Clinical Pathophysiology Review 3 8:30 AM, March 4, 2003

1
Clinical PathophysiologyReview 3830 AM, March
4, 2003

• Fred A. Zar, MD, FACP
• Director, M2 Clinicopathophysiology Course
• Professor of Clinical Medicine
• University of Illinois at Chicago

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Respiratory Pathophysiology
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COPD Pathophysiology and Consequences

• Airway inflammation
• Increased mucus and protease activity
• Cough and sputum
• Increased Airway Resistance
• Wheeze and rhonchi
• Pursed lip breathing
• Increased Work of Breathing
• Decreased exercise yet increased metabolism
• Breathing may require 2535 of energy (nml 35)
• Weight loss
• Hyperinflation
• Inspiratory muscle dysfunction
• Hoovers sign, increased AP diameter
• Impaired Regional Ventilation
• V/Q mismatch gt hypoxemia gt pulmonary HTN

4
Smoking and COPD

• Smoking leads to activation of macrophages and
  neutrophils
• Pulmonary inflammation
• gt chronic bronchitis
• Proteases released elastase, cathepsins,
  metalloproteinases
• gt inhibited by antiproteases
• alpha1 antitrypsin, elafin, secretory
  leukoprotease inhibitor
• gt injury to extracellular matrix gt emphysema

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Emphysema

• Definition
• Airspace enlargement distal to terminal
  bronchiole
• Due to destruction of alveolar wall
• Locations
• Centrilobular
• Panacinar

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Chronic Bronchitis

• Definition
• Cough and sputum
• Most days for 3 months
• 2 consecutive yrs
• Pathologic Correlate
• Mucus gland hypertrophy
• Goblet cell hyperplasia

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COPD Therapy

• Drug Mechanism Clinical Effect
• ß2 agonists Smooth muscle relaxation Bronchodilat
  ion
• Decreases mast cell degran
• Anticholinergics Muscarinic antagonists Bronchodil
  ation
• Corticosteroids Inhibit cytokine production Do
  not alter course
• Decreases eosinophils Decreases reactivity
• Increases ß responsiveness Decreases
  inflammation
• Theophylline Phosphodiesterase
  inhib. Bronchodilation
• Adenosine receptor inhib. Better resp. muscle
  function
• Skeletal muscle contraction

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Asthma

• Chronic inflammatory disorder with reversible
  airways obstruction
• Cell mediated
• Mast cells, eosinophils, T lymphs, macros, PMNs,
  epithelial
• Increased bronchial responsiveness to a variety
  of stimuli
• Allergens, exercise, cold, pollution, infection,
  drugs, GERD
• Symptoms and signs
• Wheeze, SOB, coughing, chest tightness
• Can be induced with histamine or methacholine
  challenge
• Pulsus paridoxicus drop of SBP with inspiration
  of gt 10 mm Hg
• Dual response
• Early(5 min) due to mast cell release of
  histamine, LT, PG, PAF
• Late (4 hr) due to eosinophil release of LT and
  cytokines

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Asthma Classification

• Class Symptoms Night Sx FEV1 Therapy
• Mild Intermittent lt 2x/wk lt 2x/mo gt 80 PRN
  ß-agonist
• Mild Persistent 36x/wk gt 2x/mo gt 80 Daily
  GC or LA
• or MCD
• PRN ß-agonist
• Moderate Persistent Daily gt 1x/wk 6080 Above
  long
• acting ßagonist
• anticholinergic
• theophylline
• Severe Persistent Continuous Nightly lt
  60 Above high
• dose inhaled GC

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Asthma Blood Gases

• Stage pO2 pCO2 pH
• I Nml Nml Nml
• II Nml Low High
• III Low Low High
• IV Low High Low

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Asthma Therapy

• Drug Mechanism Clinical Effect
• ß2 agonists Smooth muscle relaxation Bronchodilat
  ion
• Decreases mast cell degran
• Anticholinergics Muscarinic antagonists Bronchodil
  ation
• Corticosteroids Inhibit cytokine
  production Decreases inflammation
• Decrease eosinophils Decreases reactivity
• Increases ß responsiveness
• Theophylline Phosphodiesterase
  inhib. Bronchodilation
• Adenosine receptor inhib. Better resp. muscle
  function
• Skeletal muscle contraction
• Leukotreine inh Decrease leukotreine
  effect Antiinflammatory
• Cromolyn/ Mast cell stabilization Antiinflammato
  ry
• Nedocromil

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Pulmonary Fibrosis

• Pathogenesis
• Initial insult gt immune response gt alveolitis
  gt WBC/macro cytokine releasegt injury to
  epithelial cells and alveolar basal lamina gt
  repair with fibrosis
• Associated Diseases
• Idiopathic (cryptogenic fibrosing alveolitis)
• CTD RA, scleroderma, PMS
• Sarcoidosis
• Occupational lung disease silicosis, asbestosis
• Hypersensitivity pneumonitis
• Eosinophilic granuloma
• Drugs

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Pulmonary Fibrosis Manifestations

• Dyspnea
• Rapid shallow breathing
• Inspiratory crackles (Velcro)
• Digital clubbing
• Later right heart failure

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PressureVolume CurveObjectively assesses
elastic recoil

• Parameters
• Xaxis lung volume
• Yaxis pleural (esophageal) pressure
• Compliance slope (?Y/?X or ?P/?V)
• Vmax maximum expiratory flow rate
• Dependent on recoil and airway resistance
• Alterations in disease states
• Emphysema loss of elastic recoil
• Increased slope, shift to left, higher volumes
• Pulmonary fibrosis increased elastic recoil
• Decreased slope, shift to right, lower volumes

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PressureVolume CurvesObstructive vs.
Restrictive Disease

• Obstructive Restrictive
• Example Emphysema Pulmonary fibrosis
• Elastic recoil Decreased Increased
• Compliance Increased Decreased
• PV slope Increased Decreased
• Curve shift Left Right
• Volumes Higher Lower

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Pathophysiologic Consequences(Emphysema,
Decreased Elastic Recoil)

• Increased lung compliance
• Increased lung distension
• Increased airway collapse
• Decreased Vmax
• Increased work of breathing
• Increased ventilatory drive
• Increased FRC and RV
• V/Q mismatch
• Decreased diffusion capacity

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Pathophysiologic Consequences(Pulmonary
Fibrosis, Increased Elastic Recoil)

• Decreased lung compliance
• Decreased lung distension
• Increased Vmax
• Increased work of breathing
• Increased ventilatory drive
• Decreased TLC, FRC, RV
• V/Q mismatch
• Decreased diffusion capacity

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Respiratory Muscles

• Inspiratory
• Diaphragm
• Contractsgt increased intraabd pressure gt
  pushes abd out gt pushes lower rib cage
  and chest wall out
• Contractility best with low lung volumes
• Accessory muscles (SCM)
• Recruited during increased ventilatory demands
• Elevate rib cage
• Expiratory
• Abdominal muscles
• Increase abd pressure, displace diaphragm upward

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Pulmonary Function Testing

• Dynamic Lung Function
• Spirometry
• Flow loops
• Maximum voluntary ventilation
• Static Lung Function
• Lung volumes
• Lung capacities
• Gas exchange
• Diffusion capacity (CO)
• Arterial blood gases

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Indications For Pulmonary Function Testing

• Assess SOB
• Determine presence/degree of pulmonary disease
• Determine pathophysiology of pulmonary disease
• Assess course, prognosis and response to therapy
• Assess disability

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Dynamic Lung Function Abnormalities

• Obstructive Lung Diseases
• Decreased FEV1/FVC
• Decreased Vmax (FEF2575,FEF50)
• Inwardbowed decrease slope of exp flowvolume
  loop

• Restrictive Lung Disease
• Decreased FVC and FEV1
• Normal to high FEV1/FVC
• Preserved Vmax (FEF2575,FEF50)
• Outwardbowed increase slope of exp flowvolume
  loop

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PFT Classification of Pulmonary Diseases

• Obstructive Lung Disease
• Chronic Bronchitis
• Emphysema
• Asthma
• Acute Bronchitis
• Bronchiectasis
• Bronchiolitis Obliterans

• Restrictive Lung Disease
• Pulmonary
• Pulmonary Fibrosis
• Pulmonary Edema
• Focal Lung Disease
• Tumor
• Pneumonia
• Atelectasis
• Lung Resection
• ExtraPulmonary
• Obesity
• Kyphoscoliosis
• Neuromuscular Disease
• Pleural Effusion

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Spirometry in Pulmonary Diseases

• Obstructive Restrictive
• FVC
• FEV1
• FEV1/FVC
• FEF50
• MVV

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Lung Volumes in Pulmonary Diseases

• Obstructive Restrictive
• TLC
• VC
• FRC
• RV
• DLCO

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Respiratory Failure

• Definitions
• Hypoxemic respiratory failure PaO2 lt 50 mmHg
• Hypercapnic respiratory failure PaCO2 gt 50 mmHg
• Mechanisms of Hypoxemia
• Hypoventilation
• V/Q Mismatch
• Pulmonary Shunts

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Hypoventilatory Respiratory Failure

• Due to inappropriate volume and/or frequency of
  respirations
• Increased PaCO2 with concomitant decrease PaO2
• Acutely causes acidosis, pulmonary hypertension
• Causes
• CNS disease any destructive process
• Endocrine/metabolic hypothyroidism, metabolic
  alkalosis
• Neuromuscular lesions of anterior horn cells,
  peripheral nerves, motor end plate, muscle itself
• Structural COPD, kyphoscoliosis, obesity

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V/Q Mismatch Respiratory Failure

• The most common respiratory failure
• Usually with some hypoventilation
• Ideal gas exchange occurs with a V/Q ratio of 0.8
• 4L/min alveolar ventilation and 5l/min cardiac
  output
• If V/Q decreases
• Less air reaches alveoli per given amount of
  perfusion
• Less exchange of O2 and CO2
• Alveolar endcapillary PO2 drops and PCO2
  increases
• Healthier alveoli can compensate for CO2 but
  not O2
• ABG shows low PaO2 and low PaCO2
• If V/Q increases
• More air reaches alveoli per given amount of
  perfusion
• More exchange of O2 and CO2
• Alveolar endcapillary PO2 increases and PCO2
  drops
• O2 dissociation curve flat at high levels, cant
  compensate

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Pulmonary Shunt Respiratory Failure

• Completely unventilated alveoli (extreme V/Q
  mismatch)
• Causes
• Atelectasis, edema, consolidation, ARDS
• Venous blood is shunted from pulmonary into
  systemic arterial system without getting
  oxygenated
• V/Q 0 (no ventilation to a perfused alveolus)
• Results in hypoxemia and hypocapnia like V/Q
  mismatch

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Clinical Approach to Respiratory Failure

• Whats the PaCO2?
• If normal or low gt excludes hypoventilation
• If high, compute alveolararterial O2 gradient
• Calculating the Aa gradient
• PaO2 is measured via an arterial blood gas
• PAO2 is calculated
• (Pb PH2O)FIO2 PACO2/r
• (747 47)0.21 PaCO2 x 1.2
• 147 (PaCO2 x 1.2)
• Normal gradient is 1015 mmHg
• If increased poor gas exchange V/Q mismatch
  or shunt

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Treatment of Respiratory Failure By Type

• Type Treatment
• Hypoventilation Mechanical ventilation
• V/Q mismatch Controlled increased FIO2
• Target PAO2 5060 mmHg
• Bronchodilators, antibiotics, Rx CHF
• Shunting Mechanical ventilation
• Positive EndExpiratory Pressure (PEEP)
• Target PAO2 5060 mmHg
• Target FIO2 lt 60

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Respiratory Acidosis and Alkalosis

• Acute Respiratory Acidosis
• pH decreases 0.08 pH units / 10 mmHg PCO2
  increase
• HCO3 increases 1 meq/L / 10 mmHg PCO2 increase
• Compensated (Chronic) Respiratory Acidosis
• pH decreases 0.03 pH units / 10 mmHg PCO2
  increase
• HCO3 increases 3.5 meq/L / 10 mmHg PCO2 increase
• Acute Respiratory Alkalosis
• pH increases 0.08 pH units / 10 mmHg PCO2
  decrease
• HCO3 decreases 2 meq/L / 10 mmHg PCO2 decrease
• Compensated (Chronic) Respiratory Alkalosis
• pH usually normal
• HCO3 decreases 5.0 meq/L / 10 mmHg PCO2 decrease

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Consequences of Acute CO2 Retention

• Acidosis
• Impaired tissue metabolism
• Cerebral Vasodilation
• Cerebral edema
• Pulmonary Vasoconstriction
• Pulmonary hypertension
• CO2 Narcosis
• Lethargy gt coma
• Hypoxemia
• Organ dysfunction

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Dyspnea

• Definition
• Synonyms Breathlessness, shortness of breath
  (SOB), difficulty in breathing (DIB)
• Uncomfortable awareness of breathing difficulty
• Pathophysiologic Cause
• Discrepancy between the drive to breath and the
  level of ventilation achieved.

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Acute And Chronic Dyspnea

• Acute Dyspnea
• Pulmonary edema
• Asthma
• Chest wall injury
• Pneumothorax
• Pulmonary embolism
• Pneumonia
• ARDS
• Pleural effusion
• Pulmonary hemorrhage

• Chronic, Progressive Dyspnea
• COPD
• CHF
• Interstitial Fibrosis
• Asthma
• Effusions
• Thromboembolic disease
• Pulmonary vascular disease
• Psychogenic dyspnea
• Anemia (Hb lt 7.0)
• Tracheal stenosis
• Hypersensitivity disorders

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Systemic vs. Pulmonary Circulation

• Systemic Circulation
• Normal pressures 120/80
• SVR 19.6 torr/L/min
• Pulmonary Circulation
• Normal pressures 25/15
• SVR 2.6 torr/L/min

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Pulmonary Vascular Resistance

• Normal parameters
• Pressures 25/15
• Vascular resistance 2.6 torr/L/min
• Decreased vascular resistance
• Parasympathetic tone
• Acetylcholine
• Beta2 agonists
• Bradykinin
• Prostaglandins PGE1, PGI2
• Nitric oxide

• Increased vascular resistance
• Sympathetic tone
• Prostaglandins PGF2a, PGF2
• Thromboxane
• Angiotensin
• Histamine
• Serotonin
• Alveolar hypoxia or hypercapnia
• Acidosis

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Pulmonary Hypertension Etiologies

• Increased Left Atrial Pressure
• Congestive heart failure
• Mitral stenosis
• Increased Pulmonary Flow
• Left to right shunt
• Increased Pulmonary Vascular Resistance
• Vasoconstriction
• Hypoxia
• Obstructive
• Primary pulmonary hypertension
• Pulmonary embolism (clot, tumor, fat, parasite)
• Obliterative
• Emphysema
• Pulmonary fibrosis

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Pulmonary Hypertension Signs

• Heart Exam
• Increased P2
• Wide split of S2
• R ventricular heave
• S4
• Pressures
• Increased R ventricular enddiastolic pressure
• Increased RA pressure
• Increased CVP

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Risk Factors for DVT/Pulmonary Embolism

• Venous Stasis
• Immobility age, obesity, bed rest, trauma,
  surgery, neuro Dx
• Heart disease CHF, atrial arrhythmia, myocardial
  infarction
• Pregnancy
• Vein Wall Injury
• Prior DVT
• Pelvic, hip, leg fracture or surgery
• Hypercoagulable States
• Malignancies
• Estrogen pregnancy, exogenous
• Nephrotic syndrome
• Hereditary Ptn C and S deficiencies, factor V
  Leiden, homocystinemia, prothrombin gene
  mutations, high factor levels, antiphospholipid Ab

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Pulmonary Embolism Pathophysiology

• Release of Platelet Factors
• Serotonin and thromboxane A2
• Vasoconstriction gt pulmonary HTN, RV
  dysfunction, chest pain, low BP, hypoxemia
• Decreased alveolar perfusion
• Increased dead space (increased V/Q) gt hypoxemia
  and hypocapnia
• Reflex bronchoconstriction gt wheezing
• Loss of surfactant
• Atelectasis, alveolar edema and bleed gt SOB,
  crackles, chest pain
• Decreased V/Q gt hypoxemia
• Irritant and J receptor stimulation gt
  hyperventilation and SOB

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Pulmonary Embolism Symptoms

• Dyspnea
• Pleuritic chest pain
• Cough
• Hemoptysis
• Syncope

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Pathophysiology of Chronic Pulmonary HTN

• Phenomenon Physical Exam (Sx)
• Increased pulmonary artery pressure gt Increased
  P2
• Right ventricular hypertrophy gt RV S4
• Right heart failure gt RV S3
  Increased JVP, edema Hepatomegaly
  (Fatigue and dyspnea)

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Sleep Medicine
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Sleep Architecture(Cycles every 90120 minutes)

• NonRapid Eye Movement (NREM) Sleep
• Stage 1 Transition from wakefulness
• EEG fast theta (47 Hz) easily aroused and deny
  being asleep
• Stage 2 Intermediate sleep, 4050 of total
  sleep time
• EEG slower and higher amplitude, sleep spindles
  1214 Hz bursts, kcomplexes double negative
  wave
• Stage 3 and 4 Deep sleep, 20 of sleep
• EEG High amplitude, slow (13 Hz)
• Rapid Eye Movement (REM) Sleep
• EEG Low voltage, high frequency wakefulness
• EMG atonic
• EYE rapid eye movements

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Determinants of Sleep

• Homeostasis
• Enough sleep amount that allows alertness for
  the day
• 8 hours, yet highly variable
• Circadian Rhythms
• Suprachiasmatic nucleus near hypothalamus
• Receives input via the retinohypothalamic tract
• Changes With Age
• Arousals increase, deep sleep decreases, latency
  increases

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Obstructive Sleep Apnea

• Definition
• Repetitive episodes of upper airway obstruction
• Frequent apnea and hypoxemia
• Symptoms
• Nighttime symptoms
• Snoring, apnea/gasping, flailing of limbs,
  frequent awakenings, GE reflux urination
• Daytime symptoms
• Tiredness upon awakening, morning HA, excessive
  sleepiness, loss of libido/impotence
• MVA, work accidents, school/work problems, social
  embarrassment, marital problems,
  memory/concentration trouble, depression

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OSA Predisposing Factors

• Age
• Obesity
• MgtF 21
• Upper airway obstruction
• Craniofacial anomalies
• Medications
• Alcohol
• Smoking
• Genetics

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OSA Physical Exam

• Short fat neck
• Obesity
• Upper airway narrowing
• Large tonsils
• Enlarged uvula
• Long soft palate
• Micrognathia/retrognathia

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Sleep Apnea Clinicopathologic Effects

• Acute
• Brady/tachyarrhythmias
• Chronic
• Systemic HTN
• Pulmonary HTN
• CHF
• Myocardial infarction
• Stroke
• Hypercapneic respiratory failure

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OSA Polysomnographic Findings

• Apneas
• gt 30 per hour
• Terminated by arousal
• Often occur over 50 of sleep time
• Architecture
• Destroyed
• Decreased Stage 3 and 4
• Decreased REM

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OSA Therapy

• Discontinue medications and alcohol
• Weight loss
• Tennis ball on back
• Nasal CPAP
• Surgical correction
• Uvulopharyngoplatoplasty
• Tracheotomy

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Narcolepsy Manifestations(Due to sudden onset of
REM sleep)

• Cataplexy
• Bilateral loss of muscle tone after strong
  emotion
• Laughter, anger, amusement, exertion
• Last seconds to minutes
• Hypnagogic hallucinations
• Vivid nightmares at sleep onset
• Sleep Paralysis
• Unable to move at sleep onset (hypnagogic) or
  offset (hypnapompic)
• Sleep Attacks
• Episodic overwhelming sleepiness during the day

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Multiple Sleep Latency Criteria for Narcolepsy

• Mean sleep latency of lt 8 minutes
• gt 2 sleep onset REM periods during naps
• No other apparent cause (i.e. sleep deprivation)

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Narcolepsy Treatment

• Behavioral
• Structured sleep schedule with naps
• Diet avoid heavy meals
• Physical activity during the day
• Pharmacological
• Sleep attacks pemoline, methylphenidate,
  dexamphetamine, metamphetamine, modafinil
• Cataplexy TCAs, fluoxetine, GHB
• Psychosocial

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Sports Medicine
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Sports Medicine Ligament Sprains

• Definition of a ligament
• Dense fibrous collagen, connects bone to bone
• Grading of sprain injuries
• Grade 1 partial tear, no functional
  laxity heals in 24 weeks
• Grade 2 partial tear, some laxity, intact
  endpoint heals in 46 weeks
• Grade 3 complete ligament injury heals in 23
  months
• Evaluation
• History of injury
• Exam for site of pain and laxity
• Image

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The Ligament Healing Process

• Hemorrhagic Phase
• Immediate
• Clot forms in injured area
• Inflammatory Phase
• 12 weeks
• WBCs enter and phagocytize debris
• Clot converted to granulation tissue
• Reparative Phase
• 18 weeks
• Fibroblasts lay down extracellular matrix and
  immature collagen fibers
• Remodeling Phase
• 4 weeks to 1 year
• Maturation to mature collagen

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Treatment of Ligament Sprains

• RICE
• Rest, Ice, Compression, Elevation
• Immobilization
• Some initially yet not too long (prevents full
  healing)
• Antiinflammatories
• OK, but need to allow some inflammation
• Prolotherapy
• Injections of sugar/salt solutions to increase
  inflammation

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Sports Medicine Tendon Strains

• Definition of a tendon
• Dense fibrous collagen, connects muscle to bone
• Grading of strain injuries
• Grade 1 partial tear, no weakness
• Grade 2 partial tear, some weakness
• Grade 3 complete tear, loss of motor function,
  palpable defect
• Evaluation and diagnosis
• History of injury
• Exam for function
• Image usually not necessary
• Repair mechanism
• Same as for sprains
• Muscles will atrophy from disuse
• Treatment
• RICE, ? NSAIDs, steroid injections vs.
  prolotherapy
• Surgical repair

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Tendinosis

• Tendon degeneration from tendon overuse
• Minimal inflammatory cells
• Normal repair does not occur

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Dislocation

• Background
• Usually due to major trauma
• Named by distal bone over proximal bone
• Common injury to multiple ligaments
• Examination
• Gross joint deformity
• Check neurovascular integrity
• Treatment
• Emergent joint reduction

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Bone Fractures Descriptions

• Bone name
• Comminution
• Number of pieces
• Angulation
• Which way is it pointing
• Translation
• Bones separated and not overlapping
• Shortening

• Other Descriptors
• Segmental (a series of Fx)
• Impaction
• Avulsion (bone pulled off)
• Pattern
• spiral/oblique/transverse

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Fracture Healing and Treatment

• Day 1 3
• Bleeding and clot formation
• Week 1
• Macrophage migration
• Weeks 1 6
• Clot reorganizes into callous
• Months 2 12
• Remodeling to mature bone

• Treatment
• RICE
• Immobilize
• NSAIDs
• Bone stimulation

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Developmental Bone Disease
65
Achondroplasia

• Genetics
• Autosomal dominant
• Mutation on chromosome 4 of fibroblast growth
  factor receptor 3 (FGFR3) (Arg gt gly)
• Pathophysiology
• Failure of enchondrial bone ossification (long
  bones)
• Intramembranous ossification (skull/spine) normal
• Thus, normal head and trunk size, small arms and
  legs

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Spina Bifida

• Pathophysiology
• Failure of posterior neural tube closure (weeks 3
  6)
• 1 1,000 births
• Decreased by prenatal AFP screening and folate
  administration
• Clinical manifestations
• Occulta occult failure of arches to fuse, no Sx,
  hair tuft
• Meningocele Meninges herniate through defect, no
  neurologic defect
• Meningomyelocele Meninges and cord herniate, leg
  paralysis and hydrocephalus

67
Other Congenital Bone/Joint Diseases

• Downs Syndrome
• Weak C1C2 ligaments gt subluxation
• Osteogenesis imperfecta
• Defective type I collagen
• Brittle bones, osteoporosis, transparent sclera
• Congenital clubfoot
• 1800 births
• Adducted, inverted forefoot
• No motor or nerve deficit
• Developmental Dysplasia of the Hip
• Due to external or inherited forces
• Legg Calve Perthes Disease
• Avascular necrosis of femoral head
• Slipped Capital Femoral Epiphysis

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Scoliosis

• Lateral curvature of spine
• Measured by Cobbs angle gt
• Treatment
• Immature spine
• Brace if gt 25o
• Mature spine
• Fusion if gt 40o

Scoliosis
Kyphosis
69
Breast Disease
70
Nipple Discharge

• Normal
• Physiologic, pregnancy
• Spontaneous
• Papilloma 70
• Ductal ectasia fibrocystic disease (20)
• Cancer 10
• Workup
• Exam
• Mammogram

71
Breast Cancer Epidemiology

• The most common female nonskin cancer
• The second most common cancer death (lung)
• The most common cause of death in women 4555
• Known Risk Factors
• Sex, age, genetics
• Proliferative breast diseases with or without
  atypia
• Lobular carcinoma in situ
• Prolonged estrogen
• menarche, menopause, parity, exogenous

72
The National Surgical Adjuvant Breast Project
Antiestrogens and breast cancer

• The Study
• 13,388 woman at risk for breast CA
• Over 60 or 3559 with 5year risk gt 1.66,
  lobular CA in situ
• Randomized to tamoxifen vs. placebo x 5 years
• The results
• Less breast CA by 50, bone Fx
• More Endometrial CA x 2.5, DVT/PE

73
Prognostic Factors for Breast CA

• Number of axillary lymph nodes
• Tumor size
• TNM stage
• Histologic grade
• Nuclear grade
• Absence of estrogen and/or progestin receptors
• HER2 positivity (coded for by c-erbB-2 oncogene)

74
Treatment of Invasive Breast CA

• Breast Conserving Therapy (BCT)
• Excision with clean margins and XRT
• BCT vs. mastectomy
• diseasefree survival
• overall survival
• Contraindications for lumpectomy
• Locally far advanced CA by exam or mammogram
• Multicentric carcinoma
• Persistent () margins during surgery
• Pregnancy (1st and 2nd trimester)
• CTD (esp. scleroderma)
• Large tumorbreast ratio

75
Adjuvant Systemic Therapy for Breast Cancer

• Indications for Chemotherapy
• Tumor gt 2 cm or positive lymph nodes
• Indications for Hormone Therapy
• Receptor positivity

76
Family Hx Reasons to screen for BRCA1/2

• BRCA 1 or BRCA 2 mutation
• Breast AND ovarian cancer
• Male breast cancer
• gt 2 members lt 50 with breast cancer
• Ashkenazi and gt 1 members lt 50 with breast cancer
• Ashkenazi and ovarian cancer

77
Other Female Malignancies
78
Ovarian Cancer Risk Factors(The most common
fatal genital cancer)

• Age
• Peaks at 56, declines after 80
• Incessant Ovulation
• Early menarche, late menopause, nulliparous
• Fertility drugs
• Risk declines with OCPs
• Genetic
• Family history, BRCA 1 and BRCA 2
• Caucasian

79
Ovarian Neoplasms

• Epithelial (85)
• 4555 malignant (M) vs. benign (B)
• Serous (MB) gt mucinous (B)gt endometrioid (M),
  Brenner (B), Clear cell (M), Undifferentiated (M)
• Germ Cell
• Teratoma (dermoid) (B) all others (M)
  teratocarcinoma, dysgerminoma, endodermal sinus
  tumor, choriocarcinoma, embryonal cell CA,
  gonadoblastoma
• Stromal
• Granulosa cell (makes Est), SertoliLeydig Cell
  (makes Tt), ovarian fibroma, ovarian sarcoma

80
Ovarian Cancer Management

• Surgery
• Debulking as much as possible
• Adjuvant chemotherapy
• If metastatic or highrisk
• Radiation Therapy
• Dysgerminomas

81
Endometrial Carcinoma(The most common
gynecologic CA in USA)

• Risk Factors
• Unopposed estrogen
• Anovulatory cycles, nulliparous, tamoxifen,
  obesity
• Familial
• e.g. Lynch syndrome
• OCPs are protective
• Clinical Presentation
• Abnormal uterine bleeding
• Postmenopausal or heavy premenopausal
• Prognosis (5year survivals)
• Stage 1 95, Stage IIIIV 26)

82
Squamous Intraepithelial Neoplasia (SIN) and
Cervical CA

• SIN Definition
• Dysplasia confined to the epithelium of GI/CU
  tract
• Gynecologic foci cervix, endometrium, vaginal
• Risks
• HPV, immunosuppression
• Early sex, multiple partners, high risk partners,
  prior STDs, high parity
• Smoking, low SE status
• Other gynecologic malignancies
• Clinical Manifestations
• Usually asymptomatic
• Vaginal bleed, postcoital bleed, vaginal DC

83
Papanicolaou Smear Indications

• Beginning
• Age 18 or sexual activity, whichever is first
• Frequency
• Every year until 3 negative and not high risk
• Cessation
• Age 60 75
• ? Total hysterectomy

84
Reproductive Endocrinologyand Gynecology
85
Gonadotropin Physiology

• Hypothalamus
• Pulsatile release of GnRH
• Stimulates pit FSH and LH
• Inhibited by Est and Prog
• Anterior Pituitary
• Releases FSH and LH
• Stimulates ovarian Est and Prog
• Inhibited by Est and Prog
• Ovaries
• Release Est and Prog
• Release androgens

86
Menstrual Phases

• Follicular Phase Luteal Phase
• Pituitary FSH gt LH secretion LH surge (also FSH)
• Ovary Estradiol secretion Prog gt Est secretion
• Follicular maturation Ovulationgtcorpus luteum
• Uterus Proliferative Secretory

87
Ovarian Hormone Synthesis

• Theca Cells
• Respond to LH
• Produce androgens from cholesterol
• Androstenedione, testosterone
• Granulosa Cells
• Respond to FSH
• Produce estrogen from androgens
• Requires aromatase enzyme

88
Abnormal Uterine Bleeding

• Dysfunctional Uterine Bleeding
• Vaginal bleeding not associated with an
  anatomical source or a systemic disease. Usually
  anovulatory. Dx of exclusion.
• Menorrhagia/Hypermenorrhea
• Heavy cyclic bleeding (gt 80 ml)
• Metrorrhagia
• Bleeding that is prolonged menstrual or
  intramenstrual
• Menometrorrhagia
• Combination of the above
• Oligomenorrhea
• Cycles gt 35d, often unpredictable
• Polymenorrhea
• Cycles lt 21d 24d

89
Uterine Leiomyomatas (Myomas, Fibroids)

• Epidemiology
• 20 over 30, gt40 over 40
• African American 36 fold higher
• Anatomy
• Submucosal, intramural, subserosal, pedunculated,
  parasitic
• Pathogenesis
• Estrogen dependent
• Symptoms
• Abnormal uterine bleeding
• Pelvic pain, urinary frequency, rectal discomfort
• Diagnosis
• PE, US, hysterosalpingogram, hysteroscopy, MRI
• Therapy
• Hormones, minimally invasive surgery, myomectomy,
  hysterectomy

90
Endometriosis Clinical

• Definition
• Presence of ectopic uterine mucosal tissue
• Locations
• Ovarian gt uterine gt ureterosacral ligaments,
  peritoneum, retroperitoneum, bowel, pleura
• Pathogenesis
• Retrograde menstruation
• Vascular or lymphatic dissemination
• Coelemic metaplasia
• Symptoms
• Pain, dysmenorrhea, dyspareunia, abnormal uterine
  bleeding, infertility

91
Endometriosis Treatment

• Observation
• Hormonal
• OCPs, depoprovera, danazol, GNRH agonist,
  pregnancy
• Surgical
• Excision, fulguration, TAHBSO

92
Puberty

• Definitions and sequence
• Thelarche breast development, mean age 10
• Adrenarche Body hair development, mean age 10
• Menarche Menses onset, mean age 13
• Age of onset one year earlier in African
  Americans
• Precocious puberty
• 2.5 SD below mean age
• Delayed puberty
• No changes at 14
• No thelarche age 15
• No menses within 2 years of thelarche and
  adrenarche or by age 16

93
Menopause

• Definitions
• Menopause cessation of menstrual cycles for one
  year
• Perimenopause Menstrual irregularities, Sx of
  Est loss
• Mean age 51 52
• Related ovarian follicular physiology
• Fetus has 7,000,000 follicles
• At menarche 400,000 follicles
• At menopause 10,000 follicles (nonfunctional)

94
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95
Primary Amenorrhea(No menarche by age 16,
usually genetic or anatomic)

• Chromosomal abnormalities (45)
• Androgen insensitivity syndrome 46 XY, defective
  Tt receptor, testes make MIF
• Vanishing testes syndrome 46 XY, failure of full
  testicular development
• Absent testes determining factor 46 XY, no
  testes so no Tt or MIF
• 5alpha reductase deficiency 46 XY, female
  phenotype yet virilization after puberty with
  deep voice, baldness, increase muscle mass
• 17OHase deficiency 46 XX or XY, cannot make
  gonadotropins, female with HTN
• Turners 45 XO, streak ovary
• Physiologic delay in pregnancy (20)
• Müellarian agenesis (15)
• Absence of fallopian tubes, uterus, upper 1/3
  vagina
• Transverse vaginal septum/imperforate hymen (5)
• Hypothalamic GnRH deficiency (5)
• 1o congenital (with anosmia Kallmans)
• 2o Anorexia nervosa, exercise, wt loss, stress,
  invasion
• Hypopituitarism (2)

96
Approach to Primary Amenorrhea

• Puberty present (eugonadal, makes Est)
• Check uterine/vaginal anatomy
• Check karyotype, testosterone level
• Pregnancy test
• Puberty absent (hypogonadal, no Est)
• Check LH and FSH (cant measure GnRH)
• Low stress?, low BW?, pit failure?
• High Gonadal failure
• Check karyotype (XO or XY)
• Check prolactin and TSH

97
Secondary Amenorrhea(No menses x 6 months or 3
cycles)

• Pregnancy most common
• Ovarian (40)
• Polycystic ovary syndrome (40)
• High testosterone gt anovulation, endometrial
  atrophy
• Ovarian failure (if lt 40 yo primary)
• Autoimmune oophoritis
• Hypothalamic (35)
• Functional GnRH deficiency (same reasons as under
  1o amenorrhea)
• Infiltrative
• Pituitary (20)
• Hyperprolactinemia (90) gt decreased GnRH
• Empty sella, hypothyroidism, other pituitary
  tumors, Sheehans, infiltrative
• Uterine (5)
• Ashermans (gt90), endometriosis

98
Approach to Secondary Amenorrhea

• Rule out pregnancy
• ßHCG
• Physical exam
• R/O Ashermans
• Prolactin level
• If very high, CT or MRI of pituitary
• TSH
• If very high hypothyroidism
• FSH and LH
• If very high ovarian failure, if lt 30 gt
  karyotype
• If low stress?, low BW?, pit failure?
• DHEAS and testosterone
• Only if virilized, looking for PCOS
• 17OHprogesterone
• Looking for congenital adrenal hyperplasia

99
Progestin Withdrawal Test

• If bleeding occurs
• Uterus and endometrium are intact
• Estrogen is sufficient, progesterone was lacking
• Anovulation
• Hypothalamic dysfunction (stress)
• Polycystic ovarian syndrome
• LateOnset Congenital Adrenal Hyperplasia (17OH)
• If bleeding does not occur
• Insufficient estrogen or uterine cause
• Hypothalamic dysfunction (stress)
• Pituitary dysfunction
• Uterine cause

100
Geriatrics
101
Pathophysiology of Bedrest

• Pulmonary
• Decreased oxygenation
• Decreased ability to clear secretions
• Vascular
• Venous stasis gt DVT gt PE
• Orthostasis
• Skin
• Pressure ulcers

• Musculoskeletal
• Atrophy and contractures
• Osteoporosis
• Electrolytes
• Hypercalciuria gt stones
• Gastrointestinal
• Reflux esophagitis
• Constipation
• Anorexia

102
Geriatrics Vision Changes in the Elderly

• Visual Acuity
• Decreased accommodation (presbyopia)
• Color Vision
• Lens yellows, blue green blending
• Extraocular Muscles
• Weaken
• Tear ducts
• Less tear production gt corneal irritation
• Illumination disturbances
• Require more light yet more glare
• Poor night vision

103
Geriatrics Hearing Changes in the Elderly

• Presbycusis
• Agerelated hearing loss, usually gt 65 yo
• Higher frequency loss
• Loss of speech discrimination
• Interview techniques
• Turn off all background noise
• Sit them in a corner and at eye level
• Well-lighted area
• Speak clearly and slowly, low tone
• Mime
• Use amplifiers

104
Neurology
105
Pyramidal Motor System

• Anatomy
• Corticospinal and corticobulbar system
• Originates motor, premotor, sensory cortex
• Terminates on alpha motor neurons in the
  intermediate gray of spinal cord and brain stem
• Function
• Executes isolated dextrous muscle movements
• Present only in primates and above
• Modified by reticulospinal, tectospinal and
  vestibulospinal tracts
• Effect of lesions
• Upper motor neuron paralysis

106
Extrapyramidal Motor System

• Anatomy
• Originates basal ganglia and cerebellum
• Links indirectly to pyramidal system via thalamus
  and cortex
• Function
• Basal ganglia initiation and planning of
  movement
• Cerebellum monitors, smoothes and terminates
  movements
• No direct initiation of movements
• Lesions
• Basal ganglia bradykinesia
• Cerebellum ataxia

107
Basal Ganglia Dysfunction

• Anatomy
• Caudate nucleus
• Putamen
• Globus pallidus
• Substantia nigra
• Subthalamic nucleus
• (Thalamus)

• Effects of dysfunction
• Involuntary movements
• Altered voluntary movements
• Slow
• Interrupted
• Uncoordinated
• Posture and tone altered
• Neurotransmitter correlates
• Dopamine gt Ach hyperkinetic
• Ach gt Dopamine hypokinetic

108
Upper Motor Neuron (Central) Weakness

• Hemiparesis
• Hyperreflexia
• Unilateral clasp knife spasticity (rigidity)
• May see spontaneous spasms
• Anatomic associations
• LE external rotation
• UE decreased arm swing, internal rotation when
  extended
• Facial spares forehead, eye wider, nasolabial
  fold flat

109
Localizing an Upper Motor Neuron (Central)
Weakness

• Cerebral Cortex
• Trouble with language, spatial attention, touch
  recognition, vision
• Internal Capsule
• Face, UE and LE weak but no other cranial nerve
  or cortical symptoms
• Brainstem
• Cranial nerves involved
• Spinal cord
• Face not involved

110
Lower Motor Neuron (Peripheral) Weakness

• Anterior horn cell to muscle
• Muscle atrophy
• Fasciculations and fibrillations
• Decreased/absent reflexes
• Flaccidity
• Cramping

111
UMN vs. LMN Weakness

• UMN LMN
• Location Cortex gt SC Ant. horn cellgtmuscle
• Muscle size Normal Atrophic
• Reflexes Increased Decreased
• Fasciculations Absent Present
• Tone Clasp knife rigidity Decreased (flaccid)

112
Babinskis Sign

• Primitive defensive flexion of hip, knee and
  dorsiflexion of ankle
• In primates, dorsiflexion of toes
• When we start walking, the latter is inhibited to
  allow toe plantar flexion
• Thus a normal response in an adult is flexion of
  the hip, knee and dorsiflexion of the ankle with
  plantar flexion of the toes.
• Abnormal upgoing toes

113
GuillainBarré Syndrome

• Pathogenesis
• Immunologic attack on peripheral myelinated
  fibers
• Etiology
• Campylobacter jejuni, other infections,
  vaccinations
• Clinical Manifestations
• Ascending weakness
• Peripheral sensory loss
• Loss of reflexes
• CSF increased protein but not cells

114
Peripheral Neuropathies

• Axonal Degeneration (Dying Back)
• Toxic injury to neurons
• Etiologies EtOH, DM, Pb, paraneoplastic
• Symmetric, longest fibers first
• Ischemic
• Loss of peripheral vascular or vaso nervorum
  blood supply
• Etiologies DM, pressure induced neuropathies,
  vasculitis
• Asymmetric
• Demyelination
• Immune mediated injury to myelinated fibers
• Etiologies e.g. Guillain Barré syndrome
• Symmetric loss of motor and sensory function and
  DTRs

115
Muscle Motor Weakness

• Etiologies
• Inflammation dermatomyositis, inclusion body
  myositis
• Abnormal proteins muscle dystrophies
• Toxins
• Metabolic high Ca, low K, low glucose,
  hypothyroid
• Neuromuscular junction myasthenia gravis,
  EatonLambert
• Clinical Manifestations
• Proximal gt distal muscle weakness
• No sensory loss
• Preservation of reflexes

116
Brain EdemaIncreased brain volume due to
increased water content

• Vasogenic Cytotoxic Interstitial
• Pathophysiology Endothelial Neuronal Pressure
• injury injury
• Causes Tumor Hypoxia Hydroceph-
• Infection Hypoosmo alus
• Trauma larity Meningitis
• Infarct
• HTN
• Therapy Steroids None Shunt

117
Aphasia

• Definition
• Disorder of language due to brain dysfunction
• Classification
• Expressive (Broca)
• Receptive (Wernicke)
• Global
• Other Characteristics
• Fluent vs. nonfluent
• Comprehension
• Repetition

118
Memory Types

• Episodic
• Memory of events
• Remote (mos to yrs), longterm memory, hardest to
  lose
• Recent (min to days), new learned ability, test
  by asking patient to remember 3 common words for
  a few minutes
• Immediate (s), not encoded, max 7 items,
  easiest to losetest via digit repetition
• Easiest to lose
• Semantic
• Memory of words and meanings
• Test via naming of objects or persons
• Procedural
• Skills
• Toughest t lose

119
Memory Loss

• Failure to create memories
• Hippocampal system
• Failure to have adequate storage
• Loss of neurons
• Failure to retrieve
• Loss of neurons that used to contain memories

120
Acute Pain Types

• First pain
• Adelta fibers
• Immediate, brief, sharp, localized
• Second pain
• C fibers
• Seconds later, enduring, dull/burning, not
  localized

121
Pain Pathways

• Ascending Pathway
• Pain receptors
• Synapse in dorsal horn
• Cross to form ascending spinothalamic tract
• Thalamus
• Lateral thalamic nucleus
• To somatosensory cortex gt feel pain
• Medial thalamic nucleus
• To frontal cortex gt realize pain

• Descending Pathway
• Periaqueductal gray region
• Serotonin
• To frontal cortex
• Suppress response to pain
• To spinal cord
• Suppress sensation of pain

122
Diseases of the Pain Pathways

• Reflex Sympathetic Dystrophy (Causalgia)
• Postnerve injury hypersensitivity to
  catecholamines released by sympathetic nervous
  system
• Hypereshtesia, vasoconstriction, muscle atrophy,
  contracture
• Rx analgesics, sympathetic blockade
• Fibromyalgia
• Decreased descending serotonin release
• Increased perception of pain from nonnoxious
  stimuli
• Rx SSRIs

123
Myasthenia Gravis

• Pathophysiology
• Autoimmune destruction of postsynaptic
  neuromuscular junction nicotinic acetylcholine
  receptors (AchRs)
• Antibody binds and induces cell mediated attack
• Accelerated loss of AchRs
• Clinical Manifestations
• Weak proximal muscles, eye lids and EOM, cranial
  nerves, diaphragm
• Diagnosis
• Improvement after acetycholinesterase inhibitor
  (edrophonium, Tensilon) challenge
• EMG Decrement in action potentials with
  repetitive stimulation
• Assay for antiacetylcholine receptor antibodies
  (8090 )
• Therapy
• Long acting acetylcholinesterase inhibitors,
  steroids, cytotoxics, thymectomy, plasmapheresis,
  IVIG

124
Duchenne Muscular Dystrophy

• Pathophysiology
• Variable mutations of dystrophin gene at Xp21
  locus (Xlinked rec)
• Dystrophin protects sarcolemmal membrane from
  degradation by intracellular proteases, absence
  gt muscle necrosis, Ca influx
• Clinical Manifestations
• Male onset 23 years, wheelchair in teens, death
  in 20s
• Proximal weakness with calf pseudohypertrophy
  (fat, fibrosis, inflam)
• Protruberant abdomen, lumbar lordosis
• Cardiac CHF, arrhythmias
• CPK elevated
• EMG myopathic small polyphasic potentials
• Treatment and Prognosis
• Symptomatic, prednisone slows progression
• Usually death in 3rd decade from respiratory or
  cardiac disease

125
Duchenne Muscular Dystrophy
Gowers Sign
Calf pseudohypertrophy
126
Polymyositis

• Pathophysiology
• Tcell mediated muscle injury
• Secondary Ab formation (Jo1, Mi2, SRP)
• Clinical Diagnostic Findings
• Symmetric proximal muscle weakness with pain
• Elevated plasma muscle enzymes
• Myopathic changes on electromyography
• Characteristic muscle biopsy abnormalities and
  the absence of histopathologic signs of other
  myopathies
• Dermatomyositis
• Gottrons papules and heliotrope eyelids
• Humorally mediated vasculitis
• Adult form associated with malignancy
• Therapy
• Steroids, cytotoxics, plasmapheresis, IVIG

127
Dermatomyositis
Gottrons papules
Heliotrope eyelids
128
Myophosphorylase Deficiency(McArdles Disease)

• Pathophysiology
• Autosomal recessive mutation of myophosphorylase
  gene on 11q13
• Phosphorylase removes 1,4 glucosyl residues from
  glycogen releasing G1 phosphate.
• Absence drastically reduces glucose availability
  for muscle
• Clinical Manifestations
• Exercise intolerance with cramping and
  myoglobinuria
• Second wind once FFA utilization kicks in
• Elevated CPK
• Treatment
• None

129
Tremor Characteristics

• Toandfro oscillation around a joint
• Regular or irregular
• Predictable and simple

130
Resting (Repose) Tremor

• Characteristics
• Occurs with inactivity of limb
• Examination
• Resting hand pill rolling
• Resting tongue
• Etiology
• Parkinsonism (4 6 Hz)
• Parkinsons disease, heavy metal toxicity (Fe,
  Cu), drug (MPTP)
• Midbrain stroke
• Treatment
• Dopamine agonists

131
Parkinsonism

• Classical Characteristics
• Bradykinesia
• Tremor (46 Hz, initially unilateral)
• Cogwheel rigidity
• Loss of postural reflexes
• Etiology
• Death of dopaminergic neurons in substantia nigra
• Dopamine antagonists
• Therapy
• Ldopa, dopamine agonists
• Amantadine (blocks DA reuptake)
• COMT inhibitors
• Selegeline (MOA inhibitor)

132
Intention (Action) Tremor

• Characteristics
• Occurs with action of an extremity
• Examination
• Fingertonose and heeltoshin test
• Etiology
• Cerebellar disease (34 Hz)
• EtOH, trauma, stroke, tumor, degeneration, MS
• Midbrain stroke
• Treatment
• Physical therapy

133
Postural Tremor

• Characteristics
• Occurs with antigravity posturing
• Examination
• Outstretched arms and fingers
• Tongue protrusion
• Etiology
• Exaggerated physiologic tremor (1012 Hz)
• Catecholamine excess
• Endocrine pheo, hyperthyroid, hypoglycemia
• Drugs ßagonists, reuptake inhibitors, xanthine
  oxidase inhibitors, catecholamines
• Stress
• Essential tremor (410 Hz)
• Etiology unknown
• 50 inherited (familial tremor)
• Treatment
• ßblockers, EtOH, primidone

134
Tremor Summary

• Tremor Type Frequency Cause Treatment
• Resting 4 6 Hz Parkinsons Dopaminergics
• Action 3 4 Hz Cerebellar None
• Postural
• Exaggerated 10 12 Hz Catechols Treat cause
• physiologic ßblockers
• Essential 4 10 Hz Unknown ßblockers,
• primidone

135
Chorea

• Definition
• Irregular, unpredictable, random, rapid, jerky
• Pathophysiology
• Dopamine excess in striatum
• Estrogen effect (mild)
• Etiology
• Huntingtons disease (and misc. hereditary forms)
• Sydenhams chorea (acute rheumatic fever)
• Cerebral palsy
• Pregnancy, OCPs
• Treatment
• Dopamine antagonists

136
Huntingtons Disease

• Etiology
• Autosomal dominant progressive chorea and
  dementia
• Defective huntingtin protein (chromosome 4)
• Degeneration of cholinergic and GABAergic cells
  in BG
• Relative excess dopamine
• Manifestations