Clinical Pathophysiology
Review 3
8:30 AM, March 4, 2003
Fred A. Zar, MD, FACP
Director, M2 Clinicopathophysiology Course
Professor of Clinical Medicine
University of Illinois at Chicago
Respiratory Pathophysiology
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 25–35% of energy (nml 3–5%)
– Weight loss
• Hyperinflation
– Inspiratory muscle dysfunction
– Hoover’s sign, increased AP diameter
• Impaired Regional Ventilation
– V/Q mismatch –> hypoxemia –> pulmonary HTN
Smoking and COPD
• Smoking leads to activation of macrophages and
•
neutrophils
Pulmonary inflammation
– > chronic bronchitis
• Proteases released: elastase, cathepsins, metalloproteinases
– > inhibited by antiproteases
• alpha–1 antitrypsin, elafin, secretory leukoprotease inhibitor
– > injury to extracellular matrix –> emphysema
Emphysema
• Definition
– Airspace enlargement distal to terminal bronchiole
– Due to destruction of alveolar wall
• Locations
– Centrilobular
– Panacinar
Chronic Bronchitis
• Definition
– Cough and sputum
– Most days for 3 months
– 2 consecutive yrs
• Pathologic Correlate
– Mucus gland hypertrophy
– Goblet cell hyperplasia
COPD: Therapy
Drug
Mechanism
ß2 agonists
Smooth muscle relaxation Bronchodilation
Decreases mast cell degran
Muscarinic antagonists
Bronchodilation
Inhibit cytokine production Do not alter course
Decreases eosinophils
Decreases reactivity
Increases ß responsiveness Decreases inflammation
Phosphodiesterase inhib. Bronchodilation
Adenosine receptor inhib. Better resp. muscle function
Skeletal muscle contraction
Anticholinergics
Corticosteroids
Theophylline
Clinical Effect
•
•
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 > 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
Asthma Classification
Class
Mild Intermittent
Mild Persistent
Symptoms
< 2x/wk
3–6x/wk
Night Sx
< 2x/mo
> 2x/mo
FEV1
> 80%
> 80%
Moderate Persistent
Daily
> 1x/wk
60–80%
Severe Persistent
Continuous
Nightly
< 60%
Therapy
PRN ß-agonist
Daily: GC or LA
or MCD
PRN ß-agonist
Above + long–
acting ß–agonist
± anticholinergic
± theophylline
Above + high–
dose inhaled GC
Asthma: Blood Gases
Stage
I
II
III
IV
pO2
Nml
Nml
Low
Low
pCO2
Nml
Low
Low
High
pH
Nml
High
High
Low
Asthma: Therapy
Drug
Mechanism
ß2 agonists
Smooth muscle relaxation Bronchodilation
Decreases mast cell degran
Muscarinic antagonists
Bronchodilation
Inhibit cytokine production Decreases inflammation
Decrease eosinophils
Decreases reactivity
Increases ß responsiveness
Phosphodiesterase inhib. Bronchodilation
Adenosine receptor inhib. Better resp. muscle function
Skeletal muscle contraction
Decrease leukotreine effect Anti–inflammatory
Mast cell stabilization
Anti–inflammatory
Anticholinergics
Corticosteroids
Theophylline
Leukotreine inh
Cromolyn/
Nedocromil
Clinical Effect
Pulmonary Fibrosis
• Pathogenesis
– Initial insult –> immune response –> alveolitis –>
WBC/macro cytokine release–> injury to epithelial cells and
alveolar basal lamina –> repair with fibrosis
• Associated Diseases
–
–
–
–
–
–
–
Idiopathic (cryptogenic fibrosing alveolitis)
CTD: RA, scleroderma, PMS
Sarcoidosis
Occupational lung disease: silicosis, asbestosis
Hypersensitivity pneumonitis
Eosinophilic granuloma
Drugs
Pulmonary Fibrosis: Manifestations
•
•
•
•
•
Dyspnea
Rapid shallow breathing
Inspiratory crackles (Velcro®)
Digital clubbing
Later right heart failure
Pressure–Volume Curve
•
Objectively assesses elastic recoil
Parameters
–
–
–
–
X–axis = lung volume
Y–axis = 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
Pressure–Volume Curves
Obstructive vs. Restrictive Disease
Example
Elastic recoil
Compliance
P–V slope
Curve shift
Volumes
Obstructive
Restrictive
Emphysema
Decreased
Increased
Increased
Left
Higher
Pulmonary fibrosis
Increased
Decreased
Decreased
Right
Lower
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
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
Respiratory Muscles
• Inspiratory
– Diaphragm
• Contracts–> increased intra–abd pressure –> pushes abd out
–> 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
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
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
Dynamic Lung Function Abnormalities
•
Obstructive Lung Diseases
– Decreased FEV1/FVC
– Decreased Vmax (FEF25–
75,FEF50)
– Inward–bowed decrease slope
of exp flow–volume loop
•
Restrictive Lung Disease
– Decreased FVC and FEV1
– Normal to high FEV1/FVC
– Preserved Vmax (FEF25–
75,FEF50)
– Outward–bowed increase slope
of exp flow–volume loop
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
– Extra–Pulmonary
•
•
•
•
Obesity
Kyphoscoliosis
Neuromuscular Disease
Pleural Effusion
Spirometry in Pulmonary Diseases
Obstructive Restrictive
FVC
FEV1
FEV1/FVC
FEF50
MVV
Lung Volumes in Pulmonary Diseases
Obstructive Restrictive
TLC
VC
FRC
RV
DLCO
Respiratory Failure
• Definitions
– Hypoxemic respiratory failure = PaO2 < 50 mmHg
– Hypercapnic respiratory failure = PaCO2 > 50 mmHg
• Mechanisms of Hypoxemia
– Hypoventilation
– V/Q Mismatch
– Pulmonary Shunts
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
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
•
If V/Q decreases
•
If V/Q increases
– 4L/min alveolar ventilation and 5l/min cardiac output
–
–
–
–
–
Less air reaches alveoli per given amount of perfusion
Less exchange of O2 and CO2
Alveolar end–capillary PO2 drops and PCO2 increases
“Healthier” alveoli can compensate for CO2 but not O2
ABG shows low PaO2 and low PaCO2
–
–
–
–
More air reaches alveoli per given amount of perfusion
More exchange of O2 and CO2
Alveolar end–capillary PO2 increases and PCO2 drops
O2 dissociation curve flat at high levels, can’t compensate
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
Clinical Approach to Respiratory Failure
• What’s the PaCO2?
– If normal or low –> excludes hypoventilation
– If high, compute alveolar–arterial O2 gradient
• Calculating the A–a 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 10–15 mmHg
– If increased = poor gas exchange = V/Q mismatch or shunt
Treatment of Respiratory Failure By Type
Type
Treatment
Hypoventilation
V/Q mismatch
Mechanical ventilation
Controlled increased FIO2
Target PAO2 = 50–60 mmHg
Bronchodilators, antibiotics, Rx CHF
Mechanical ventilation
Positive End–Expiratory Pressure (PEEP)
Target PAO2 = 50–60 mmHg
Target FIO2 < 60%
Shunting
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
Consequences of Acute CO2 Retention
• Acidosis
– Impaired tissue metabolism
• Cerebral Vasodilation
– Cerebral edema
• Pulmonary Vasoconstriction
– Pulmonary hypertension
• CO2 Narcosis
– Lethargy –> coma
• Hypoxemia
– Organ dysfunction
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.
Acute And Chronic Dyspnea
•
Acute Dyspnea
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–
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–
–
–
–
–
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Pulmonary edema
Asthma
Chest wall injury
Pneumothorax
Pulmonary embolism
Pneumonia
ARDS
Pleural effusion
Pulmonary hemorrhage
•
Chronic, Progressive Dyspnea
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COPD
CHF
Interstitial Fibrosis
Asthma
Effusions
Thromboembolic disease
Pulmonary vascular disease
Psychogenic dyspnea
Anemia (Hb < 7.0)
Tracheal stenosis
Hypersensitivity disorders
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
Pulmonary Vascular Resistance
•
Normal parameters
– Pressures = 25/15
– Vascular resistance = 2.6
torr/L/min
•
•
Increased vascular resistance
–
–
–
Decreased vascular resistance –
– Parasympathetic tone
–
– Acetylcholine
–
– Beta–2 agonists
–
– Bradykinin
–
– Prostaglandins: PGE1, PGI2
– Nitric oxide
Sympathetic tone
Prostaglandins: PGF2a, PGF2
Thromboxane
Angiotensin
Histamine
Serotonin
Alveolar hypoxia or hypercapnia
Acidosis
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
Pulmonary Hypertension: Signs
• Heart Exam
–
–
–
–
Increased P2
Wide split of S2
R ventricular heave
S4
• Pressures
– Increased R ventricular end–diastolic pressure
– Increased RA pressure
– Increased CVP
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
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–
–
–
Malignancies
Estrogen: pregnancy, exogenous
Nephrotic syndrome
Hereditary: Ptn C and S deficiencies, factor V Leiden, homocystinemia,
prothrombin gene mutations, high factor levels, antiphospholipid Ab
Pulmonary Embolism: Pathophysiology
•
Release of Platelet Factors
– Serotonin and thromboxane A2
– Vasoconstriction –> pulmonary HTN, RV dysfunction, chest pain, low
BP, hypoxemia
•
Decreased alveolar perfusion
– Increased dead space (increased V/Q) –> hypoxemia and hypocapnia
– Reflex bronchoconstriction –> wheezing
•
Loss of surfactant
– Atelectasis, alveolar edema and bleed –> SOB, crackles, chest pain
– Decreased V/Q –> hypoxemia
– Irritant and J receptor stimulation –> hyperventilation and SOB
Pulmonary Embolism: Symptoms
•
•
•
•
•
Dyspnea
Pleuritic chest pain
Cough
Hemoptysis
Syncope
Pathophysiology of Chronic Pulmonary HTN
Phenomenon
Physical Exam (Sx)
Increased pulmonary artery pressure –> Increased P2
Right ventricular hypertrophy –>
RV S4
Right heart failure –>
RV S3
Increased JVP, edema
Hepatomegaly
(Fatigue and dyspnea)
Sleep Medicine
Sleep Architecture
(Cycles every 90–120 minutes)
• Non–Rapid Eye Movement (NREM) Sleep
– Stage 1: Transition from wakefulness
• EEG fast theta (4–7 Hz); easily aroused and deny being asleep
– Stage 2: Intermediate sleep, 40–50% of total sleep time
• EEG: slower and higher amplitude, sleep spindles: 12–14 Hz bursts,
k–complexes: double negative wave
– Stage 3 and 4: Deep sleep, 20% of sleep
• EEG: High amplitude, slow (1–3 Hz)
• Rapid Eye Movement (REM) Sleep
– EEG: Low voltage, high frequency ~ wakefulness
– EMG: atonic
– EYE: rapid eye movements
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 retino–hypothalamic tract
• Changes With Age
– Arousals increase, deep sleep decreases, latency increases
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
OSA: Predisposing Factors
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•
•
•
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•
•
•
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Age
Obesity
M>F 2:1
Upper airway obstruction
Craniofacial anomalies
Medications
Alcohol
Smoking
Genetics
OSA: Physical Exam
• Short fat neck
• Obesity
• Upper airway narrowing
– Large tonsils
– Enlarged uvula
– Long soft palate
• Micrognathia/retrognathia
Sleep Apnea: Clinicopathologic Effects
• Acute
– Brady/tachyarrhythmias
• Chronic
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–
–
–
–
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Systemic HTN
Pulmonary HTN
CHF
Myocardial infarction
Stroke
Hypercapneic respiratory failure
OSA: Polysomnographic Findings
• Apneas
– > 30 per hour
– Terminated by arousal
– Often occur over 50% of sleep time
• Architecture
– Destroyed
– Decreased Stage 3 and 4
– Decreased REM
OSA: Therapy
•
•
•
•
•
Discontinue medications and alcohol
Weight loss
Tennis ball on back
Nasal CPAP
Surgical correction
– Uvulopharyngoplatoplasty
– Tracheotomy
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
Multiple Sleep Latency Criteria for Narcolepsy
• Mean sleep latency of < 8 minutes
• > 2 sleep onset REM periods during naps
• No other apparent cause (i.e. sleep deprivation)
Narcolepsy Treatment
• Behavioral
– Structured sleep schedule with naps
– Diet: avoid heavy meals
– Physical activity during the day
• Pharmacological
– Sleep attacks: pemoline, methylphenidate, dex–
amphetamine, metamphetamine, modafinil
– Cataplexy: TCA’s, fluoxetine, GHB
• Psychosocial
Sports Medicine
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 2–4 weeks
– Grade 2: partial tear, some laxity, intact endpoint
heals in 4–6 weeks
– Grade 3: complete ligament injury
heals in 2–3 months
• Evaluation
– History of injury
– Exam for site of pain and laxity
– Image
The Ligament Healing Process
•
•
•
•
Hemorrhagic Phase
– Immediate
– Clot forms in injured area
Inflammatory Phase
– 1–2 weeks
– WBCs enter and phagocytize debris
– Clot converted to granulation tissue
Reparative Phase
– 1–8 weeks
– Fibroblasts lay down extracellular matrix and immature collagen fibers
Remodeling Phase
– 4 weeks to 1 year
– Maturation to mature collagen
Treatment of Ligament Sprains
• RICE
– Rest, Ice, Compression, Elevation
• Immobilization
– Some initially yet not too long (prevents full healing)
• Anti–inflammatories
– OK, but need to allow some inflammation
• Prolotherapy
– Injections of sugar/salt solutions to increase inflammation
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
Tendinosis
• Tendon degeneration from tendon overuse
• Minimal inflammatory cells
• Normal repair does not occur
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
Bone Fractures: Descriptions
•
•
Bone name
Comminution
– Number of pieces
•
Angulation
– Which way is it pointing
•
Translation
– Bones separated and not
overlapping
•
Shortening
•
Other Descriptors
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–
–
–
Segmental (a series of Fx)
Impaction
Avulsion (bone pulled off)
Pattern
• spiral/oblique/transverse
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
Developmental Bone Disease
Achondroplasia
• Genetics
– Autosomal dominant
– Mutation on chromosome 4 of fibroblast growth factor
receptor 3 (FGFR–3) (Arg –> gly)
• Pathophysiology
– Failure of enchondrial bone ossification (long bones)
– Intramembranous ossification (skull/spine) normal
– Thus, normal head and trunk size, small arms and legs
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
Other Congenital Bone/Joint Diseases
•
•
•
•
•
•
Down’s Syndrome
– Weak C1–C2 ligaments –> subluxation
Osteogenesis imperfecta
– Defective type I collagen
– Brittle bones, osteoporosis, ± transparent sclera
Congenital clubfoot
– 1:800 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
Scoliosis
•
•
•
Lateral curvature of spine
Measured by Cobb’s angle –>
Treatment
– Immature spine
• Brace if > 25o
– Mature spine
• Fusion if > 40o
Scoliosis
Kyphosis
Breast Disease
Nipple Discharge
• Normal
– Physiologic, pregnancy
• Spontaneous
– Papilloma 70%
– Ductal ectasia + fibrocystic disease (20%)
– Cancer 10%
• Workup
– Exam
– Mammogram
Breast Cancer: Epidemiology
•
•
•
•
The most common female non–skin cancer
The second most common cancer death (lung)
The most common cause of death in women 45–55
Known Risk Factors
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–
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Sex, age, genetics
Proliferative breast diseases with or without atypia
Lobular carcinoma in situ
Prolonged estrogen
• menarche, menopause, parity, exogenous
The National Surgical Adjuvant Breast Project
Antiestrogens and breast cancer
• The Study
– 13,388 woman at risk for breast CA
• Over 60 or 35–59 with 5–year risk > 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
Prognostic Factors for Breast CA
•
•
•
•
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Number of axillary lymph nodes
Tumor size
TNM stage
Histologic grade
Nuclear grade
Absence of estrogen and/or progestin receptors
HER–2 positivity (coded for by c-erbB-2 oncogene)
Treatment of Invasive Breast CA
• Breast Conserving Therapy (BCT)
– Excision with clean margins and XRT
• BCT vs. mastectomy
– disease–free survival
– overall survival
• Contraindications for lumpectomy
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Locally far advanced CA by exam or mammogram
Multicentric carcinoma
Persistent (+) margins during surgery
Pregnancy (1st and 2nd trimester)
CTD (esp. scleroderma)
Large tumor:breast ratio
Adjuvant Systemic Therapy
for Breast Cancer
• Indications for Chemotherapy
–Tumor > 2 cm or positive lymph nodes
• Indications for Hormone Therapy
–Receptor positivity
Family Hx Reasons to screen for BRCA1/2
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•
•
•
•
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BRCA 1 or BRCA 2 mutation
Breast AND ovarian cancer
Male breast cancer
> 2 members < 50 with breast cancer
Ashkenazi and > 1 members < 50 with breast cancer
Ashkenazi and ovarian cancer
Other Female Malignancies
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
Ovarian Neoplasms
• Epithelial (85%)
– 45:55 malignant (M) vs. benign (B)
– Serous (M=B) > mucinous (B)> 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), Sertoli–Leydig Cell (makes Tt),
ovarian fibroma, ovarian sarcoma
Ovarian Cancer: Management
• Surgery
– Debulking as much as possible
• Adjuvant chemotherapy
– If metastatic or high–risk
• Radiation Therapy
– Dysgerminomas
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
• Post–menopausal or heavy premenopausal
• Prognosis (5–year survivals)
– Stage 1 = 95%, Stage III–IV = 26%)
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, post–coital bleed, vaginal DC
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
Reproductive Endocrinology
and Gynecology
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
Menstrual Phases
Follicular Phase
Luteal Phase
Pituitary
FSH > LH secretion
LH surge (also FSH)
Ovary
Estradiol secretion
Prog > Est secretion
Follicular maturation
Ovulation–>corpus luteum
Proliferative
Secretory
Uterus
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
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 (> 80 ml)
• Metrorrhagia
– Bleeding that is prolonged menstrual or intramenstrual
• Menometrorrhagia
– Combination of the above
• Oligomenorrhea
– Cycles > 35d, often unpredictable
• Polymenorrhea
– Cycles < 21d – 24d
Uterine Leiomyomatas (Myomas, Fibroids)
•
Epidemiology
•
Anatomy
•
Pathogenesis
•
Symptoms
•
Diagnosis
•
Therapy
– 20% over 30, >40% over 40
– African American 3–6 fold higher
– Submucosal, intramural, subserosal, pedunculated, parasitic
– Estrogen dependent
– Abnormal uterine bleeding
– Pelvic pain, urinary frequency, rectal discomfort
– PE, US, hysterosalpingogram, hysteroscopy, MRI
– Hormones, minimally invasive surgery, myomectomy, hysterectomy
Endometriosis: Clinical
• Definition
– Presence of ectopic uterine mucosal tissue
• Locations
– Ovarian > uterine > ureterosacral ligaments, peritoneum,
retroperitoneum, bowel, pleura
• Pathogenesis
– Retrograde menstruation
– Vascular or lymphatic dissemination
– Coelemic metaplasia
• Symptoms
– Pain, dysmenorrhea, dyspareunia, abnormal uterine
bleeding, infertility
Endometriosis: Treatment
• Observation
• Hormonal
– OCPs, depo–provera, danazol, GNRH agonist, pregnancy
• Surgical
– Excision, fulguration, TAH–BSO
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
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 (non–functional)
Primary Amenorrhea
(No menarche by age 16, usually genetic or anatomic)
•
Chromosomal abnormalities (45%)
•
•
Physiologic delay in pregnancy (20%)
Müellarian agenesis (15%)
–
–
–
–
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
5–alpha reductase deficiency: 46 XY, female phenotype yet virilization after puberty
with deep voice, baldness, increase muscle mass
– 17–OHase deficiency: 46 XX or XY, cannot make gonadotropins, female with HTN
– Turner’s: 45 XO, streak ovary
– Absence of fallopian tubes, uterus, upper 1/3 vagina
• Transverse vaginal septum/imperforate hymen (5%)
• Hypothalamic GnRH deficiency (5%)
•
– 1o: congenital (with anosmia = Kallman’s)
– 2o: Anorexia nervosa, exercise, wt loss, stress, invasion
Hypopituitarism (2%)
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 (can’t measure GnRH)
• Low: stress?, low BW?, pit failure?
• High: Gonadal failure
– Check karyotype (XO or XY)
– Check prolactin and TSH
Secondary Amenorrhea
•
•
(No menses x 6 months or 3 cycles)
Pregnancy most common
Ovarian (40%)
–
–
–
–
Polycystic ovary syndrome (40%)
High testosterone –> anovulation, endometrial atrophy
Ovarian failure (if < 40 yo = primary)
Autoimmune oophoritis
• Hypothalamic (35%)
•
•
– Functional GnRH deficiency (same reasons as under 1o amenorrhea)
– Infiltrative
Pituitary (20%)
– Hyperprolactinemia (90%) –> decreased GnRH
– Empty sella, hypothyroidism, other pituitary tumors, Sheehan’s, infiltrative
Uterine (5%)
– Asherman’s (>90%), endometriosis
Approach to Secondary Amenorrhea
•
•
•
•
•
•
•
Rule out pregnancy
– ß–HCG
Physical exam
– R/O Asherman’s
Prolactin level
– If very high, CT or MRI of pituitary
TSH
– If very high = hypothyroidism
FSH and LH
– If very high = ovarian failure, if < 30 –> karyotype
– If low = stress?, low BW?, pit failure?
DHEA–S and testosterone
– Only if virilized, looking for PCOS
17OH–progesterone
– Looking for congenital adrenal hyperplasia
Progestin Withdrawal Test
• If bleeding occurs
– Uterus and endometrium are intact
– Estrogen is sufficient, progesterone was lacking
– Anovulation
•
• Hypothalamic dysfunction (stress)
• Polycystic ovarian syndrome
• Late–Onset Congenital Adrenal Hyperplasia (17–OH)
If bleeding does not occur
–
–
–
–
Insufficient estrogen or uterine cause
Hypothalamic dysfunction (stress)
Pituitary dysfunction
Uterine cause
Geriatrics
Pathophysiology of Bedrest
•
Pulmonary
– Decreased oxygenation
– Decreased ability to clear
secretions
•
Vascular
– Venous stasis –> DVT –> PE
– Orthostasis
•
Skin
– Pressure ulcers
•
Musculoskeletal
– Atrophy and contractures
– Osteoporosis
•
Electrolytes
– Hypercalciuria –> stones
•
Gastrointestinal
– Reflux esophagitis
– Constipation
– Anorexia
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 –> corneal irritation
• Illumination disturbances
– Require more light yet more glare
– Poor night vision
Geriatrics: Hearing Changes in the Elderly
• Presbycusis
– Age–related hearing loss, usually > 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
Neurology
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
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
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 > Ach = hyperkinetic
– Ach > Dopamine = hypokinetic
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
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
Lower Motor Neuron (Peripheral) Weakness
•
•
•
•
•
•
Anterior horn cell to muscle
Muscle atrophy
Fasciculations and fibrillations
Decreased/absent reflexes
Flaccidity
Cramping
UMN vs. LMN Weakness
Location
Muscle size
Reflexes
Fasciculations
Tone
UMN
LMN
Cortex –> SC
Normal
Increased
Absent
Clasp knife rigidity
Ant. horn cell–>muscle
Atrophic
Decreased
Present
Decreased (flaccid)
Babinski’s 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
Guillain–Barré 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
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 DTR’s
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, Eaton–Lambert
• Clinical Manifestations
– Proximal > distal muscle weakness
– No sensory loss
– Preservation of reflexes
Brain Edema
Increased brain volume due to increased water content
Vasogenic
Pathophysiology Endothelial
injury
Causes
Tumor
Infection
Trauma
Infarct
HTN
Therapy
Steroids
Cytotoxic
Interstitial
Neuronal
injury
Hypoxia
Hypoosmo–
larity
Pressure
None
Shunt
Hydrocephalus
Meningitis
Aphasia
• Definition
– Disorder of language due to brain dysfunction
• Classification
– Expressive (Broca)
– Receptive (Wernicke)
– Global
• Other Characteristics
– Fluent vs. non–fluent
– Comprehension
– Repetition
Memory Types
•
Episodic
– Memory of events
• Remote (mos to yrs), long–term 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 lose
test via digit repetition
•
•
– Easiest to lose
Semantic
– Memory of words and meanings
– Test via naming of objects or persons
Procedural
– Skills
– Toughest t lose
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
Acute Pain Types
• First pain
– A–delta fibers
– Immediate, brief, sharp, localized
• Second pain
– C fibers
– Seconds later, enduring, dull/burning, not localized
Pain Pathways
•
Ascending Pathway
– Pain receptors
– Synapse in dorsal horn
– Cross to form ascending
spinothalamic tract
– Thalamus
• Lateral thalamic nucleus
– To somatosensory cortex –>
“feel” pain
• Medial thalamic nucleus
– To frontal cortex –>
“realize” pain
•
Descending Pathway
– Periaqueductal gray region
• Serotonin
• To frontal cortex
– Suppress response to pain
• To spinal cord
– Suppress sensation of pain
Diseases of the Pain Pathways
• Reflex Sympathetic Dystrophy (Causalgia)
– Post–nerve 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 non–noxious stimuli
– Rx: SSRIs
Myasthenia Gravis
•
Pathophysiology
•
Clinical Manifestations
•
Diagnosis
•
Therapy
– Autoimmune destruction of post–synaptic neuromuscular junction
nicotinic acetylcholine receptors (AchRs)
– Antibody binds and induces cell mediated attack
– Accelerated loss of AchRs
– Weak: proximal muscles, eye lids and EOM, cranial nerves, diaphragm
– Improvement after acetycholinesterase inhibitor (edrophonium,
Tensilon®) challenge
– EMG: Decrement in action potentials with repetitive stimulation
– Assay for anti–acetylcholine receptor antibodies (80–90% +)
– Long acting acetylcholinesterase inhibitors, steroids, cytotoxics,
thymectomy, plasmapheresis, IVIG
Duchenne Muscular Dystrophy
•
•
•
Pathophysiology
– Variable mutations of dystrophin gene at Xp21 locus (X–linked rec)
– Dystrophin protects sarcolemmal membrane from degradation by
intracellular proteases, absence –> muscle necrosis, Ca influx
Clinical Manifestations
–
–
–
–
–
–
Male onset ~2–3 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
Duchenne Muscular Dystrophy
Gower’s Sign
Calf pseudohypertrophy
Polymyositis
•
Pathophysiology
•
Clinical Diagnostic Findings
•
Dermatomyositis
•
Therapy
– T–cell mediated muscle injury
– Secondary Ab formation (Jo–1, Mi–2, SRP)
–
–
–
–
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
– Gottron’s papules and heliotrope eyelids
– Humorally mediated vasculitis
– Adult form associated with malignancy
– Steroids, cytotoxics, plasmapheresis, IVIG
Dermatomyositis
Gottron’s papules
Heliotrope eyelids
Myophosphorylase Deficiency
(McArdle’s Disease)
•
Pathophysiology
– Autosomal recessive mutation of myophosphorylase gene on 11q13
– Phosphorylase removes 1,4 glucosyl residues from glycogen releasing
G–1 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
Tremor Characteristics
• To–and–fro oscillation around a joint
• Regular or irregular
• Predictable and simple
Resting (Repose) Tremor
• Characteristics
– Occurs with inactivity of limb
• Examination
– Resting hand = pill rolling
– Resting tongue
• Etiology
– Parkinsonism (4 – 6 Hz)
• Parkinson’s disease, heavy metal toxicity (Fe, Cu), drug (MPTP)
– Midbrain stroke
• Treatment
– Dopamine agonists
Parkinsonism
• Classical Characteristics
–
–
–
–
Bradykinesia
Tremor (4–6 Hz, initially unilateral)
Cogwheel rigidity
Loss of postural reflexes
• Etiology
– Death of dopaminergic neurons in substantia nigra
– Dopamine antagonists
• Therapy
–
–
–
–
L–dopa, dopamine agonists
Amantadine (blocks DA re–uptake)
COMT inhibitors
Selegeline (MOA inhibitor)
Intention (Action) Tremor
• Characteristics
– Occurs with action of an extremity
• Examination
– Finger–to–nose and heel–to–shin test
• Etiology
– Cerebellar disease (3–4 Hz)
• EtOH, trauma, stroke, tumor, degeneration, MS
– Midbrain stroke
• Treatment
– Physical therapy
Postural Tremor
•
Characteristics
•
Examination
•
Etiology
– Occurs with antigravity posturing
– Outstretched arms and fingers
– Tongue protrusion
– Exaggerated physiologic tremor (10–12 Hz)
• Catecholamine excess:
– Endocrine: pheo, hyperthyroid, hypoglycemia
– Drugs: ß–agonists, reuptake inhibitors, xanthine oxidase inhibitors, catecholamines
– Stress
– Essential tremor (4–10 Hz)
•
• Etiology unknown
• 50% inherited (familial tremor)
Treatment
– ß–blockers, EtOH, primidone
Tremor Summary
Tremor Type
Frequency
Cause
Treatment
Resting
Action
Postural
Exaggerated
physiologic
Essential
4 – 6 Hz
3 – 4 Hz
Parkinson’s Dopaminergics
Cerebellar None
10 – 12 Hz
Catechols
4 – 10 Hz
Unknown
Treat cause
ß–blockers
ß–blockers,
primidone
• Definition
Chorea
– Irregular, unpredictable, random, rapid, jerky
• Pathophysiology
– Dopamine excess in striatum
– Estrogen effect (mild)
• Etiology
– Huntington’s disease (and misc. hereditary
forms)
– Sydenham’s chorea (acute rheumatic fever)
– Cerebral palsy
– Pregnancy, OCP’s
• Treatment
– Dopamine antagonists
Huntington’s Disease
• Etiology
–
–
–
–
Autosomal dominant progressive chorea and dementia
Defective huntingtin protein (chromosome 4)
Degeneration of cholinergic and GABA–ergic cells in BG
Relative excess dopamine
• Manifestations
– Middle age onset
– Chorea
– Violent outbursts, psychosis, withdrawal
• Treatment
– Dopamine antagonists
– Genetic screening
Tardive Dyskinesia
• Pathogenesis
– Chronic (> 6 weeks) exposure to dopamine antagonists
– Hypersensitive striatal dopamine receptors
• Clinical Manifestations
– Orofacial repetitive movements
– Limb and trunk involuntary movements
• Treatment
– Discontinue neuroleptic
– Reserpine
Hemiballismus
• Definition
– Violent, sudden, large amplitude, unilateral gyrations
• Pathophysiology
– Stroke in subthalamic nucleus
• Treatment
– Dopamine antagonists, usually resolves in several months
Tics
• Definition
– Brief, stereotypic, suppressible
– May be vocalizations, swearing, gestures
– Worse with stress
• Pathophysiology
– Unclear
– Dopamine excess causing disinhibition of limbic system
• Treatment
– Time
– Dopamine antagonists
• Definitions
Dystonias
– Sustained, involuntary contractures
– Focal: cervical (torticollis), fingers (writer’s cramp),
orbicularis oculi (blepharospasm)
– Generalized
• Etiology
– Often occupational, worse with stress
– Some focal are hereditary
– Generalized may be due to central lesions
• Treatment
– Anticholinergics
– Botulinum toxin injections
Bedside Visual Field Testing
•
•
•
Macular Function Testing
– Visual acuity: form (letter) discrimination (Snellen)
– Color vision testing: subjective red discrimination
Peripheral Visual Field Function Testing
– Motion detection
– Light detection
– Dynamic perimetry: confrontational or Goldmann
Higher Cortical Function Testing
–
–
–
–
–
Object recognition
Object sorting
Face recognition
Visual–motor coordination
Geographic directions
Neuroanatomy of the Visual System
•
Anterior visual pathway
– Carries axons from retinal ganglion cells to lateral geniculate bodies
• Optic nerves –> chiasm –> tracts –> LGN
• Nasal fibers cross at chiasm, lesion there gives bitemporal hemianopsia
• Tracts carry fibers from one side of each eye –> lesion gives homonomous hemianopsia (e.g.
L sided lesion gives a R homonomous hemianopsia)
• Posterior visual pathway
– –> radiations –> occipital lobe –> calcarine/peristriate/parastriate cortex–> occipital
cortex (Brodmann 17)
•
Examination
– Foveal functions: VA, color, contrast
– Retina/optic nerve: visual fields
Total Blindness
• Loss of function of both globes/retina/optic nerves
• Chiasmal destruction
• Bilateral occipital lobe infarction
Partial Blindness
• Scotoma
– Non–seeing visual field surrounded by seeing visual field
– Same stimulus
• Hemianopsia
– Visual loss with a vertical margin
• Central loss
– Poor acuity, color
– Do not act blind
• Peripheral loss
– VA OK
– Act blind
– Subjective dimness
Occipital Blindness
• Blood Supply
– Medial surface from PCA
– Pole supplied by MCA
• Infarction
– Usually spares the macula
• Hypoperfusion
– Usually spares the periphery
Endocrinology
Hypothalamic Hormones
Hormone
TRH
GnRH
CRH
GHRH
SS
PIF
PRF
Structure
3 aa
10 aa
41 aa
40 + 44 aa
14 + 28 aa
DA
?
Made
A. HT
A. HT
CNS
Arcuate n.
CNS
CNS
CNS
Effect
TSH, Pl, GH
FSH, LH,GH
ACTH, ß–end
GH, eat, sleep
GH,TSH,ADH,TSH
Prolactin
Prolactin
(–) Feedback
TSH
Est, Pr, GC
GC
GH, IGF1,SS
Many
Hypopituitarism
• Etiologies
– Tumor, ischemia, genetic, vascular, infiltration, inflam,
iatrogenic, infection, trauma
• Diagnosis
– Basal hormone levels and target gland hormone levels
• Therapy
–
–
–
–
–
–
ACTH deficiency: GC, ± MC
TSH deficiency: thyroxine
FSH/LH deficiency: Est/Prog/Tt
GHRH deficiency: hGH in children
Prolactin: none
Vasopressin: DDAVP
Pituitary Tumors
Secretion
Disease
Diagnosis
Therapy
None
GH
Prolactin
ACTH
TSH
LH/FSH
± hypopituitarism
gigantism/acromegaly
galact/infertility/impot
Cushing’s disease
hyperthyroidism
may be none
Levels/MRI
Post glu GH, IGF1
Pro level > 250ng/ml
Dex suppress
TSH and T4
Levels
surgery, XRT, drugs
surgery, drugs, XRT
drugs, surgery, XRT
surgery, drugs, XRT
surgery, XRT/drugs
surgery, XRT/drugs
Regulation of Body Calcium
• Basic Distribution
– Total body = 1–2 kg: 99% bone
– In blood, 50% ionized, ~50% bound to albumin
• Hormonal Control
Hormone
PTH
Vitamin D
Calcitonin
Bone
Release
Sl. release
Incorp.
Renal
Reabsorp
Excretion
Excretion
Small Bowel
Absorption
Absorption
None
Manifestations of Hypercalcemia
•
•
•
•
Neuropsychiatric
– Altered MS
Gastrointestinal
– Anorexia, N+V, constipation
Cardiovascular
– Short QT
– Increased contractility
– Digitalis toxicity
Renal
–
–
–
–
Nephrogenic DI
Impaired GFR
Nephrocalcinosis
Nephrolithiasis
Causes of Hypercalcemia
•
Endocrine
–
–
–
–
–
Hyperparathyroidism
Hyperthyroidism
Addison’s disease
Pheochromocytoma
Familial hypocalcuric hypercalcemia
• Malignancy
•
– Metastases
– Ectopic PTH, PTHrP, 1,25(OH)D
Granulomatous Diseases
– Sarcoidosis
– TB
– Fungal
•
Miscellaneous
–
–
–
–
Immobilization
Acute renal failure
Milk–alkali syndrome
Medications
•
•
•
•
•
Thiazides
Lithium
Vitamin A
Vitamin D
Aminophylline
Primary Hyperparathyroidism
•
Epidemiology/Etiology
– 1–2/1,000/yr > 60yo
– Single adenoma 85%, 4 gland hyperplasia 12%, CA 3%
•
Associations
– MEN 1: 95% hyperplasia + pancreatic and pituitary tumors
– MEN 2A: 50% hyperplasia + medullary CA thyroid and pheo
•
Biochemical Features
– Serum: high Ca and Cl, low P and HCO3, high PTH, high alk phos
– Urine: high calcium, phosphorus and cAMP
Non–Primary Hyperparathyroidism
•
Secondary
– Etiology
• Renal failure or malabsorption –>
hypocalcemia –> increased PTH
– Diagnosis
• High serum PTH with low/nml Ca
• High phosphorus
• Low 25 or 1–25 OH D3
– Therapy
• Calcium supplements
• Calcitrol (1–25 OH D3)
•
Tertiary
– Etiology
• Renal failure –> chronic
hypocalcemia –> chronic
increased PTH –> permanent
parathyroid hyperplasia
– Diagnosis
• High serum PTH with high Ca
– Therapy
• As for secondary
• Surgery if severe or symptomatic
Hyperparathyroidism Summary
Type
Primary
Secondary
Tertiary
Primary Event
PTH autonomy
Low serum Ca
PTH autonomy
Serum PTH
Elevated
Elevated
Elevated
Serum Calcium
Elevated
Low/normal
Elevated
Evaluation of Hypercalcemia
• Required
– Serum Ca, PTH, 24h urine Ca
• Only if indicated
–
–
–
–
PTHrP
Vitamin D levels
Vitamin A level
Lithium level
Therapy of Hypercalcemia
• Specific therapy
– Treat underlying disorder
• Nonspecific therapy
–
–
–
–
–
–
NS hydration
Loop diuretics
Biphosphonates
Calcitonin
Glucocorticoids
Gallium nitrate
Multiple Endocrine Neoplasia Syndromes
General Rules
•
•
•
•
Autosomal Dominant inheritance
Hyperplasia precedes neoplasia
Tumors usually multifocal
Familial screening critical
Multiple Endocrine Neoplasia Syndromes
•
MEN 1
– Primary hyperparathyroidism (~100%), from hyperplasia
– Pancreatic tumors (50–70%)
• Gastrinoma > insulinoma, VIP, glucagonoma, PP, non–secreting
– Pituitary tumors (50%)
• Prolactin > GH, ACTH, null cell
•
MEN 2a
•
MEN 2b
–
–
–
–
Medullary CA thyroid (>90%)
Pheochromocytoma (40–50%)
Primary hyperparathyroidism (10–50%), hyperplasia
Cutaneous lichen amyloidosis
– Medullary CA thyroid (>90%)
– Pheochromocytoma
– Mucosal neuromas, intestinal ganglioneuromas, marfanoid
Osteoporosis: Etiology
• Epidemiology
– 1/3 and 1/6 of elderly men and women –> hip Fx
– > 25 million people in US
• Risk factors
–
–
–
–
–
Behavioral: inactivity, EtOH, smoking
Nutritional: low Ca or vitamin D intake, caffeine, low body mass
Hereditary: Caucasian/Asian, family history, body build
Gender related: female, early menopause
Medications: GC, thyroxine, anticonvulsants, heparin/warfarin, MTX,
cyclosporin, GnRH, lithium
– Endocrine: Cushing’s, hypogonadism, hyperthyroidism,
hyperparathyroidism
– End organ: Renal, liver
– Bone resorption: RA, immobilization
Osteoporosis: Diagnosis and Treatment
• Diagnosis
– Bone densitometry
– T score = SD above or below mean of sex–matched young adults
• Normal > –1.0, osteopenia –2.5 to – 1.0, osteoporosis < –2.5
• Treatment
– Lifestyle modification: exercise, dietary Ca and vitamin D, stop
smoking and EtOH and caffeine
– Medications: Estrogens, Ca, vitamin D, calcitonin, biposphonates,
SERMs
Iodine Metabolism
• Requirements and bioavailability
– Requirement = 60 µg/d
– Typical intake = 250–300 µg
– 20% thyroid uptake, rest excreted in urine
• Thyroid hormone synthesis
–
–
–
–
>90% organified: bound to tyrosine on thyroglobulin
Forms monoiodotyrosine and diiodotyrosine
These are enzymatically coupled to form T3 and T4
Digestion of thyroglobulin releases T3 and T4
Thyroid Hormones
Creation
Activity (T4=1)
T1/2
Thyroxine
T4
Thyroid 100%
1
5–7d
Triiodothyronine Reverse T3
T3
RT3
T4 80%
T4 > 90%
Thyroid 20%
10
0
1d
4h
Thyroid Hormone Regulation
• Increased by
– TSH
• Increases I uptake, digestion of Tg, release of T4 and T3
– Iodine deficiency
• Enhanced response to TSH
• Decreased by
– Iodine excess
• Reduces organification (Wolff–Chaikoff effect)
• Decreases secretion of T4 and T3
Hypothalamic TRH Regulation
• Increased by
– Catecholamines
• Decreased by
– T4 and T3
– Somatostatin
Pituitary TSH Regulation
• Increased by
– TRH from hypothalamus
• Increased production and release
• Decreased by
– T3
– Dopamine
– Glucocorticoids
Radioactive Iodine Uptake
•
Methodology
– Oral radiolabeled I, scan thyroid and determine amount of uptake
•
Use
– Determines etiology of hyperthyroidism
• If high: increased production = Grave’s, Hashimoto, Plummer’s, adenoma, TSH
• If low: inflammatory release = subacute thyroiditis; exogenous thyroid hormone
– Helps calculate dose of radioactive iodine ablative therapy
– Evaluates suppressibility of thyroid
Hyperthyroidism: Clinical Manifestations
•
General
•
Cardiovascular
•
Neurologic
•
GI
•
Reproductive
•
Lab
– Weakness and fatigue
– Palpitations, tachycardia, (atrial fibrillation)
– Nervousness, tremor, (psychosis)
– Sweat, heat intolerance
– Insomnia
– Weight loss with decreased appetite, hyperdefecation
– Oligo–amenorrhea, infertility, gynecomastia
– Anemia, low chol, high alk phos, high Ca
Etiologies of Hyperthyroidism
• Graves’ Disease
–
–
–
–
Thyroid stimulating immunoglobulin –> TSH receptor
Diffuse toxic goiter, high RAIU, T4, low TSH
Ophthalmopathy and pretibial myxedema
Associated with MG, vitiligo, ITP
• Plummer’s Disease
– Elderly, etiology not clear
– Toxic multinodular goiter, high RAIU, T4, low TSH
• Subacute (de Quervain’s) Thyroiditis
– Destructive release of T4, PAINFUL, fever, high ESR
– Viral infection in many cases
– low RAIU, T4, low TSH
Etiologies of Hyperthyroidism
• Lymphocytic thyroiditis
– ? Variant of Hashimoto’s, may be post–partum
– Painless, low RAIU, high T4, low TSH
– Antithyroid antibodies in 50%
• Toxic Adenoma
– Nodule > 3cm, high RAIU, high T4, low TSH
– Focal scan uptake
• Factitious
• Jod Basedow
• TSH or TRH secreting tumors
Hypothyroidism: Clinical Manifestations
•
•
•
General
•
•
•
GI
– Weakness and fatigue, muscle cramps
Cardiovascular
– Bradycardia
Neurologic
–
–
–
–
–
Slow mentation, (psychosis)
Dry skin from decreased sweating
Cold intolerance
Carpal tunnel syndrome
Pituitary enlargement
– Weight gain, constipation
Reproductive
– Oligo–amenorrhea, infertility, galactorrhea
Lab
– Anemia, hi CPK, high chol and TG, low Na
Etiologies of Hypothyroidism
•
•
•
•
Hashimoto’s thyroiditis (chronic lymphocytic)
– Autoimmune destruction, may be initially hyperthyroid
– Antibody to thyroperoxidase (90%) and thyroglobulin (70%)
– Associations: Addison’s (Schmidt syndrome), PA, DM
Iatrogenic
– Post–surgery or RAI for hyperthyroidism
– Post XRT for Hodgkin's or head/neck CA
– Drugs: lithium, aminoglutethimide, amiodarone
Miscellaneous
– Postpartum, burnt–out Graves’, iodide excess, gland replaced,
congenital absence or mutations
Rare
– Iodine deficiency, TSH blocking Ab
Thyroxine Therapy
• Slower if
– Older, severe, long–standing
• Dose
– Maintenance = 50–175 µg/day (< if old)
– Measure TSH in 4 – 6 wks
• Things to watch for
– Addisonian crisis
– Angina
Euthyroid Sick Syndrome
• Thyroid Function Abnormalities
–
–
–
–
Decreased conversion of T4 to T3 –> low T3
May see low T4 and rarely low FTI
rT3 usually high
TSH usually low or normal
• Treatment
– NONE
Drug Effects on Thyroid Function
•
•
•
•
TSH Secretion
– Decreased: Dopamine, GC, somatostatin
T4 and T3 production
– Increased: I (acutely), amiodarone
– Decreased: Li, I, amiodarone, aminoglutethimide
– Increased metab: phenobarb, carbamazepine, dilantin
T4–>T3 conversion
– Decreased: ß–blockers, amiodarone, ipodate, PTU, GC
TBG production
– Increased: Est, tamoxifen, clofibrate, 5FU, narcotics
– Decreased: androgens, anabolic steroids, GC
– Displaces: ASA, dilantin, furosemide, fenclofenac, phenylbutazone
Cushing’s Syndrome: Manifestations
(glucocorticoid excess)
•
History
– Wt gain, weak, fatigue
– Acne, hirsuitism, bruising, poor
healing
– Infertility, amenorrhea
– Emotional lability
– Fractures
•
Physical Exam
– Truncal obesity
– SC, temporal and dorsal fat
pads increased
– Moon facies
– Plethora
– Striae
– Proximal muscle weakness
– Hypertension
Cushing’s Syndrome: Laboratory
•
•
•
•
•
Glucose intolerance or diabetes
Hypokalemic metabolic alkalosis
Hypercalcuria ± hypercalcemia
Polycythemia
Decreased lymphocytes and eosinophils
Cushing’s Syndrome: Etiologies
•
ACTH Dependent
– Pituitary Tumor (Disease)
• ACTH secreting tumor
• ACTH suppressible by high dose
dexamethasone
– Ectopic ACTH
• Small cell CA lung
• Carcinoid
• Not suppressible
•
ACTH Independent
– Exogenous steroids
– Adrenal sources
• Adenoma
– Most common; surgical cure
• Carcinoma
– May secrete other steroids
• Micronodular hyperplasia
• Macronodular hyperplasia
Cushing’s Syndrome: Diagnostic Tests
•
Elevated spot cortisol
•
– Many false (+)
•
Elevated 24h urine free cortisol
– > 250 µg, < 65 µg r/o Cushing’s
– Best screen (have creat also)
•
•
Overnight dex suppression
– 1 mg at MN –> AM cortisol
– < 5 µg/dl r/o Cushing’s
– F(+); obesity, depression
•
Low–dose dex suppression
– 0.5 mg q6h x 2d
– Measure 24h urine and AM
cortisol on 2nd day
– < 25µg and 5 µg/dl
High dose dex suppression
– 2 mg q 6h x 2d
– Measure 24h urine cortisol
baseline and on 2nd day
– If suppresses > 50% = pituitary
– If not = ectopic
ACTH
– Differentiates dependency
Cushing’s Disease: Therapy
• Surgery
– Adenectomy
– Hypophysectomy
– Adrenalectomy + XRT
• Medical (adjunctive)
– Decrease ACTH: Bromocriptine, cyproheptadine, valproate
– Decrease cortisol: ketoconazole, metyrapone,
aminoglutethimide, and others
– Block cortisol effect: RU456
• XRT
Adrenal Insufficiency: Manifestations
• History
– Anorexia, nausea
– Weak, fatigue
• Physical Exam
– Hypotension, orthostasis
• Laboratory
– Low Na, high K (not seen if secondary), low glucose
– Eosinophilia
• ACTH stim test:
– ACTH (1–24) (cosyntropin) 250 µg IV, measure cortisol in
30–60 min. (+) if < 18 µg/dl
Diabetes Mellitus: Diagnostic Criteria
Any one of the following:
• Symptoms and a casual plasma glucose of 200 mg/dl
– Symptoms = polyuria, polydipsia and weight loss
– Casual = any time, no relation to food
• Fasting plasma glucose of 126 mg/dl
– Fasting = no caloric intake for 8 hours
• 2–hour plasma glucose of 200 mg/dl on an oral GTT
– Glucose load of 75 mg of anhydrous glucose in water
Diabetes Care 21:S5–19, 1998.
Type I Diabetes Mellitus
• Pathophysiology
–
–
–
–
–
Antibody–mediated destruction of ß cells (Type 1A)
Idiopathic destruction of ß cells (Type 1B)
Genetic predisposition (HLA–DR3 and DR4)
Twin concordance < 50%
“complete” absence of insulin
• Hyperglycemia, weight loss, ketoacidosis, polys
• Other causes
– Surgical removal or gland injury
– Fibrocalcific/fibrocalculus pancreatic disease
Type II Diabetes Mellitus
•
Epidemiology
•
Pathophysiology
•
Risk factors
– > 10% of US population
– Insulin resistance (post–receptor cascade)
– Decreased insulin response to plasma glucose
–
–
–
–
–
–
–
–
Family Hx
> 20% above ideal BW
Age > 45
Prior glucose intolerance or gestational DM
Hypertension
HDL < 35 mg/dl or triglyceride > 250 mg/dl
Sedentary life style
Baby > 9 lbs
Diabetes Mellitus: Complications
•
•
•
•
•
•
Vascular (micro and macro)
Renal
Retinopathy
Joint/connective tissue
Periodontal
Neurologic
Chronic Therapy of Diabetes
• Diet and Exercise
– Attempt to maintain a reasonable (not ideal) weight
– 60% CHO, 10–20 % ptn, 20–30% fat, < 10% saturated fat
• Insulin
– Required for all type I diabetics
Name
Onset
Peak
Duration
Monemeric (Lispro)
Regular
NPH/Lente
Ultralente
Glargine
3–4 h
4–8 h
16 h
24 h
> 24 h
10–15 m
30 m
40–60 m
50–70 m
70 – 105 m
60 m
2h
6–10 h
12 – 16 h
none
Drugs For Type II Diabetes
• Sulfonylureas
– Stimulates insulin release
• Biguanides
– Improve peripheral sensitivity to insulin
• Thiazolidones
– Improve peripheral sensitivity to insulin
• Meglitinides
– Stimulates insulin release
• Glucosidase Inhibitors
– Interfere with absorption of carbohydrates