischemic heart disease
Epi of MI
45% occur in people younger than 65
10% of MIs occur in people younger than 40
Blacks and white are equally affected
In middle age, men have a higher relative risk
Women are generally protected during reproductive years
Postmenopausal decline in estrogen production is usually associated with accelerated coronary artery disease
Process of a Heart Attack
Coronary artery atheromatous plaque undergoes an acute change
When exposed to subendothelial collagen and necrotic plaque contents, platelets adhere, become activated, and aggregate
they are going to vasospasm and constrict further in response to these local mediators (so instead of dilating, they constrict).
Tissue factor activates the coagulation cascade, adding the bulk of the thrombus
Occlusion can occur within minutes
Obstruction diminishes the blood flow to the region of the myocardium.
Within seconds the oxygen will be depleted and without oxygen, aerobic metabolism will stop
Noxious metabolites (lactate) accumulate
Myocardial contractility ceases
Ultrastructural changes occur in the myocyte
Myofibrillar relaxation, glycogen depletion, mitochondrial swelling
(Reversible!!)
In about 20 – 30 minutes, myocyte necrosis begins
2 – 3 hours of half thickness
6 hours for transmural
(Irreversible!!)
MI Timeline
Within 30 minutes Relaxation of myofibrils Glycogen loss Mitochondrial swelling (Reversible injury)
30 minutes – 4 hours
Sarcolemmal disruption and mitochondrial densities
No gross findings
Subtle waviness of mycoytes at the border of the infarct
4 – 12 hours
Beginning to have dark mottling
Early coagulation necrosis, edema, and hemorrhage
12 – 24 hours Dark mottling Ongoing coagulative necrosis Pyknosis of nuclei Hypereosinophilia of myocytes Contraction band necrosis Early neutrophilic infiltrate
1 – 3 days
Mottling with yellow-tan infarct center
Coagulation necrosis with loss of nuclei and striations
Brisk neutrophilic infiltrate
3 – 7 days Hyperemic border with central yellow-tan softening Disintegration of dead myofibers Dying neutrophils Macrophages at infarct border
7 – 10 days peak of macrophages maximally yellow-tan & soft depressed tissue at the site of the infarct brisk phagocytosis Granulation tissue at the margins
10 – 14 days
Red-gray depressed borders
Well established granulation tissue with new blood vessels and early collagen deposition
2 – 8 weeks
Grey-white scar from border to center
Collagen deposition
Decreased cellularity
> 2 months
Complete scar
Dense collagen
When is the time period where you are most vulnerable to complication down the road, if you survive the heart attack and the heart is at its most weakened?
3 – 7 days
macrophages are chomping up on the dead myocytes and the nuclear debris.
Summarized Timeline
So the earliest change that we find is sort of this wavy, maybe hyper-eosinophilic area - these are the earlier microscopic changes that we see.
Next step in the process is the recruitment of neutrophils – this occurs in the 12-24 hour mark
As we progress, neutrophils will be replaced by macrophages
Macrophages[replaced] by smooth muscle cells & fibroblast depositing collagen
Ultimately you’re left with fibrosis in that area if you survive & the development of a collagenous scar (bottom right)
LAD supplies…
most of the apex, the anterior wall of the LV, and the anterior 2/3 of the ventricular septum
– The dominant artery perfuses the posterior 1/3
occlusions account for 40 – 50% of myocardial infarcts
RCa supplies…
the entire right ventricular free wall and the posterobasal wall of the LV
occlusions account for 30 – 40% of myocardial infarcts
LCx supplies…
the lateral wall of the LV
occlusions account for 15 – 20% of myocardial infarcts
Transmural infarction
Caused by occlusion of a vessel with full thickness necrosis of the myocardium
Usually caused by chronic coronary atherosclerosis, acute plaque changes, and thrombosis
Subendocardial infarction
Partial thickness, although that can occur in complete occlusions
The subendocardial zone is normally the least perfused region and is most vulnerable to disruptions in flow
May result from severe, prolonged reduction in systemic blood pressure in individuals with otherwise non-critical stenosis
Multifocal infarction
Typically seen with pathology involving the small intramural vessels
Microembolization, vasculitis, vasospasms like someone who uses cocaine
MI Presentation
Typically present with prolonged chest pain described as crushing, stabbing, or squeezing
Often associated with a rapid weak pulse, diaphoresis, and nausea and vomiting
25% may be entirely asymptomatic
– Diabetics
MI Diagnosis
diagnosed by clinical symptoms, laboratory tests, and characteristic EKG changes
Laboratory diagnosis exploits blood levels of proteins that leak out of irreversibly damaged myocytes
– Troponins, CK-MB, lactate
Troponins rise later than all the other proteins but STAY HIGH LONGER after an MI***
MI Treatment
Morphine to relieve pain Reperfusion Antiplatelet agents Anticoagulation Nitrates for induce vasodilation Beta blockers to decrease myocardial oxygen demand Antiarrhythmics to manage arrythmias Angiotensin converting enzyme to limit ventricular dilation Oxygen supplementation
Myocardial Rupture
3 – 5 days after an MI are most at risk
you can end up with rupture of the left ventricular free wall which leads to hemopericardium or blood within the pericardial sac.. That blood will compress the heart, reduce its ability to contract & that leads to condition called cardiac tamponade.
You can also develop ruptures of the ventricular septum if that’s the area that was infarcted.. This can develop a function ventricular septal defect & a left to right shunt & all of the complications that occur because of that.
The papillary muscles in subendocardial ischemia or transmural.. can rupture which can lead to an onset of severe mitral regurgitation
Chronic Ischemic Heart Disease
progressive congestive heart failure as the result of accumulated ischemic myocardial damage
usually appears after an infarction due to the functional decompensation of the hypertrophied, noninfarcted myocardium
Ischemic heart disease leads to the development of…
Left ventricular hypertrophy
Cardiac dilation
Cardiomegaly
Heart failure
Valvular Disease
most commonly stenosis, insufficiency, or some combination of both.
Valvular stenosis is a failure of the valve to open completely, which is going to impede FORWARD flow
Valvular Insufficiency results from a failure of a valve to CLOSE completely, so this leads to regurgitation or REVERSED flow, so pressure overload in the chamber prior to
Primary vs. Secondary Valvular Disease
Primary: defects & generation of the valvular tissue ITSELF
Secondary or functional insufficiency: often happens because of DILATION of one of the CHAMBERS of the heart, so dilation of the left ventricle may prevent the proper closure of an otherwise normal valve
Most common acquired valvular diseases
- Aortic stenosis
- Aortic insufficiency
- Mitral stenosis
- Mitral insufficiency
So left sided heart problems are the ones that are the most common, most frequently encountered.
Aortic stenosis
Calcification and sclerosis of anatomically normal or congenitally bicuspid aortic valves
Consequence of recurrent chronic injury due to factors similar to atherosclerosis in other areas
Hyperlipidemia
Hypertension
Inflammation
Chronic progressive injury leads to valvular degeneration and incites deposits of hydroxyapatite (same calcium found in bone)
Obstruction to the left ventricular outflow tract leads to gradual narrowing of the valve orifice and an increasing pressure gradient across the valve
Left ventricular pressures rise
Left ventricular hypertrophy
Systolic and diastolic dysfunction occur
Angina, congestive heart failure, and death
TXT: Valve replacement
Aortic insufficiency
Dilation of the ascending aorta secondary to hypertension or aging
Mitral stenosis
Rheumatic heart disease
Rheumatic fever is an acute, immunologically mediated, multisystem inflammatory disease classically occurring a few weeks following group A streptococcal pharyngitis
Results from a host immune response to GAS antigens that cross react with host proteins
Antibodies against streptococcal M proteins that cross react with cardiac self antigens
Leads to complement activation, cytokine production, and T-cell/macrophage activation
Mitral insufficiency
Myxomatous degeneration
Marked thickening of the spongiosa layer with deposition of myxomatous material
Attenuation of the collagenous fibrosa layer
Secondary changes
Fibrous thickening of the leaflets
Fibrous thickening of the left ventricular endocardial surface
Thrombi on the atrial surface of the leaflets
Mitral Annular Calcification
degenerative changes in the mitral valves typically affect the fibrous annulus
Leads to irregular, stony hard, sometimes ulcerated nodules at the base of the leaflets
Usually doesn’t affect valvular function
Regurgitation to due contraction of the valve ring
Stenosis by impairing valve opening
Arrhythmias due to penetration of calcium into the atrioventricular conduction system
These calcific nodules provide a site for thrombus formation
Increase risk of embolic stroke and infective endocarditis
Mitral Valve Prolapse
one or both of the mitral valve leaflets are floppy and balloon back into the left atrium during systole
Affects 2 – 3 % of individuals in the US
7:1 female to male ratio
Often benign, but may lead to sudden cardiac death
Leaflets are enlarged, redundant, thick, and rubbery
The tendinous cords may be elongated, thinned, or ruptured
Mitral valve annulus is dilated
What is found during Rheumatic Fever?
focal inflammatory lesions are found in various tissues
Aschoff bodies in the heart
Foci of T lymphocytes, occasional plasma cells, and activated macrophages
Anitschkow cells
Pathognomonic
Acute Rheumatic Fever
Diffuse inflammation and Aschoff bodies may be found anywhere in the heart
Inflammation of the endocardium and left-sided valves result in fibrinoid necrosis within the cusps or tendinous cords
Overlying these necrotic foci are small vegetations (verrucae)
Subendocardial lesions develop (MacCallum plaques
Valve most commonly seen effected by Rheumatic fever?
Mitral Valve
Pathologic changes in RF
a fish mouth deformity of the valve (fusion of the commissures here so the normal mitral leaflets start to thicken, they get fused here at the commissures)
Tight mitral stenosis
Progressive left atrium dilation
Pulmonary congestion and vascular changes
Right ventricular hypertrophy
Comparison between mitral prolapse and mitral stenosis from RF?
In contrast to mitral valve prolapse, where had thinning and elongation of the tendinous cords, we see thickening and reduplication of these cords which can cause further dysfunction
Rheumatic Fever Clinical
Characterized by
Migratory polyarthritis of the large joints
Pancarditis inflammation of the heart muscle
Subcutaneous nodules
Erythema marginatum of the skin
Sydenham chorea
Involuntary, rapid, purposeless movements
Infective Endocarditis
microbial infection of the heart valves or mural endocardium (just adjacent to the valves) that leads to the formation of (infected) vegetations
Often associated with destruction of the underlying cardiac tissues (as well as the valves themselves)
Most infections are bacterial (but there are a wide variety of causes)
Classified into acute and subacute forms
Acute endocarditis
typically caused by infection of a previously normal heart valve by a highly virulent organism (Staph aureus)
Rapidly produces necrotizing and destructive lesions
Difficult to cure with antibiotics alone
Subacute endocarditis
endocarditis is typically cause by organisms with lower virulence (Strep viridans) that cause insidious infections of deformed valves
most important predisposing factors to developing endocarditis
Obvious infection
Contaminated needle shared by IVDU
Dental or surgical procedures
Nonbacterial thrombotic endocarditis
Sterile vegetations characterized by deposition of small sterile thrombi on the leaflets of the cardiac valves
Single or multiple
Nondestructive
Illicit no inflammatory response
May embolize
Libman-Sacks endocarditis
Mitral or tricuspid valvulitis with small sterile vegetations
Occasionally encountered in systemic lupus erythematosus
Single or multiple
Located on the undersurfaces of the atrioventricular valves
Associated with intense valvulitis
INFLAMMATION!!!*
these are the only lesions that are located on the undersurface of valves**
Three major morphologic patterns of cardiomyopathy
Dilated cardiomyopathy
Hypertrophic cardiomyopathy
Restrictive cardiomyopathy
Dilated Cardiomyopathy (DCM)
most common (90% of cases)
Characterized by progressive dilation and systolic dysfunction, usually with concomitant hypertrophy
– Ejection fraction < 40%
Genetic factors, alcohol, peripartum, myocarditis, hemochromatosis, chronic anemia, doxorubicin toxicity, sarcoidosis
Enlarged, heavy, and flabby heart
– Dilation of all four cardiac chambers
Mural thrombi are common
May result in secondary valvular dysfunction
Typically affects those between 20 and 50
Presents with slowly progressive signs and symptoms of CHF
– Dyspnea, fatigue, poor exertional capacity
Hypertrophic Cardiomyopathy
common, clinically heterogenous, genetic disorder characterized by myocardial hypertrophy, poorly compliant left ventricular myocardium leading to abnormal diastolic filling, and intermittent ventricular outflow obstruction
Thick walled, heavy, and hypercontracting
Ejection fraction is 50 – 80%
Autosomal dominant disorder with variable penetrance
Banana-like left ventricular cavity
Central abnormality in HCM
reduced stroke volume due to impaired diastolic filling
Reduced chamber size
Reduced compliance of the ventricle
Those with significant outflow obstruction develop increased pulmonary venous pressures and dyspnea
hypertrophic obstructive cardiomyopathy
this is the characteristic young athlete, who had no problems but just died suddenly during the filed of play
Intramural arteries thicken Focal myocardial ischemia is common Atrial fibrillation Ventricular arrhythmias Mural thrombi and embolization Cardiac failure Sudden death
Restrictive Cardiomyopathy
characterized by a primary decrease in ventricular compliance resulting in impaired ventricular filling during diastole
– Ejection fracture 45 – 90%
Systolic function is usually unaffected
Causes of Restrictive Cardiomyopathy
Radiation Amyloidosis Sarcoidosis Metastatic tumors Inborn errors of metabolism
(secondary changes)
Myocarditis
a diverse group of pathologic entities in which infectious microorganisms and/ or a primary inflammatory process cause myocardial injury
May cause direct myocyte injury or elicit a destructive immune response
The intense cytokine response produces myocardial dysfunction out of proportion to the degree of actual myocyte damage
Myocarditis is a PRIMARY disease, and should be distinguished from secondary causes of inflammation (ie, ischemic heart disease)
Causes of Myocarditis
Viral infections are the most common cause of myocarditis in the US
Coxsackie A and B and other enteroviruses
Occasionally, CMV, HIV, and influenza may be implicated
Nonviral agents are common outside of the US
Trypanosoma cruzi, trichinella spiralis, toxoplasmosis, borrelia burgdorferi, and Corynebacterium diphtheriae
Pericarditis
inflammation can occur secondary to a variety of cardiac, thoracic, or systemic disorders, metastases, or cardiac surgical procedures
Primary pericarditis is rare (viral)
Serous pericarditis
Characteristically produced by non-infectious diseases (RF, SLE, scleroderma, tumors, and uremia)
Fibrinous pericarditis
Most frequent type of pericarditis
Serous fluid mixed with fibrinous exudate
Acute MI, postinfarction syndrome (Dressler syndrome), uremia, radiation, RF, SLE, and trauma
Primary cardiac tumors
Myxomas (most common tumor in adults) Fibromas Lipomas Papillary fibroelastomas Rhabdomyomas (most common pediatric tumor) Angiosarcomas
**Most common heart tumor is a metastasis**
respiratory epithelium
pseudostratified columnar with cilia and goblet cells
2 types of pneumocytes
Type 1- where gas exchange occurs and really hard to see.
Long thin cell with a very small nucleus. Gas exchange occurring across the cytoplasm.
As you breathe in the oxygen. they are at high risk of dying so they have a high turnover rate.
Type 2-can terminally differentiate and become type 1 cells. They also have macrophage functions. They also make surfactant.
Surfactant and newborns
what surfactant does is it follows La Place’s Law and it lines these airways. And it decreases surface tension. So by having a hydrophobic surface towards the center of the alveoli, the fluid is thinned out and surface tension is less. And that’s important because the second breath the child takes is against less resistance because the child is not born with great muscles, they’re thin as can be.
. So they realized that if you gave surfactant to a child born before 24 weeks, they could survive.
Also give steroids to the mother to jack up surfactant production by the type 2 pneumocytes.
Pulmonary function tests
TLC: total lung capacity (5 to 7 l)
VC: vital capacity (3 to 5 l) TV: tidal volume (1 to 2 l)
FVC: forced vital capacity (3 to 4 l)
FEV1: forced expiratory volume in 1 second (2 to 3 l) FEV1/FVC ratio (60 to 70%)
Three mechanisms to have obstructive lung disease
You can have obstruction because there’s something blocking the way (fluid or mucus)
You can have decreased diameter because the muscular hypertrophy or construction
You can have a loss of tether
Three types of obstructive lung disease with their definitions
Emphysema: abnormal permanent enlargement of airspaces without obvious fibrosis
Chronic bronchitis: persistent cough with sputum for at least 3 months in at least 2 consecutive years
Asthma: hyperreactive airways leading to episodic reversible bronchoconstriction
Emphysema
so you can breathe the air in. But you can’t get that carbon dioxide out which is bad for two reasons.
One, the carbon dioxide levels are going to rise in your blood. But number two you don’t have room for more oxygen.
Emphysema Supersimplified pathogenesis
tip the balancing act towards the elastases and the enzymes will destroy the lung and break down the lung. (Neutrophil elastase Proteinase 3 Cathepsins
Matrix metalloproteinases) and away from the “anti-enzymes” (1-Antitrypsin
Secretory leukoprotease inhibitor Elafin
Tissue inhibitors of matrix metalloproteinases)
Example is Tobacco blocks the antitrypsin and leads to the influx of a lot of neutrophils; and neutrophils stimulate the release of these proteins as well. So anything that leads to break down the lung and prevents the breakdown of lung, will lead to dissolving are melting of the lung tissue and that’s what causes emphysema.
Emphysema a1-antitrypsin deficiency
1-2% of patients with COPD
Autosomal recessive disorder
1AT is a serine protease inhibitor—elastase Made in the liver
Defective 1AT does not neutralize elastase—emphysema Defective 1AT accumulates in the liver—cirrhosis
Mutated SERPINA1 gene
PiZZ—panacinar emphysema at a young age
PiSS, PiMZ and PiSZ–reduced levels of normal—emphysema if smokers
Chronic bronchitis
You plug the airways with mucus . So a smoker is most risk of developing this because the tobacco smoke harms the respiratory epithelium and predisposes to infection. So then you keep getting infections of the airways you get bronchitis, you get pneumonia, you get bronchitis
Bronchiolar and bronchial injury leading the bronchospasm, and hypersecretion of mucus, infection.
Obstruction and airways continued in repeated injury, smoking, continued in repeated infection chronic bronchitis.
Asthma
You got more goblet cells than normal. You’ve got inflammatory cells. You’ve got thickened muscle and way too many seromucinous glands. So all of that is a response to whatever this immune trigger is. Bronchoconstriction leads to muscle thickening. Whatever the insult is damages the epithelium and leads to more seromucinous gland production of fluids and also hypertrophy of the seromucinous glands.
Asthma Focus on T-cells
Process of Asthma
an antigen being presented by a macrophage and then shit really hits the fan because the T cells get revved up and they stimulate the B cells which secretes the antibodies that cross link on the mast cell. That lead to lead mediator release of leukotrienes, cytokines, and histamines and cause bronchospasm and edema and airway inflammation and so on.
Still don’t have a way to stop the T cells, so we treat asthma the same old fashioned way with bronchodilators and steroids. Bronchodilators to help the airways stay open and steroids to try and knock down this inflammatory cascade.
Atelectasis
Incomplete expansion or collapse of lung (airless lung)
REVERSIBLE DISORDER
3 types
Resorption atelectasis: due to airway obstruction
Compression atelectasis: due to pleural cavity expansion hemothorax, pneumothorax
Contraction atelectasis: due to lung or pleural fibrosis
Restrictive lung diseases
Spinal disorders Neurologic disorders Sarcoidosis Hypersensitivity pneumonitis Pneumoconiosis Idiopathic
Hypersensitivity pneumonitis
Extrinsic allergic alveolitis
Immunologic reaction to inhaled antigens Antigens not identified in up to 66% of cases Acute and chronic presentations
ACUTE PRESENTATION
Single large bolus exposure to antigen
Dyspnea, cough, fever/chills 4-6 hours later
CXR: diffuse granular infiltrates Pathology: Pulmonary edema Pathogenesis: Type III hypersensitivity reaction (immune complex disease) Prognosis: Improvement in a day or so Reexposure: Recrudescence
CHRONIC PRESENTATION
Prolonged exposure to small amounts of antigen Insidious dyspnea, dry cough, fatigue
CXR: Mostly upper lobe interstitial reticulonodular infiltrates Lab: serum antibodies, skin tests?
BAL: Increased CD8+ lymphocytes
Pathology: Chronic bronchiolitis, interstitial pneumonia, and granulomas Pathogenesis: Type III and IV hypersensitivity reactions
Prognosis: Improvement in 33%, stable in 33%, worsening in 33% if antigen not removed
Hypersensitivity Pneumoconiosis
Pathologic response related to:
intensity of exposure
duration of exposure quantity of exposure size of particle
physiochemical properties of particle route of clearance
efficiency of clearance host response
interactions with other environmental pollutants
examples causing pneumoconiosis
Asbesto Silica Silicates (talc, kaolin, mica) Mixed dust Coal Metals
fluid filled skin lesions
Vesicle: a circumscribed collection of free fluid less than 0.5cm in diameter
Bulla: a circumscribed collection of free fluid greater than 0.5cm in diameter
Pustule: a circumscribed collection of purulent exudate that varies in size (pimples)
Cyst: a cavity containing fluid or semisolid material surroudned by an epithelial layer
Disorders of Pigmentation and Melanocytes
Freckle
Lentigo
Melanocytic Nevi
Melanoma
Freckles
small- Focal abnormality in pigment production
Hyperpigmentation: increased amount of melanin pigment. Normal density of melanocytes
Lentigo
Liver spots- age spots
They’re not related to sunlight exposure, they are stable in color that’s why they are very difficult to remove.
The pathology is unknown
Excessive melanotic maculae in the oral and perioral distribution related to which two diseases?
Addison’s disease
Peutz-Jeghers
Addison’s Disease
Adrenal failure
Activation of pituitary gland leading to increased ACTH and MSH .
Stimulate melanocytes in the skin and mucosa
Peutz-Jeghers
INHERITED!!! (they’re going to have a family history)
They’ll also have other things in the skin and GI tract too.
Neurofibromatosis
Café au lait spots
Histologically similar- larger and arise independently of sun exposure
Neurofibromatosis is more a genetic disease and this is only one of the manifestations of that because the location of the skin lesions, different types of tumors, and even manifestations on the eyes too.
Vitiligo
Hypopigmentation (loss of melanocytes or melanin production)
Melanocytes are destroyed
White patches of skin
May be an autoimmune disease
May be associated with another autoimmune disease
Melanocytic Nevus (Pigmented Nevus Mole)
Benign neoplasms
Numerous subtypes
Acquired are the most common type
Dysplastic Nevi
May be direct precursors of melanoma Many never progress Mutations or epigenetic changes NRAS and BRAF genes Inherited loss of function mutations in CDKN2A
Melanoma
Most deadly of all skin cancers
Strongly linked to acquired mutations caused by exposure to UV radiation in sunlight
Relatively common neoplasm
Some studies suggest that periodic sunburns early in life are the most risk factors
Predisposing factors/environmental factors
Mutations in cell cycle regulators
Blistering sunburn can double the chances of developing melanoma later in life
Strong dose-response relationship
ABCs of Melanoma
Asymmetrical Borders (irregular) Color Diameter (1/4in or 6mm) Evolving (changing)
Melanoma Therapy
Antibody Therapy
Chemotherapy
Compared to those who have never tanned indoors, indoor tanners….
have a 20% percent higher risk of melanoma
have an 87% higher risk of melanoma if they start tanning before 35
are 2.5 times more likely to develop SCC and 1.5 more likely to develop Basal cell carcinoma
Benign Epithelial Tumors
Seborrheic Keratoses
Acanthosis Nigricans
Fibroepithelial Polyp
Epithelial or Follicular
Inclusion Cyst
Tumors of the Dermis
Benign Fibrous Histiocytoma
Dermatofibrosarcoma Protuberans
Tumors of Cellular Migrants of the Skin
Mycosis Fungoides
Mastocytosis
Acanthosis Nigricans
Dark velvety patches
May be an important sign of underlying conditions
GI Adenocarcinomas- middle aged and older individuals
Type 2 diabetes
Fibroepithelial Polyp or intraoral Polyp
skin tag
intraorally associated with an area of trauma usually
Premalignant and Malignant Epidermal Tumors Related to Sun Exposure
Actinic Keratosis
Squamous Cell Carcinoma
Basal Cell Carcinoma
Actinic Keratosis
Sun damaged skin-hyperkeratosis
Exposure to ionizing radiation and arsenicals
It seems like the skin is very dry, but they’re going to have this type of ulcerations.. But these ulcerations are not healing
Squamous Cell Carcinoma
DNA damage induced by exposure to UV light
P53 dysfunction
Can progress from actinic keratosis, chemical exposure, thermal burn sites or in association with HPV infection in the sitting of immunosuppression
Cutaneous cell carcinoma has potential for metastasis but is less aggressive than squamous cell carcinoma at mucosal sites
Basal Cell Carcinoma
Locally aggressive tumor
Rarely metastasize
Pearly papules containing prominent blood vessels ( telangiectasias)
Advanced lesions may ulcerate
Acute Inflammatory Dermatoses
Urticaria
Acute Eczematous Dermatitis
Erythema Multifomre
acute lesions-days to weeks
Inflammatory infiltrates-edema
Urticaria
hives – mast cell degranulation
Antigen induced release of vasoactive
mediators from the mast cells
Eczematous dermatitis
T cell-mediated inflammatory reactions
(type IV hypersensitivity)
Acute allergic reaction due to antigen exposure
Erythema Multiforme
Uncommon – self-limited hypersensitivity reaction to certain infections and drugs
Macules, papules, vesicles, bullae Any age
Herpes simplex, penicillin, barbiturates, salicylates, cancer (lymphomas), lupus, polyarteritis nodosa.
CHARACTERISTICS
Target like lesions Central necrosis Macular erythema
Stevens-Johnson syndrome
A febrile form associated with extensive involvement of the skin
Fever-flu like symptoms
Often in children but not exclusively
Blisters
Complications: Dehydration, sepsis
pneumonia
Multiple organ failure
Etiology
Medications- Antibiotics, carbamazepine and others
SLE HIV/AIDS
Immune reaction
Toxic Epidermal Necrolysis (TEN)
Defuse necrosis- cutaneous and mucosal epithelial surfaces
Flu like symptoms
A history of drug exposure Large blisters
More severe than SJS
Dehydration, sepsis, pneumonia and multiple organ failure
TEN v. SJS
It is called SJS when less than 10% of the skin is involved
Diagnosis is based on a skin biopsy
Hospitalization
Skin regrows over 2 to 3 weeks. Recovery can take months
Chronic Inflammatory Dermatoses
Psoriasis - This is autoimmune. Again you can have different severities, different locations, different manifestations. Some ppl have very little or have extension on almost every part of skin.
Seborrheic Dermatitis - more common than psoriasis- regions with high density of sebaceous glands- scalp and forehead, nasolabial folds Flaky scales Unknown etiology
Lichen planus
Pruritic, purple, polygonal, planar, papules and plaques
Disorder of skin and mucosa
White dots or lines, Whickham striae
Blistering (Bullous) Diseases
Pemphigus
Bullous Pemphigoid
Dermatitis Herpetiformis
Pemphigus
Inflammatory- Pemphigus- Autoantibodies
Primary lesions are superficial vesicles and bullae that rupture easily
Oral ulcers may persist for months
Bullous Pemphigoid
Chronic inflammatory subepidermal blistering disease
Dermatitis Herpetiformis
Inflammatory disorder
Blisters- Itchy papulovesicular eruptions
May be associated with Celiac disease
Bilateral and symmetric
Noninflammatory Blistering Disorders
Epidermolysis Bullosa
- blisters at sites of pressure, rubbing or trauma
Inherited disorder- minor to fatal
Porphyria
Porphyria
Metabolic disorders- excretion of porphyrins- purple red pigments
Genetic factors and environmental factors
Sensitivity to light
Lesion in the skin- blistering
Affects the nervous system
Attacks may be triggered by smoking stress and certain medications
Complications
High blood pressure
Chronic kidney failure
Live damage
Disorders of Epidermal Appendages
Acne vulgaris
Rosacea
Acne vulgaris
Hair follicles clogged
Primarily- areas with high number of oil glands Genetics
Role of diet and smoking is unclear
Hormones
Rosacea
Common skin disease Etiology unknown-
Triggers- heat, stress, sunlight, alcohol, caffeine, spicy foods
People over 30
Flare-ups
Redness on nose, cheeks, chin and forehead Dilated blood vessels
Papules, pustules and swelling May be burning and sorenes
Panniculitis
Group of diseases
Inflammation of the subcutaneous adipose tissue
Skin tender nodules
Erythema Induratum ( nodular vasculitis) TB, hepatitis C
Erythema nodosum- Associated with infections, IBD, oral contraceptives, pregnancy sarcoidosis
Skin Infection
Verrucae (Warts)
Molluscum Contagiosum
Impetigo
Superficial Fungal Infections
Why is in important for dentists to understand Hemostasis and Coagulation Disorders?
Gingival bleeding often the first sign of a bleeding disorder
Dental extractions often herald bleeding diatheses
HEMOSTASIS
Maintenance of clot-free, flowing blood within the vascular system, while also allowing the rapid formation of a solid clot to close ruptures/injury
FIBRINOLYSIS
The dissolution/breaking apart of fibrin clots; a normal component of hemostasis
THROMBOSIS
the formation of a clot within the uninterrupted vascular system; a pathologic extension of hemostasis
DIATHESIS
A condition which makes the body tissues react with heightened susceptibility; clot too easy
(e.g., bleeding diathesis)
COAGULOPATHY
Any disorder of blood coagulation (bleeding or thrombosis)
Development of a Hemostatic Plug
Blood Vessel Injury (usu. endothelial)
Immediate Vasoconstriction (neurogenic) Platelet
Adhesion to Collagen
Platelet Activation
Coagulation Cascade-Permanent Fibrin/Platelet Clot
(Induction of Fibrinolysis)
The Vascular Endothelium and the Balance of Clot Formation
The vascular endothelium, when uninjured, it has an anticoagulant function, or blood flow function and when injured, it has a pro-coagulant function.
Two components of the platelets that are very important in normal blood clotting
Dense Bodies and Alpha Granules
Platelet Activation
Adhesion & Shape Change: platelets adhere to
nonendothelial injury site
(e.g., collagen). Big players: vWF, GPIb
Platelets bind to vWF via GP1b on its surface basically forming the bridge that allow the platelet to adhere to the collagen.
Secretion: Alpha granules and dense bodies released.
Aggregation: platelets attach to each other via GPIIb/IIIa and fibrinogen which is one of the many coagulation proteins that normally circulates in your vascular system and is made in the liver. So fibrinogen is the bridge b/w platelets in the step of aggregation.
Where is vWF made?
In the endothelial cells
*only one of the coagulation proteins not made in the liver
Role of Calcium in normal homeostasis
Ca++ critical in all stages of platelet activation; the more Ca++ in platelets, the more activation there is
Relationship of vessel injury and activation
The more vessel injury there is, the more platelet activation there is
Extrinsic arm of Coagulation Cascade
Starts with Tissue Damage
When there’s tissue damage, there’s something called tissue factor released from the endothelium, and it initiates the coagulation cascade.
the coagulation cascade starts with INACTIVE Factor 7 which (with the tissue factor and the platelet activation) turns factor 7 to factor 7A. “A” means that its ACTIVATED
activated factor seven then jumps right into this final pathway of the coagulation cascade. This final pathway is called the common pathway.
The final common pathway always ends with factor 10 getting activated.
Then factor 5 gets activated through factor 2 (Prothrombin –> Thrombin (IIa))
And Thrombin (IIa) transforms Fibrinogen is into fibrin.
Intrinsic Pathway
Begins with more subtle microscopic injuries are called intrinsic injuries.
As a result of that, factor 12 is activated to factor 12A, factor 11 then factor nine, then finally factor 8.
Which factors are Vitamin K-dependent?
Factors II, VII, IX, and X
Gall bladder and bleeding disorders
if the gall bladder is not functioning properly, you can’t absorb a fat-soluble vitamin like vitamin K, you might have a bleeding disorder because 4 factors are going to be effected by deficiency of vitamin K
if you’re suspicious of a bleeding disorder, how do you confirm or rule out your suspicions?
run a coagulation profile
How Are Abnormalities of Hemostasis Diagnosed?
Incidental lab result in a pre-op or medical work-up
Patient presents with bleeding complaints
Patient gives a personal or family history of bleeding
The Coagulation Profile
Platelet count (CBC) Bleeding Time (BT) PT PTT Specific Factor Assays
Normal amount of platelets are
150,000-400,000
Abnormal Bleeding Time (BT)
Qualitative Platelet Defects and Vessel Wall/CT Disorders like Marfan’s syndrome
Decreased platelet count and Prolonged BT
Thrombocytopenia
Prolonged PT
Deficiencies of Extrinsic Pathway (i.e., VII)
Prolonged PTT
Deficiencies of Intrinsic Pathway
Prolonged PT and
PTT
Deficiencies of Common Pathway
Two Classifications of Coagulation Disorders
1) Bleeding Diathesis (aka abnormal bleeding)
2) Thrombotic Diathesis
Vascular Disorders
Relatively common
Mostly acquired and often treatable
Mostly small hemorrhages (petechiae, purpura)
Coag. Profile: Normal or +/- prolonged BT
structural abnormality of the blood vessels and connective tissue disroders like Marfans, or something like that.
Vascular Disorders: Acquired Causes
Infectious (esp. meningococcemia, rickettsiae, bacterial endotoxins)
Drug-Induced Vasculitides
Collagen-Vascular Diseases (e.g., SLE)
Age (poor connective tissue, malnutrition)
Vitamin C Deficiency (scurvy)-rare
Cushing’s Syndrome (wasting)
Vascular Disorders: Hereditary Causes
Ehlers-Danlos Syndrome (connective tissue disorder)
Henoch-Scholein Purpura (vasculitis)
Hereditary Hemorrhagic Telangiectasia
Platelet Disorders General Categories
– Thrombocytopenias (reduced platelet count)
– Thrombocytopathies (defective platelet function)
Thrombocytopenias
Vast majority acquired/iatrogenic
Signs/symptoms: (small vessel) bleeding from skin, mucous membranes of gingiva, GI, and GU tracts (hematuria)–petechiae, purpura
Bleeding from surgery or trauma when counts
20-50,000
Spontaneous bleeding only if <20,000
Increased risk of intracranial bleeds if <10,000
Coag. Profile: low plt count, prolonged BT
Thrombocytopenias: Causes
Infiltrative bone marrow diseases
(leukemias, metastatic cancers)
Defective platelet production (aplastic anemia, suppressive drugs/ chemotherapeutic agents, alcoholism, B12/ folate deficiency, HIV/AIDS)
Increased platelet destruction in blood (infectious agents, certain drugs, splenomegaly, anti-platelet Ab’s in ITP & AIDS, TTP, prosthetic heart valves, HTN, DIC, atherosclerosis)
“Dilutional thrombocytopenia” (from massive transfusions)
(Rare hereditary diseases)
Thrombocytopathies
Defective platelets
Vast majority acquired/iatrogenic
Similar presentations to patients with thrombocytopenias
Coag. Profile: Normal platelet count, prolonged BT
Thrombocytopathies: Acquired Causes
**Aspirin (ASA): 1000mg prolongs BT significantly and irreversibly for 10 days!
NSAID’s (ibuprofen, indomethacin, etc.): effects last only 1-2 days, except ibuprofen, which lasts 10 days as ASA does
Uremia (end stage renal disease)
Liver Disease
Alcoholism
Thrombocytopathies: Hereditary Causes
Bernard-Soulier Syndrome: Aut. rec.,
GPIb deficiency–adhesion dysfunction
Glanzmann’s Thrombasthenia: Aut. rec., GPIIb/ IIIa deficiency–aggregation dysfunction
Storage Pool Disorders: Usually aut. rec., alpha and dense granule deficiencies–secretion dysfunction
The Hemophilias (Factor Deficiencies)
Vast majority acquired
Presentation: Deep bleeding
(e.g., hemarthroses, GI/GU bleeding), ecchymoses (bruises)/hematomas following trauma, prolonged bleeding following a cut or surgery.
Petechiae/purpura UNCOMMON
Coag. Profile: (usu.) Normal plt count; prolonged PT &/or PTT
Acquired Hemophilias: Major Causes
Vitamin K Deficiency &/or Intestinal Malabsorption
Liver Disease
Renal Insufficiency/Failure
DIC
Acquired vWD
Acquired Anti-Factor Antibodies (Inhibitors)
Vitamin K Deficiency
Deficient factors II, VII, IX, and X
Prolonged PT (and PTT)
Common in malnourishment, alcoholism, gallbladder disease/biliary obstruction, intestinal disease (with malabsorption), neonatal period (esp. preemies and breast-fed neonates)
Treatment: Oral/IM/IV Vitamin K
PT/PTT correct (if liver healthy) within days with oral tx, 24hrs with IM tx, and 3hrs with IV tx
Liver Disease
All coag. factors (except vWF) synthesized in liver; therefore, all potentially affected in severe liver disease (e.g., cirrhosis)
85% of liver disease patients have at least one
hemostatic abnormality
15% have clinical bleeding
Vit K-dependent factors affected first
Coag. Profile: prolonged PT early in disease course; prolonged PTT only with severe disease; (+/- decreased platelet count &/or prolonged BT)
Treatment:
– Fresh Frozen Plasma (FFP)-has all factors except XII
– Treat underlying liver disease, transplant
Causes of Coagulopathies in Liver Disease
Decreased factor production in damaged liver cells (bleeding)
Production of abnormal (nonfunctional) factors
(bleeding)
Decreased platelet # or function (bleeding)
Impaired clearance of activated factors
(thrombosis)
Disseminated Intravascular Coagulation (DIC)
Complex, secondary complication to a variety of conditions
Patients usually hospitalized &/or severely debilitated (sepsis, malignancies, shock, severe burns, transfusion reactions, liver disease, **obstetrical complications)
Begins as excessive, multifocal thromboses; after a period, platelets and factors consumed, causing life- threatening hemorrhage &/or thromboses (strokes, MI’s, ARF)
Coag. Profile: Prolonged PT and PTT, decreased platelets and fibrinogen, increased fibrin split products
Treatment: Very difficult; double edged sword; treating underlying condition is best approach, but often impossible
Hereditary Hemophilias
Von Willebrand’s Disease (VWD)
Hemophilia A
Hemophilia B (Christmas Disease)
(All other factor deficiencies-exceedingly rare)
VWD
Very common (frequency 1%), but highly variable & often subclinical until a procedure is performed (often dental!)
Most cases autosomal dominant; variable family histories; men and women equally affected
3 types: I-III (mild-severe), III being rare and aut. recessive
Defective platelet adhesion and decreased Factor VIII level/activity
Variable Presentations: Asymptomatic to spontaneous bleeding from mucous membranes, menorrhagia, etc. Usually similar to platelet coagulopathy presentations
VWD Coagulation Profile
(variable) +/- prolonged BT; normal plt count; +/- prolonged PTT
* *Abnormal Ristocetin Test, decreased Factor VIII levels
Diagnosis: often difficult due to variability of disease; must have a high index of suspicion
Treatment: Cryoprecipitate (VWF + VIII) before surgical/dental procedures
Hemophilia A
the most common hereditary coagulation disorder causing serious (deep) bleeding
Factor VIII deficiency &/or dysfunction
X-linked recessive: Mothers are carriers, passing disease on to their sons (only rare female carriers with symptomatic disease)
Presentation: Deep bleeding, hemarthroses with crippling deformities; petechiae and ecchymoses characteristically absent
30% with no family history (brothers, maternal uncles, etc.); new mutations?
Coag Profile: Normal platelet count; Prolonged PTT; decreased Factor VIII assay
or activity
Treatment: Frequent cryoprecipitate or
**Factor VIII concentrate (recombinant lowest risk of disease transmission)
Complications: Crippling joint deformities, AIDS, hepatitis, hemochromatosis, life-threatening hemorrhages
Factor VIII Activity in Hemophilia A and severity
6-50% Factor VIII activity = mild disease
2-5% Factor VIII activity = moderate ds
< 2% Factor VIII activity = severe ds
Hemophilia B (Christmas Disease)
X-linked recessive (mother to sons)
Factor IX deficiency or dysfunction
Clinically indistinguishable from Hemophilia A
Presentation: Depends on Factor IX level/ activity; from asymptomatic to deep bleeding/hemarthroses
Coag. Profile: Normal plt count; prolonged PTT & reduced Factor IX assay/activity
Treatment: Factor IX concentrate
Thrombotic Disorders: Causes
Hematologic Abnormalities: Excessive platelet production (e.g., essential thrombocytosis), RBC production (p. vera, COPD), or WBC production (leukemias)
Malignancies (hypercoagulability, DIC)
Multiple Myeloma (increased protein in circulation)
Oral Contraceptives, Pregnancy
Smoking, Atherosclerosis
Prosthetic Heart Valves
Post-operative Periods (immobilization and increased platelets)
(Rare) Hereditary Deficiencies of Natural Coagulation Inhibitors
Anemia
Definition:
Reduction in red cell measurement on CBC:
Hb less normal range or decreased Hct (ratio of packed RBCs to total blood volume)
Low RBC count
Reduces oxygen carrying capacity
Leads to hypoxia/ischemia
Bleeding and Anemia
You can have anemia if you have a profuse bleeding. But anemia doesn’t cause bleeding
HEMATOCRIT(HCT) or PCV ( packed cell volume) or erythrocyte volume fraction (EVF)
the volume percentage of red blood cells in the blood. It can indicate if there is a problem, but cannot determine the underlying condition
Who has more RBCs? Males or Females?
Males they have more, females have less.
Mechanistic Classification of Anemia
Blood Loss
Decreased Production
Hemolytic (increased destruction)
Common Clinical Features of Anemia
Weakness Fatigue Dyspnea on mild exertion Light-headedness, headache Pallor and/or jaundice Rapid pulse Skin atrophy; brittle, concave finger nails (koilonychia)
Iron Deficiency Anemia cells look like
Microcytic and hypochromic cells
Iron and Hepicidin
Absorption closely modulated by hepcidin
Hepcidin inhibits iron absorption in enterocyte and iron release by macrophages
In iron deficient states, hepcidin levels are low and iron absorption is increased
Absorbed proximal duodenum
Absorption regulated by hepcidin made in liver and released in response to intrahepatic iron levels
When body has enough iron, hepcidin inhibits absorption into blood by keeping it in mucosal cells (as mucosal ferritin)
When hepcidin low, more iron absorbed
PICA is a symptom of
Iron deficiency microcytic anemia
Iron Deficiency Anemia
Oral manifestations: “Burning” tongue Patchy or diffuse erythema Atrophy of filiform papillae Taste alteration Fissuring Angular Cheilitis
PLUMMER VINSON SYNDROME
Iron deficiency anemia caused by malnutrition, malabsoption
Northern European women 30-50 yrs
Esophageal web-
Anemia, glossitis and dysphagia
risk of squamous cell carcinoma (esophagus, oral, pharyngeal)
Decreased RBC production
Lack of nutrients: B12 and folate
Bone marrow issues: aplastic anemia, red cell aplasia, acute leukemia, metastatic tumors
Erythropoietin deficiency: renal failure
Chronic disease /inflammation /malignancy: decreased GI absorption of iron, reduced release from macrophages, relative low erythropoietin
Increased RBC destruction
Inherited:
Sickle cell disease
Thalassemia (specifically the major one because the other ones are not going to have the same manifestations)
Hereditary Spherocytosis (which is a very rare inherited disease).
Acquired: there are different things that can cause increased destruction:
Malaria
Parvo 19 infection
HUS (hemolytic uremic syndrome - something related to kidney function)
TTP thrombotic thrombocytopenic purpura
DIC disseminated intravascular coagulation (this can happen with different conditions. This will not only cause problems with RBCs but the major issue is with the platelets. The crazy coagulation that can happen and it can effect the number of RBCs.)
Drug Induced (you will see in Pharmacology different medications that can have this effect too.) And
Autoimmune hemolytic anemia. Like that is related to how the immune system works.
RBC Hemolysis
Shortened erythrocyte life span < 100 days (normal lifespan is 120)
Accumulate products of hemoglobin catabolism (iron)
Marked increase in erythropoiesis
Problems within erythrocyte (intracorpuscular /intrinsic)
Problems outside erythrocyte (extra corpuscular /extrinsic)
Hemolytic anemia cellular appearance
This occurs in hemolytic anemia.
You see irregularities
Target cell – has something in the center
People can call it in diff ways – some look like helmets = they call is schistocytes, fragmented red cells
They call it in completely different names
In reality, cells in different shape.
Major consequences of anemia
Clinical presentation depends on
severity
speed of onset
underlying pathogenic mechanism
Compensatory mechanisms
increase in plasma volume
increase in cardiac output
increase in respiratory rate
Hyperbilirubinemia, jaundice, and pigmented gallstones
Inappropriately high levels of iron absorption from gut (iron overload)
Childhood-Growth retardation, skeletal abnormalities
Severe long-standing anemia
Fatty change
Reversible accumulation of fatty vacuoles in cytoplasm in response to hypoxia (and to some other insults)
Main organs affected
Liver, myocardium, kidneys
Pernicious anemia
problems with vitamin B12 deficiency
Macrocytic megaloblastic anemia
Bigger cells – takes more volume in blood
Lack intrinsic factor
Autoimmune destruction of parietal cells in fundus Atrophic gastritis
Defective DNA synthesis
Common signs of anemia and neuro changes Symmetric paresthesia, Jaundice from hemolysis of RBCs, removal of abnormal RBC
Demyelination of dorsal + lateral tracts in spinal cord
Gives rise to sensory ataxia. Neuropsychiatric symptoms such as psychosis and dementia
Macrocytic Anemia (2 types)
Megalobastic = B12 and folate deficiency
Non-megalobastic = alcohol reticulocytosis, liver disease, hypothyroidism
Cobalamin /vitamin B12 deficiency
Necessary for DNA synthesis
In acidic stomach, B12 binds to intrinsic factor(IF) stomach
Vit B12 + IF / small bowel ,intestinal absorption in terminal ileum- transcobalamin
Deficiency: decreased absorption or
decreased intake for vegans
B12 deficiency Malabsorption causes
Malabsorption may be limited:
Lack intrinsic factor so cannot absorb B12 from gut (pernicious anemia)
Gastric bypass
Malabsorption process in IBD affecting terminal ileum (Crohn) or resulting from pancreatic insufficiency (pancreatic proteases usually help release bound B12) or from bacterial overgrowth (utilizes B12)
Only anemia associated with symmetrical paresthesia?
Pernicious Anemia
Pernicious anemia Oral Manifestations
Burning sensation of tongue, lips, taste disturbances Patchy or diffuse erythema, or pallor Surface atrophy, lobulation Jaundice Skin may be yellow-gray
Folate deficiency
Important in DNA synthesis
Megaloblastic anemia
Correct macrocytosis with folate supplementation
No neurological changes**
Thalassemia
Inherited
Microcytic anemia
Abnormal production and increased RBC destruction
Classification of Thalassemias
Alpha-thalassemias
Hydrops fetalis (fatal before birth) - -/- -
Hemoglobin H disease (moderately severe anemia): - -/-alpha
Alpha thalassemia trait (similar to beta- thalassemia trait) - -/aa or -a/-a
Silent carrier -a/aa
Alpha thalassemia
More in people with certain characteristics, living in certain parts of the world – Africa, Mediterranean, middle east and Asia – can be carriers for that or have more common disease
Single mutation – carrier state
This is the most common but asymptomatic
Its only decreased on the alpha chain
Remember, you have two alpha and two beta.
Beta thalassemia
Its also a characteristic Mediterranean/middle eastern but not common in Africa
Abnormalities are going to have different manifestation: Abnormal Hb: decreased function, altered erythrocyte plasticity, Increased erythrocyte destruction (hemolysis), Extramedullary hematopoiesis
In the body, will have different manifestation
Cooley’s anemia = is the one that has major severities related with that; near absent beta chain synthesis in homozygotes or compound heterozygotes
Thalassemia presentation bone**
Frontal bossing,
“hair-on-end”
Crew cut appearance of calvaria
Enlarged jaws
‘Honeycomb’ bone pattern
The marrow is more active, it’s going to expand & its going to reduce the cortex.
Cell presentation of Thalassemia major
Microcytic and hypochromic
. Some of them have like a ‘tear drop’ shape but one of, they say, the characteristic is to have these “target cells”
Sickle cell crisis
Precipitated by hypoxia, infection, hypothermia, dehydration other
3-10 days
Manifestations
Capillary blockage: – ischemia, infarction. and severe pain
Hemolysis: anemia, jaundice
+/- fever
Consequences of crisis
Major effects on bones, lungs, liver, brain, spleen (due to vascular occlusion)
Bone pain common in children
Stroke
Sequestration crisis – rapid accumulation of RBC in spleen
Acute chest syndrome
Fever, cough, chest pain, infiltrates and inflammation
Kids feel like they’re having a heart attack
Hemolytic
Sickle Cell Anemia Head and Neck Manifestations
Reduced trabeculation “Hair-on-end” appearance of calvaria Delayed dental eruption Dental hypoplasia Ischemic Neuropathy
Autoimmune hemolytic anemia AHA
Result from drugs
lymphoproliferative disorders collagen vascular diseases malignancy
idiopathic
Microangiopathic hemolytic anemia
RBCs fragment
Occurs with HUS and TTP
Eclampsia and pre-eclampsia with elevated liver enzymes and low platelets in HELLP
HELLP: hemolysis, elevated LFTs and low platelets
Seen with DIC, snake envenomation
Exposure to ticlodipine and cyclosporine
Mechanical heart valves
G6PD deficiency
Carried on X chromosome
Chronic or intermittent
Function normally except under oxidative stress with certain meds or acute infection
Present with anemia and jaundice
Meds: quinine, sulfonamides, dapsone, primaquine, fava beans
Bite cells on smear
Confirm diagnosis by checking G6PD levels 2-3 months auer hemolytic event
Normal reticulocytes have this immediately following hemolysis
G6PD deficiency cellular appearance
Looks like someone took a bite out of the RBC (“bite cells”)
Aplastic Anemia
Decreased Production: (Pluripotent) Stem Cell Defect
DECREASE ALL BLOOD CELLS
- precursor cell failure
Reticulocytes / hypo cellular marrow
Features: anemia, bleeding disorders, susceptibility to infections
<500 granulocytes/L (Normal = 3-8,000)
<20,000 platelets/L (Normal = 150-450,000)
<10,000 reticulocytes/L (Normal = 50,000)
Microscopically, they’re not going to have cells,but you are going to see large spaces with fatty tissue.
Possible Etiology of Aplastic Anemia
Idiopathic
Radiation
Drugs: chloramphenicol, sulfonamides, alcohol, chemotherapy
Infections: CMV/EBV, Parvovirus, hepatitis, HIV
Bone marrow transplant in young, immunosuppress in older
Aplastic Anemia Oral Manifestations
pallor
gingival bleeding, mucosal petechiae, purpura, ecchymoses
gingival enlargement
mucosal ulcers
only anemia that the presentation is going to be with gingival bleeding
APLASTIC ANEMIA
Anemia of chronic disease AOCD
Normochromic, normocytic anemia
Defective mobilization of iron to erythrocytes
Low erythropoietin – common in renal disease
Low serum iron, transferrin saturation
Bone marrow not depleted
Treat: iron and erythropoietin
Polycythemia
Erythrocytosis (INCREASE IN RBCS)
Primary: Clonal, autonomous proliferation of myeloid stem cells (polycythemia vera); often thrombocystosis, leukocytosis
Secondary: increased erythropoietin levels
Compensatory response to host/environment changes: lung disease, high-altitude living, cyanotic heart disease
Response to erythropoietin-secreting tumors (RCC renal cell carcinoma, hepatoma)
Use of erythropoietin
Myelodyplastic syndrome MDS
Elderly with anemia +/or thrombocytopenia +/ or leukopenia w hyposegmented PMN
Macrocytic anemia with normal B12 and folate
Bone marrow: increased blasts, dysplastic precursors
Primary or secondary due to chemo
Common cause of death is due to low WBCs: infection
Normal WBC count
varies from 4400 to 11,000 cells/microL (4.4 to 11.0 x 109/L)
(60% are mature neutrophils)
Neutropenia
absolute neutrophil count (ANC) <1500
implication of neutropenia varies between, mild say if you have WBC between 1000 and 1500 or very severe actually people that have neutrophil count less than 200, they can just die because of an infection.
Non Malignant Causes affecting WBC and SCs
Infections: HIV, CMV, EBV etc
Medications: Harm WBC or cause BM suppression
Alcohol, B12 or folate deficiencies
Aplastic Anemia (Hypocellular marrow)
Lymphadenitis: Inflammation in LNs and can be associated with lympadenopathy
most common reason actually for Neutropenia
psychiatric medication. They all cause bone marrow suppression
Myeloid and Myeloproliferative Disorders
Acute Myeloid Leukemia (AML)
Myeloproliferative Neoplasms (MPN)
-Chronic Myeloid Leukemia (CML)
-Polcythemia Vera (PCV)
-Essential Thrmobocytosis (ET)
-Primary Myelofibrois (PMF)Acute Myeloid Leukemia (AML)
the most common acute leukemia in adults and accounts for approximately 80% of cases in this group
Because the more we live, the more we acquired in our life, some genetic abnormalities. And that’s what leads for the body to misbehave and you can get AML.
So the median age of diagnosis is 65. However, unfortunately recently we’re seeing younger and younger patients.
The incident increases with age, as I mentioned.
Even with the best treatment availability, there’s still a higher risk of relapse, and mortality.
And the five-year survival is not great at all only 24%, and because most of the patients relapse
there’s a mis-behave in the genetic in our body that pathways almost turned on. So basically, yourself are always trying to produce more and more WBC, because you cannot cope, the bone marrow cannot cope to produce all cells including
Etiology and Risk Factors
Chemical exposure Benzene, Pesticides Other environmental exposures Hair dyes, smoking, non-ionic radiation Genetic disorders Down syndrome, Bloom Syndrome, Fanconi’s anemia, Ataxia-Telangectasia, Wiskott-Aldrich Prior chemotherapy or XRT Alkylating agents, Topoisomerase II inhibitors
Antineoplastic Agents
Alkylating agents -Preceding MDS phase -Evolution to AML 5-7 yrs -Abnormalities: -5 or -7 Topoisomerase II inhibitors -No MDS phase -Monocytic morphology -11q23
How we diagnose AML?
We do bone marrow biopsy and find they have 20% leukemic cells. Defined as myoblast.
that they are precursors are early cells, like stem cells, they all expressing CD34 positive and HLA-DR. So when they express these two markers, they are very early cells, like stem cells and leukemic cells.
Acute Promyelocyte Leukemia (APL)
subset of AML cure rate is 98% 10-15% of AML (FAB M3) Higher incidence in Hispanics (20-25%) and with increase BMI Median Age at Dx is 40yrs Coagulopathy and hemorrhage CD 34 and HLA-DR negative t(15,17) associated with PML/RAR-α fusion
AML/APL difference
AML, you are stuck in myeloblast, in APL you are stuck the step afterword, which is promyelocyte,
So what happened is that you just matured cells by giving them a medication, a pill. And then the cells start maturing. And you do very well, 98% cure rate
Chronic Myeloid Leukemia (CML)
Associated with the fusion of 2 genes: BCR (on chromosome 22) and ABL1 (on chromosome 9) resulting in the BCR-ABL1 fusion gene (PHILADELPHIA CHROMOSOME)
15 to 20% of leukemias in adults
The only risk factor that we know of CMS is radiation, people that get exposed to radiation, working in radiation, or even people that get been exposed to high radiation scans or something like that frequently not just once.
Three stages of CML
1) a chronic phase, 85% of patients at diagnosis
2) an accelerated phase, in which neutrophil differentiation becomes progressively impaired and leukocyte counts are more difficult to control with treatment
3) blast crisis, a condition resembling acute leukemia
Myeloproliferative diseases (MPNs)
collectively characterized by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency. They are characterized of splenomegaly and JAK2 mutations
2-Polycthehemia Vera (PCV)
PCV is distinguished clinically from the other MPNs by the presence of an elevated red blood cell mass
However, an increased red blood cell mass alone is insufficient to establish the diagnosis, since this is also observed in conditions associated with chronic hypoxia and with erythropoietin-secreting tumors
3-Essential Thrmobosis (ET)
ET has also been called also primary thrombocytosis. It is characterized by excessive, clonal platelet production with a tendency for thrombosis and hemorrhage.
4-Primary Myelofibrosis (PMF)
PMF is the least frequent among the chronic myeloproliferative diseases
Burned out marrow
JAK-STAT signaling
JAK mutation will lead to:
1, proliferation, so you have more production of cells to certain pathways ;
2, angiogenesis you have more vessels to supply the organs so they can grow and produce more,
3 you have more immunosuppression. the body can be prone to infection, can actually allow cells to grow more and more.
Lymphoid and Natural Killers Disorders
Acute Lymphoblastic Leukemia (ALL) Chronic Lymphocytic Leukemia (CLL) Non Hodgkin’s Lymphomas (NHL) Hodgkin’s Lymphomas (HL) NK/T cell lymphomas
ALL
more frequently presents in its leukemic form than its lymphomatous form
B-ALL accounts for approximately 2% of the lymphoid neoplasms diagnosed in the US
Previous chemotherapy and exposure to radiation increase the risk of developing ALL
Signs and symptoms include fever, feeling tired, and easy bruising or bleeding
Txt: complex 3 year chemotherapy treatment
Incidence of different cancers
The most common one, on the rise. We’ll talk about it in a bit is CLL. This is hundreds per thousand patient.
The next is, AML, and then come CML and ALL.
If you notice that CLL is significantly under rise. AML actually on the rise and the CML as well, but look at ALL. If anything, you are higher risk for have a younger age and then it goes down and the plateaus doesn’t really increase the risk
Better ALL survival rate in children or elders?
The younger you are, the better you do so. If you are someone that have an ALL at 15 and 19, that cure rate is 70% now was newer drugs, probably it is around 80%. But if you are 66 year old and you get to leukemic the survival is 30%, because the drugs the chemotherapy that you really need for cure, the body cannot tolerate them. They are meant for young, and healthy pediatric people. So the older the patient gets, it’s very hard to cure.
What are the factors that we care about most in ALL?
The most important thing we look at is cytogenetics. Philadelphia chromosome: it’s seen in CML and if it’s seen in ALL, it results in a worse outcome. If someone has Philadelphia chromosome, then you’re going to treat them with chemotherapy and again you’re going to give them the pill that you gave patients with CML. The outcome is worse in this case
Age: the younger the better. We always try to give them a pediatric inspired regimen because they do much better.
If they have Philadelphia chromosome mutation or they are old, you’re always going to try to replace their stem cells and that’s what we call high risk. If they are a candidate for stem cell replacement, this is the only cure in the elderly or as they relapse we may not be able to cure them.
CLL
A subtype of leukemia arising from immunologically less mature lymphocytes that spread to the blood, bone marrow and lymphatic tissues
The longer people live, the greater the risk of CLL
Staging is different. It’s usually based on if you have WBC, if you have the spleen involved, if you have the liver involved, if you have the bone marrow involved or not.
The most important key in CLL and that’s why it’s on the rise is the microenvironment.
Risk Factors:
Family history Age and Gender
Race/Ethnicity: more common in people of Russian and European descent, and hardly ever develops in people from China, Japan, or Southeast Asian countries. It also occurs commonly in black people.
Agent Orange
Prognosis: Majority indolent disease associated with a prolonged (10 to 20 years) clinical course (about 40-50%)
Lymphomas
Non Hodgkin’s Lymphoma (NHL)
Hogkin’s Lymphoma (HL)
NK/ T cells Disorders
They start taking over the lymph node. The lymph node (or any of these organs) can no longer fit them as they start growing. This is what happens in lymphoma. It presents with large lymph nodes, large spleen, large thymus gland and you have symptoms because of this. Most of the time the symptom is PAIN.
Or you can end up (because there’s so many lymph nodes), you can end up with B symptoms which is fevers, night sweats, and weight loss.
The most common lymphoma
DL-BCL (diffuse large B cell lymphoma) – it accounts for 70% of lymphomas. Usually the problem happens in the center of the lymph nodes
If the problem happens outside the lymph nodes, it may happen in plasma cells. Plasma cells are part of lymphocytes and then you end up having a different disease called multiple Myelenoma.
Non-Hodgkin lymphoma usually the problem happens inside the germinal center inside the lymph node. The Hodgkin lymphoma is usually outside the germinal center and that’s because the cells mature a little bit more and that’s why you end up with Hodgkin lymphoma.
Types of lymphomas
Small cells or large cells
This is most of the time when they are small they are INDOLENT lymphoma – slow growing. When they become large cells, the lymph nodes are larger. The lymphocytes are large as a result. They become more aggressive.
This is an example of Non-Hodgkin lymphomas.
Some people when they take a look at this slide (C) highly aggressive type of lymphoma called Burkit Lymphoma that‘s associated with EBV virus and HIV.
Multiple types of lymphomas that range from indolent to aggressive form.
Hodgkin’s Lymphoma
Note there’s only really four types of Hodgkin lymphoma and most of the time you can cure it.
Only accounts for 10% of lymphomas.
About 80% cure rate
Cell presentation: OWL.
Looks like an owl, it’s called Reed Sternberg cells.
Very characteristic presentation.
Two cells that are close to each other, usually they have a large cytoplasm and nucleus. That’s what you see in Hodgkin lymphoma.
Multiple Myeloma (MM)
This is when you end up having a disease called multiple myeloma (MM)
It’s the second most hematologic malignancy. The most common hematologic malignancy = Non-Hodgkin’s lymphoma.
The most common Hodgkin lymphoma 70% of cases diffused largely B cell lymphoma.
It accounts for about 20% of deaths from hematological malignancies and 2% of deaths from cancers.
In 2012, there was about 90.000 patients living with myeloma and every year we’re estimating about 50,000 US people will end up with MM.
Approximately, the risk of having multiple myeloma is 0.7% in men and women. If you have about 150 people, 1 of them will have MM.
Medium age – it’s a disease of the elderly, age 65. The 5 year survival as of 2018 is only 50%. Unfortunately, we lose 50% of the patients so we’re still not doing that good. Dong better than AML, but
How do people present with MM?
What they present with is the CRAB. This stands for Hypercalcemia, Rena, Anemia, and Bone lesions. They have HIGH calcium (note).
Treatment Paradigm in MM
Induction
HDT/ASCT
Consolidation
Maintenance
key of multiple myeloma
key of multiple myeloma is lytic bone lesions
Immunotherapy
Using your own WBC from your immunity to kill your defected WBCs
Infectious Prevention
Need to treat underlying etiology and use prophylactic antibodies, anti fungal and anti viral
Immunotherapy Started in ALL
Monoclonals + cytotoxic agents– inotuzumab
Biallelic monoclonal (CD3 + CD19)– blinatumomab
Modified expanded Tcells– CART cells
Pulmonary Infections Host defenses
Nasal clearance: sneeze, blow or swallow
Tracheobronchial clearance: 3 to 10 mm
mucociliary action, IgA
Alveolar clearance: 1 to 5 mm
macrophages, IgM, IgG, C3b, T cells
Inhalation of infectious agent Pathways
Virus –> Infection of type I pnuemocytes –> alveolar injury –> interstitial pneumonia
Pyogenic bacterium –> acute inflammatory response to bacterium –> intra-alveolar pneumonia
Bacterial pneumonias (types)
Community acquired
Nosocomial
Opportunistic
Most bacteria causing pneumonia are oro- and nasopharyngeal flora
Bacterial pneumonias
Etiologies
Staphlococci (gram +): what you find on your skin
Strep (gram +): is so commonly associated with pneumonia that theres a pneumococcal streptococci (pneumo meaning air/lungs)
Haemophilus (gram -) : children
Psudomonas (gram -): cystic fibrosis
Klebsiella (gram -): alcoholics
Legionella: transplant patients
Pneumococcal Pneumonia
Streptococcus pneumoniae (pneumococcus) Gram + facultative anaerobic cocci in pairs
Found in Nasopharyngeal flora in up to 20%
Capsular polysaccharides–antigenically specific–84 types
Types 1,2,3,4 = pathogenic
Extracellular pathogen
Capsule: antiphagocytic property
Pneumolysin (is a chemical that allows it to break open pneumocytes)
Neuroaminidase
Most common cause of community-acquired pneumonia
Frequently follows a viral URI
Bronchial secretions provide environment
Vaccines for young/old offer up to 90% protection
Bacterial pneumonias Clinical Presentation
Symptoms: Fever, malaise, productive cough and +/- chest pain
Signs: Tachypnea, decreased breath sounds, dullness to percussion
Radiology: Infiltrate(s)
Treatment: Afebrile within 48 to 72 hours after antibiotics
< 10% of pneumonia admissions die!!
4 Stages of Bacterial Pneumonia
- Congestion: bacteria with edema and vascular engorgement
- Red hepatization: red cells, neutrophils and fibrin
- White hepatization: fibrin, fibroblasts with few neutrophils
- Resolution: return to normal
Bacterial pneumonias Complications
Abscess (lung tissue can die. It can be necrotic)
Empyema (pus in the pleura)
Organization (consolidation of lung/ it is permanently in that white hepatization with scarring and fibrosis)
Bacteremic dissemination…meningitis, endocarditis Bronchiectasis (end up with a chronic lung infection that scars the lung and dilates the airways )
Pulmonary abscess
Abscess formation: local necrosis of the lung
Following pneumonia
S. aureus, K. pneumoniae, pneumococcus type 3
fungi
Aspiration of infective material
Mixed organisms including oral anaerobic flora
Bacteroides, Fusobacterium, Peptococcus
Septic emboli
deep leg veins or right heart valves Neoplasia–10 to 15% of cases
post-obstructive pneumo
Bronchiectasis
Chronic necrotizing infection with dilation of airways
Bronchial obstruction
Tumor, foreign body, mucus impaction (COPD)
Congenital or hereditary conditions
Cystic fibrosis, Kartagener’s syndrome
Necrotizing pneumonia
M. Tuberculosis and Staphlococcus infections
pneumonia viruses
Lower respiratory tract only Adenovirus influenza A and B Respiratory syncytial virus Corona Parainfluennza
Systemic with pulmonary involvement Measles Herpes 1 and 2 Varicella-zoster Cytomegalovirus Ebola
Fungal respiratory infections
Candidiasis–normal oral flora
Candida albicans
usually aspiration or hematogenous spread
Histoplasmosis–Ohio and Mississippi rivers
Histoplasma capsulatum
Self-limited, chronic and disseminated forms
Coccidiomycosis–Southwest and Far West
Coccidioides immitis
All inhalers become infected
10% have fever, cough and chest pain + skin lesions
San Joaquin Valley fever complex
Pneumocystis jiroveci (carinii) A true fungus; ubiquitous Does not cause disease in immunocompetent folks Inhaled fungi attach to type I pneumocytes HIV+ with <200 T cells at risk!
Pulmonary Tuberculosis General Features
Mycobacteria grow slowly and drug sensitivities can take 6 weeks
Mycobacteria are aerobic non-spore forming nonmotile bacilli with a waxy coat
M. tuberculosis and M. bovis cause tuberculosis
M. avium and M. intracellulare afflict immunocompromised folks
M. leprae causes leprosy
M. tuberculosis infects 33% of the world’s population
M. tuberculosis kills 3 million patients yearly
Single most important infectious cause of death
Pulmonary Tuberculosis Pathogenesis
Pathogenicity: ability to escape initial macrophage and T cell attacks
Cord factor: grow in cords
Lipoarabinomannan (LAM): g- endotoxin-like substance Inhibits macrophage activation by INF-gamma Induces macrophage TNF-alpha secretion
fever, weight loss, tissue damage Induces macrophage IL-10 secretion
suppresses T-cell proliferation
CR3 uptake receptor
faciliates macrophage uptake without respiratory burst
Heat-shock protein
All leading to granulomatous inflammation and destruction by self! (granuloma formation)
Pulmonary tuberculosis Possible Outcomes
Healed lesions: scars without organisms
Latent lesions: dormant organisms
Progressive primary Tb: massive lung spread
Miliary Tb: massive hematogenous spread
Ghon complex
lesion seen in the lung in primary tuberculosis. The lesions consist of a calcified focus of infection and an associated lymph node.
primary tuberculosis
parenchymal subpleural lesion around upper/lower lobe fissure
enlarged caseous lymph nodes draining lung lesion
Latent lesions of TB
dormant organisms disseminate host weakens…cancer, infection reactivation of infection
Reactivation in 5 to 10% of cases
Lung apices where there is high O2 tension
Possible outcomes
scar with or without therapy
localized cavitation…bronchial…laryngeal…intestinal spread bronchopneumonia “galloping consumption”
lymphangitic spread to other areas of lung or other organs
vascular spread
the 2nd leading cause of death in the United States
Lung cancer
behind heart disease (#1) and 3rd is lower respiratory disease (also smoking related).
Leading cancer causing death
Lung cancer
Lung Cancer Causes
tobacco – 90% of lung cancers
Environment
Infections – NO!!!!!!!!!!!!!!
Diet – (if you eat well it probably indicates a confounding variable that you’re of a higher SES so you’re less likely to smoke)
Genes - play a HUGE role but it’s often hard to tease out as we’ll see because smokers usually grow up in households where the parents smoked
Lung cancer & Tobacco smoke
Tobacco smoke causes 90% of lung cancer
1.9% of men, 13.0% of women non-smokers!!
Duration and intensity of smoking correlate with incidence and mortality
Low tar-low nicotine cigarettes–cotinine levels!!
Involuntary or passive smoking is a proven cause of lung cancer
smoking causes these cancers
Oropharynx Larynx Esophagus Trachea Bronchus Lung Leukemia Stomach pancreas Kidney Ureter Cervix Bladder
What happens when you quit smoking?
20 minutes later your BP will drop, your CO levels will return to normal, things will taste better, your lung function will improve, your risk of heart disease will drop in a very short time, your risk of stroke will drop in a short time. Your risk of dying from lung cancer over about 20 years it will take to come back to the risk of almost a non smoker – it never comes down but close
What’s the risk of smoking and asbestos?
Synergistic-multiplicative effect with tobacco smoke
Non-tobacco procarcinogens
Asbestos
Indestructible and fire resistant fibers Amosite, tremolite, chrysotile, crocidolite Incite inflammation, fibrosis, malignancies
Nickel compounds Copper compounds Arsenic compounds Chromate compounds Mustard gas Benzene
Radiation and Lung Cancer
Radioactivity in cigarette smoke
Alpha emitters polonium-210 and lead-210
Particles accumulate at bifurcations of segmental bronchi
1.5 packs per day = 300 CXR per year to the skin
Radon…gaseous product of radium-226 decay
Half life 3.8 days; decays into 2 alpha emitting daughters Particles deposit on dust inhaled into the bronchial tree Beware of well insulated airtight homes in the Reading Prong Synergism between decay products and tobacco smoke 2nd cause of lung cancer in US according to EPA
20,000 deaths per year
Uranium
Navajo uranium miners
Lung cancer
Genetic/Molecular observations
EGFR mutations most commonly found in women (non-smokers with lung cancer)
Lung cancer Clinical features
Peak age 60-70 years, range 11-whenever
Slight male predominance
Symptoms:
asymptomatic
cough or change in existing cough
weight loss
chest pain
dyspnea
wheezing/stridor/hoarseness
sputum production/hemoptysis
SVC syndrome
Pancoast syndrome
Paraneoplastic syndromes
metastatic disease
Paraneoplastic syndromes
Symptom complexes not explained by tumor or hormones produced by organ involved by tumor.
Occurs in 1-10% of lung cancer patients
Hypercalcemia Hypocalcemia Gynecomastia Carcinoid syndrome Cushing syndrome Eaton-Lambert myasthenic syndrome Syndrome of Inappropriate ADH secretion (SIADH)
Lung cancer
Diagnostic procedures
Cytology
sputum
bronchial wash/brush
fine needle aspiration
Transbronchial biopsy
Mediastinoscopy or scalene lymph node biopsy
Surgical resection
wedge biopsy
lobectomy
pneumonectomy
Lung Cancer Classification
Small cell carcinoma (SCLC) 25%
Non-small cell carcinoma (NSCLC) [including rare salivary gland-types]
75%
Small cell carcinoma
HORROR OF HORRORS Smoking-related Widespread at the time of diagnosis Paraneoplastic syndromes Initially responsive to chemotherapy Anatomic extent of limited disease can be included within an irradiation field (limited to area 30%) There are almost NO survivors
Present with systemic complaints…H/A, fatigue…
Up to 85% have extrathoracic disease at diagnosis Present with paraneoplastic syndromes
SIADH or Cushing syndrome
5 year survival = 4%
Gross features
often virtually undetectable bronchial wall lesions Microscopic features
small cells with little cytoplasm dark nuclei without nucleoli mitotically active
Lung Squamous cell carcinoma
Non-small cell carcinoma been the most common type for years
Most common type found in men
Correlates with smoking
Usually central/hilar location = 15% 5 year survival
Microscopic features
squamous metaplasia keratinization intercellular bridges leading to dysplasia and then carcinoma
Lung Adenocarcinoma
Non-small cell carcinoma arising from a glandular cell & NOT from a squamous cell.**
And, it is most common type in women & non-smokers.
Usually peripheral location 5-25% 5 year survival associated with scars
Gross features
can be very very small, but still very very bad!
Microscopic features acinar papillary micropapillary solid lepidic
TNM staging T
T1: <= 3 cm
not within the main bronchus
T2: > 3 cm but <= 5 cm
Involves the main bronchus but not carina Invades visceral pleura
Any tumor causing atelectasis or pneumonia to hilum
T3: > 5 cm but <= 7 cm
Any tumor extending into chest wall, diaphragm, pericardium Any tumor in the main bronchus within 2.0 cm of the carina Separate cancer in the same lobe!
T4: > 7 cm
Any tumor invading mediastinum, heart, esophagus… Any tumor involving the carina
Separate cancer in same side lung but different lobe
TNM staging N
N0: No nodes
N1: Peribronchial or ipsilateral hilar nodes
N2: Ipsilateral mediastinal nodes or subcarinal nodes
N3: Contralateral hilar or mediastinal nodes; any neck nodes
TMN staging M
M0: No known metastases
M1: Separate carcinoma in other lung
Pleural nodules
Malignant pleural effusion
Distant metastasis
Regional lymph nodes (>50%)*** Adrenal gland (>50%) Liver (30-50%) Brain (20%) Bone (20%
Most common malignant neoplasms of the lung
carcinomas, sarcomas metastasis
NOT LUNG CANCER
