Day 8.2 MSK Flashcards
What are the layers of the epidermis?
From surface to base: Californians Like Girls in String Bikinis Stratum Corneum Stratum Lucidum Stratum Granulosum Stratum Spinosum Stratum Basalis
In psoriasis, how do the layers of the epidermis change?
Stratum spinosum thickness increases (this is what makes the plaques)
Stratum Granulosum thickness is decreased.
List the epithelial cell junctions
Zona occludens (tight jn) Zona adherens (intermediate jn) Macula adherens (desmosome) Gap jn Hemidesmosome
In which layer of skin are the blood vessels located?
in the dermis. nutrients get to the epidermis by diffusion.
Zona occludens
aka Tight Junction
At the top of the sides bt epithelial cells.
Prevents diffusion across the paracellular space
Made of claudins and occludins
Zona adherens
aka Intermediate Junction
bt the sides of the epithelial cells, just below the zona occludens (tight jn)
E-cadherens in the cell mbr connect to actin fillaments in the cell.
Cadherens are Ca2+dependent Adhesion molecules.
Macula adherens
aka Desmosome
On the sides bt 2 epithelial cells
sml, discrete sites of attachment, cadherins connect to intermediate filaments.
Desmoplakin connects to keratin in the cell.
Gap jn
Allows adjacent cells to communicate for electric and metabolic fns (heart cells, myocytes)
Md of connexon w central channel
Hemidesmosome
Connects epithelial cells to underlying basement mbr/extracellular matrix
Integrin maintains integrity of the BM, binds to the laminin in the BM.
Anti-hemidesmosome Ab
Bullus pemphigoid
Anti-desmosome Ab
Pemphigus vulgaris
Desmosome vs Hemidesmosome
Desmosome is on the side, bt epithelial cells
Hemidesmosome is on the bottom, bt one epithelial cell and the BM.
Anti-desmosome Ab = pemphigus vulgaris
Anti-hemidesmosome Ab = bullous pemphigoid
Unhappy triad
Knee injury
Hitting knee from lateral side (football)
Dmg to:
1. MCL (medial collateral ligament)
2. ACL (anterior cruciate ligament)
3. Lateral (56%) or Medial (44%) meniscus
Positive anterior drawer sign indicates tearing of the ACL (tibia comes anterior to the femur)
Abn passive abduction indicates a torn MCL (Lachman Test)
What are the 4 ligaments of the knee?
Anterior cruciate ligament
Posterior cruciate ligament
Lateral collateral ligament
Medial collateral ligament
Note: “anterior” and “posterior” refer to where the ligament is attached on the TIBIA. (so attached to ant tibia or attached to post tibia)
Where is the pudendal nerve blocked during delivery? (external landmark)
at the ischial spine (palpate thru vag)
Where is the appendix located? (external landmark)
McBurney’s point: 2/3 of the way from the umbilicus to the ASIS (anterior superior iliac spine)
External landmark for lumbar puncture
Level of iliac crest = L4
What are the rotator cuff muscles?
SItS: Supraspinatus Infraspinatus teres minor Subscapularis
Action of supraspinatus m
helps deltoid abduct arm- does first initial 10-15degrees of abduction
Action of infraspinatus m
laterally rotates arm
Action of teres minor m
adducts and laterally rotates arm
Action of subscapularis
adducts and medially rotates arm
Which is more anterior, the acromion or the coracoid?
coracoid
Impingement in rotator cuff
Supraspinatus (which is the rotator cuff muscle that is on top) is commonly impinged by the acromion d/t repetitive overhead activity (swimming/tennis) which causes hypertrophy of the muscle, or can also be congenital.
Dx by Empty Can Test- turn thumb downward (like emptying a can), and if it’s painful to abduct the first 10-15degrees, it’s impingement.
Repetitive elbow trauma
Degenerative injury d/t repeated use- leads to tiny tears in tendons and muscles. Can be inflammatory: Lateral epicondylitis (tennis elbow) Medial epicondylitis (golf elbow)
What structures can be dmgd in anterior shoulder dislocation?
Axillary Nerve
Posterior Circumflex Artery
Supraspinatus tendon
Bankhart lesion: anterior glenohumeral ligaments and glenoid labrum separate from articular surf of the anterior glenoid neck
Hill-Sack lesion: compression fracture- chip in posterolateral head of humerus d/t abrasion against anterior rim of the glenoid (hitting it against the rim during the dislocation)
Dislocated vs separated shoulder
Dislocated - head of humerus rotates out of glenoid cavity
Separated: clavicle separates from acromion and coracoid process of the scapula
What is leukocyte extravasation?
Neutrophils exit blood vessels at site of tsu injury/inflam.
4 steps- rolling, tight binding, diapedesis, migration.
Leukocyte extravasation: Rolling
first step.
PMLs express Sialyl Lewis-X
Endothelial cells express E-selectin on their surfaces.
E-selectin grabs the SL-X and causes the PML to “roll” along the surface.
Other adhering molcules include P-selectin, which is found 2 different places- expressed by endothelial cells, and also expressed on platelet surfaces. Also L-selectins are expressed on the surface of lymphocytes.
What enhances the synthesis/expression of endothelial adhesion molecules (E-selectin)
Acute phase cytokines: IL-1, IL-6, TNFa
Leukocyte extravasation: tight binding
2nd step.
Endothelial cells express ICAM-1
Leukocytes/PMNs express LFA-1, aka integrin.
ICAM binds integrin tightly, securing the PMN to the endothelial surface
(integrin integrates)
Leukocyte extravasation: Diapedesis
3rd step.
Leukocyte squeezes bt endothelial cells and exits the blood vessel into the interstitum.
PECAM-1 (aka CD31) on the endothelial cells and PECAM-1 (CD31) on the leukocyte mediate this.
Leukocyte extravasation: Migration
4th (last) step Leukocyte travels thru interstitum to the site of injury or infection, guided by chemotactic signals. Bacterial products in the interstitum/at the site of injury serve as chemotactic factors: CILK C5a IL-8 LTB4 Kallikrein
What factor enhances the process of binding, diapedesis, and migration?
Platelet Activating Factor (PAF)
What dz is caused by abnormal integrin?
Leukocyte adhesion syndrome
No integrin on leukocytes means they can’t tight bind with ICAM-1 on the endothelial cells.
Px: delayed separation of the umbilicus
How is muscle contraction initiated (how is Ca2+ released)?
First, an AP depolarization opens up the voltage-gated Ca2+ channels, causing NT rls. NTs bind to the post-synaptic cell and lead to muscle cell depolarization in the motor end plate. The depolarization travels along the muscle cell down T-tubules, and depolarizes voltage-sensitive dihydropyridine recetors, causing them to release Ca2+. That Ca2+ causes the ryanodine receptors on the SR to release Ca2+ (calcium-induced calcium rls). And, contraction can start.
How does muscle contraction take place, once Ca2+ has been rlsd from the SR?
The rlsd Ca2+ binds to troponin C, which is attached to the tropomyosin and moves it out of the way so that the myosin-binding groove on actin filaments is uncovered. Myosin (which is bound to ADP and Pi) attaches to the actin. Myosin rls’s the Pi and the ADP and does the power stroke (this is muscle contraction!)
After, ATP binds to the myosin, releasing it from the actin (relaxation).
Z line
end of the sarcomere unit (where 2 sarcomere units meet) (looks like ric-rac)
M line
middle of the sarcomere
middle of the thick myosin filament
A band
the length of the thick myosin filament (regardless of overlap of thick/thin fibers)- this always stays the same length (bc the myosin fiber itself can’t change lengths!)
H band
the part of the sarcomere that is only thick filament. (centered around the M line). When the sarcomere contracts toward the M line, the H band gets smaller as the thick and thin filaments overlap (because there is less length that is only thick filaments)
I band
the part of the sarcomere (and the one next to it) that is only think filaments. has the Z line (sarcomere boundary) in the middle. During muscle contraction, it gets shorter as the thick myosin and thin actin overlap.
Thick filaments, thin filaments
Thick filament - myosin
Thin filament - actin
Titin
long large molecule that anchors myosin to the z-line of the sarcomere.
How does muscle contraction affect the various bands of the sarcomere?
The H and I band shorten
The A band is Always the same length.
HIZ shrinkage.
What in initiation of muscle contraction, what blocks the rls of Ca2+ from dihydropyridine receptors?
Dihydropyridine CCBs:
Nifedipine, Amlodipine, etc
During initiation of muscle contraction, what blocks the rls of Ca2+ from the SR thru the Ryanodine receptors?
Ryanodine receptors are blocked by Dantrolene.
Dantrolene stops muscle contraction in NMS (neuroleptic malignant syndrome) and in malignant hypothermia
Type I muscle fibers
Slow twitch
Red fibers, bc incrsd mito and myogloblin concentrations (this means increased oxidative phosphorylation), which leads to
Sustained contraction.
“One slow red ox”: type 1, slow twitch, red fibers, ox-phos
Type II muscle fibers
Fast twitch White fibers (bc there is not much mito or myogloblin)- this means there is more anaerobic glycolysis. Weight training yields hypertrophy of fast-twitch (Type II) fibers.
What causes the myosin head to be cocked?
ATP –> ADP + Pi (both the ADP and Pi are still bound to the cocked myosin)
What allows the power stroke of myosin to take place?
Rls of Pi and ADP
If there is not ATP to bind the myosin heads, what pathology occurs?
Rigor mortis
What is the pathway for smooth muscle contraction and relaxation?
Contraction:
AP –> smooth musc mbr depolarizes –> voltage-gated Ca2+ chnls open –> increased Ca2+ in cytoplasm –> Ca2+ binds to calmodulin –> Ca2+/calmodulin activates MLCK (myosin light chain kinase) –> MLCK phosphorylates Myosin–> Myosin-P + actin form a cross-bridge and contract.
Relaxation: MLCP (myosin light chain phosphatase) dephosphorylates the Myosin-P, so there is just myosin (and actin, not linked), causing relaxation.
What drugs inhibit MLCK (myosin light chain kinase)? What effect does this have on the muscle?
Dihydropyridine CCBs,
Epi at the B2 receptor
Prostaglandin E2
These inhibit contraction.
Without MLCK, the myosin is not phosphorylated, so it can’t form a crossbridge w actin and cause contraction.
What drugs enhance the activity of MLCP (myosin light chain phosphatase)? What effect does this have on muscle?
Sildenafil
NO
LPS (gram-neg bacteria)
These promote relaxation.
MLCP removes the phosphate from myosin, causing relaxation of muscle. More MCLP effect means more relaxation.
What is endochondral ossification?
Longitudinal bone growth.
Cartilagenous model is first made by chondrocytes (endoCHRONDRAL ossification).
Later, osteoclasts and osteoblasts replace the cartilage with woven bone, and then remodel the woven bone to lamellar bone.
What is membranous ossification?
Flat bone growth (skull, facial bones, axial skeleton)
Woven bone is formed directly (w/o cartilage)
Later, the woven bone is remodeled to lamellar bone.
In endochondral ossification, the osteoblasts help replace the cartilage with woven bone. Where do the osteoblasts come from?
From mesenchymal stem cells in the periosteum.
List the bisphosphonates
-dronate etidronate pamidronate alendronate risedronate
Mechanism, use, toxicity of bisphosphonates
Mech: inhibit osteoclasts. reduce formation and resportion (both) of hydroxyapatite.
Use: post-menopausal osteoporosis, malignancy-assoc’d hypercalcemia, Paget’s dz of bone
Tox: corrosive esphg (don’t lay down after eating), naus/diarrhea
What is the FGF gene responsible for?
Limb lengthening.
(FGF - fibroblast growth factor)
In achondroplasia, constitutive activation of the FGF3 receptor actually inhib’s chondrocyte proliferation –> short limbs (dwarfism)
Achondroplasia
Dwarfism.
Longitudinal bone growth (endochondral ossification) does not occur –> short limbs.
Membranous ossification (flat bone growth) does occur tho, so normal head/trunk.
Normal life span and fertility.
Achondroplasia mutation pattern
> 85% of mutations occur sporadically. a/w advanced paternal age.
Can also be inherited - auto dom. inheritance.
But, homozyg dom (RR) is lethal in utero, so all pts w achondroplasia will be heterozyg (Rr).
Two pts w achondroplasia have a child. What are the chances the child has achondroplasia?
50%. All pts w achondroplasia are Rr, and it's auto-dominant. So Rr X Rr = 25% RR (these die in utero) 50% Rr (have achondroplasia) 25% rr (don't have achondroplasia)
One pt w achondroplasia and one normal pt have a child. What are the chances it will have achondroplasia?
50%. All pts w achondroplasia are Rr, and it's auto dom. Rr x rr = 50% Rr (have achondroplasia) 50% rr (don't have it)
T/F with autosomal dominant inheritance, there is no such thing as an unaffected/silent carrier.
True.
RR has it
Rr has it (since it’s dominant)
rr doesn’t have it (and doesn’t carry it)
What is osteoporosis? Risk factors?
Reduction of primary trabecular/spongy bone mass, even tho there is normal bone mineralization.
D/t: advanced age smoking thin white no weight-bearing exercise poor Ca2+ and Vit D intake hypogonadism (menopause, decreased testosterone, decreased estrogen) corticosteroid use (>3mo) heparin use (prolonged)
If a pt will be taking corticosteroids for >3mo, what other drug do they need to be taking?
A bisphosphonate (-dronate) to prevent osteoporosis.
What is Type I and Type II osteoporosis?
Type I: post-menopausal. increase bone resorption d/t decrsd estrogen lvls. estrogen replacement as prophylaxis controversial bc of side effects
Type II: Senile osteoporosis. Both M and F >70yo
What fractures are common in osteoporosis?
Vertebral crush fracture –> acute back pain, loss of height, kyphosis. Kyphosis is bc the loss of bone usu occurs in the anterior part of the vertebral body- so that part is crushed and spine curves in C shape)
Femoral neck fracture (femur fracture is life-threatening- hard to recover from)
Distal radius (Colles’) fracture- often px’g sign, esp if it was only d/t low impact.
Prophylaxis for osteoporosis
Exercise!
Eat Ca2+ before 30yo. Get Vit D
Don’t smoke or use corticosteroids.
Rx for osteoporosis
Estrogen and/or calcitonin
Bisphosphonates or PTH pulses (Teriparatide) for severe cases.
Don’t take glucocorticoids!
How to Dx osteoporosis
Dexa bone density scan
Do at lumbar spine or at femur.
What is osteopetrosis? (marble bone disease)
Genetic deficiency of carbonic anhydrase II
Failure of normal bone resorption bc of abn osteoclast fn –> thickened, dense bones that are prone to fracture.
“Erlenmeyer flask” bones that flare out.
Can result in cranial nerve impingement and palsies d/t narrowed foramina (also hearing loss)
Decreased marrow space leads to anemia, thrombocytopenia, and infection.
Serum Ca2+, phosphate, and and ALP are normal.
Anemia + Thrombocytopenia + Infection
decreased RBCs + decreased platelets + decreased WBCs = pancytopenia (aplastic anemia)
Seen in osteopetrosis
What is osteomalacia/rickets?
Soft bones d/t defective mineralization/calcification.
Caused by Vit D deficiency.
In adults: decreased Vit D –> decreased Ca2+ –> increased PTH –> decreased serum phosphate –>osteomalacia
Reversible if Vit D is replaced.
In kids: rickets
What are the actions of PTH?
PTH = phosphate trashing hormone: pull phosphate from bones and dumps it in urine.
PTH keeps the serum Ca2+ levels in the blood constant, no matter what. To do this, it will pull Ca2+ from the bone to put it in serum.
Also, PTH will decrease excretion of Ca2+ by the kidney, so that it is reabsorbed and can go to the serum.
Often, when PTH is elevated, ALP will also be elevated.
What is the relationship between Vit D and Ca2+?
Vitamin D helps absorb Ca2+ from the gut.
If there is Vit D deficiency, there will also be a Ca2+ deficiency since Ca2+ won’t be absorbed as much.
What is the relationship between PTH and Ca2+
PTH keeps the right Ca2+ levels in the blood. If the Ca2+ levels in the blood drop, PTH will take Ca2+ from bone.
If there is increased PTH, it means there will be increased Ca2+ in the blood.
What is the relationship between PTH and phosphate?
PTH - phosphate trashing hormone.
Increased PTH means more phosphate will be taken out of bone and excreted in urine (unless there is a problem with the kidney and it can’t excrete things in urine)
What is the relationship between Vit D and phosphate (PO4/3-)
Vit D increases phosphate absorption in the gut.
What does ALP indicate?
ALP = alkaline phosphatase (alk-phos)
It is high when there is excess bone remodeling.
High PTH is often assoc w high ALP, since PTH causes Ca2+ and phosphate to be taken from bone.
What is osteitis fibrosa cystica?
“Brown tumors” in the bone- actually cystic spaces that are lined by osteoclasts and filled w fibrous stroma, sometimes blood.
It’s caused by primary hyperparathyroidism (excess PTH).
Excess PTH means there will be lots of Ca2+ taken from bone and put into blood (so high serum Ca2+), low serum phosphorus (PTH dumps phosphate in urine).
There will be high ALP since there is a lot of remodeling.
What is Paget’s dz of bone?
Abn bone architecture d/t increase in osteoclastic activity (and osteblastic, somewhat).
Hat size increased
Hearing loss is common d/t auditory foramen narrowing.
Might be viral (paramyxovirus)
There is a mosaic bone pattern, and long bone “chalk-stick” fractures.
Increased blood flow from AV shunts can cause high-output heart failure.
Can lead to osteogenic sarcoma (osteosarcoma), bone pain, bone fractures, bone deformities
Rx for Paget’s dz of bone
Bisphosphonates (-dronate) to inhibit the osteoclastic activity.
Serum levels in Paget’s dz of bone
Serum Ca2+, phosphorus, and PTH levels are normal. ALP is very increased bc there is so much excess remodeling.
Polyostotic fibrous dysplasia
Bone is replaced by fibroblasts, collagen, and irregular bony trabeculae. Affects many bones.
McCune-Albright syndrome is a form of polyostotic fibrous dysplasia.
McCune-Albright syndrome
Precocious puberty (short stature)
Fibrous dysplasia of bone
Cafe-au-lait spots.
Multiple unilateral(!) bone lesions assoc w endocrine abn (prec pub), and unilateral(!) pigmented skin lesions (coast of Maine/cafe-au-lait)
Vitamin D intoxication
Too much vitamin D means the gut absorbs lots of Ca2+ and phosphate, so there is decreased PTH.
ALP is normal bc there is not remodeling
Too much Vit D can be caused by granulomatous dz like Sarcoidoses
What happens to Vit D, serum Ca2+, PTH, phosphate when there is renal insufficiency?
Renal insufficiency occurs in chronic renal dz, hemodialysis pts
Kidney is where the active form of Vit D is formed, so in kidney dmg, Vit D is decreased. This means serum Ca2+ is decreased, and PTH is increased. PTH normally dumps lots of phosphate in the urine, but in order to do that, the kidney must be working, and here it’s not. So even tho PTH is increased, there will be an increase in phosphate (since the kidney can’t get rid of it)
In which dz’s of bone is the ALP elevated?
It’s elevated when there is a lot of bone remodeling.
Osteitis fibrosa cystica (hyperparathyroidism)
Paget’s dz of bone
Also can be normal or elevated in Osteomalacia/Rickets
Lab values for osteoporosis:
Serum Ca2+, Phosphate, ALP, PTH
Everything is normal
Lab values for Paget’s dz of bone:
Serum Ca2+, Phosphate, ALP, PTH
ALP is elevated
Everything else is normal
Lab values for osteomalacia/rickets:
Serum Ca2+, Phosphate, ALP, PTH
Ca2+ decreased
Phosphate decreased
ALP normal or increased
PTH increased
Vit D is decreased, so Ca2+ is decreased, so PTH is increased, so Phosphate is decreased.
Lab values for osteopetrosis:
Serum Ca2+, Phosphate, ALP, PTH
Everything is normal
Lab values for Osteitis fibrosa cystica:
Serum Ca2+, Phosphate, ALP, PTH
Primary hyperparathyroidism. So: Ca2+ increased Phosphate decreased ALP increased PTH increased
Most common malignant primary bone tumor in kids
Osteosarcoma (osteogenic sarcoma)
Most common primary malignant bone tumor in adults
Multiple myeloma
Most common benign bone cell tumor
Osteochondroma
11;22 translocation tumor (bone)
Ewing’s sarcoma
Soap-bubble appearance of bone on xray
Giant cell tumor (osteoclastoma)
Onion-skin appearance of bone
Ewing’s sarcoma
Bone tumor that may actually be a hamartoma
Osteochondroma
hamartoma - overgrowth of local tsu- tsu that should be there, there’s just too much of it
Codman’s triangle on x-ray
elevation of the periosteum
seen in osteosarcoma
(also seen in osteogenic myelitis)
Bone tumor assoc w Gardner’s syndrome
osteoma (benign), often in skull
Gardner’s syndrome
Gardner grows lumps and bumps
Osteoma (benign), often in skull
Lipoma
Colon polyps, which can turn into colorectal carcinoma
Osteosarcoma (osteogenic sarcoma)
Malignant tumor of bone, poor pgx.
(2nd most common malignant tumor of bone, after mult myeloma)
Males 10-20yo
Metaphysis of long bones, often around distal femor or proximal tibia (so around knee)
Predisposing factors: Paget's dz of bone bone infarcts radiation familial retinoblastoma (Rb gene)
On Xray, see Codman’s triangle or sunburst pattern from elevation of periosteum
Ewing’s sarcoma
Anaplastic small blue cell malignant tumor of bone
Most common in boys <15 yo
Extremely aggressive and early metastasis, but very responsive to chemo
Onion skin appearance of bone
In diaphysis of long bones, pelvis, scapula, ribs
Translocation of 11;22
Chondrosarcoma
Malignant cartilaginous tumor
Men 30-60 yo
Usu in pelvis, spine, scapula, humerus, tibia, femur.
Usu of primary origin, but can be from osteochondroma (rare)
Expansile glistening mass w/in medullary cavity
Osteochondroma (exostosis)
Most common benign bone tumor.
Mature bone w cartilaginous cap
Usu males <25yo
Commonly originates from long metaphysis.
Malignant txformation to chondrosarcoma is rare.
Enchondroma
Benign cartilaginous neoplasm found in intramedullary bone.
Usu in distal extremities (vs chondrosarcoma)
Osteoma
Benign bone tumor assoc w Gardner’s syndrome (FAP).
New piece of bone grows on another piece of bone, often in skull.
Osteoid osteoma
Benign bone tumor
Interlacing trabeculae of woven bone surrounded by osteoblasts
<25yo
Giant cell tumor (osteoclastoma)
Benign bone tumor
Occurs mostly at epiphyseal end of long bones
Peak incidence 20-40yo
Locally aggressive (but benign) tumor often around distal femur or proximal tibia (around knee- same place as osteosarcoma).
Dbl-bubble or soap-bubble appearance on xray
Spindle-shaped cells w multinucleated giant cells (so giant cell tumor)
What bone tumors are located in the epiphysis?
Giant cell soap bubble tumor (osteoclastoma) - benign
What bone tumors are located in the Metaphysis?
Benign: osteochondroma (exostosis)
Malignant: Osteosarcoma (see codman’s triangle)
What bone tumors are located in the diaphysis?
Benign: Osteoid osteoma
Malignant: Ewing’s sarcoma
What bone tumors are located in the intramedullary (inside bone)
Benign: Enchondroma (ENside hand/foot bones)
Malignant: chondrosarcoma
Predisposing factors to osteoarthritis
age, obesity, joint deformity
What is osteoarthritis?
Mechanical problem.
Wear/tear on joints leads to destruction of articular cartilage, subchondral cysts, sclerosis, joint space narrowing, osteophytes (bone spurs), eburnation (polished, burnished ivory-like appearance of bone), Heberden’s nodes at DIP, Bouchard’s nodes at PIP, subchondral bone cysts, slight synovial hypertrophy.
Classic px of osteoarthritis
Pain in weight-bearing joints after use (eg pain in knee at the end of the day), improves with rest.
In knees, cartilage loss begins on the medial aspect (“bowlegged”)
Non-inflammatory, and v localized- no systemic sx.
Rx for osteoarthritis
acetominophen
NSAIDs and COX-2 inhibitors
Steroid injections into joint
Hyaluronic acid injections into joint (makes it more slippery)
Opioids for pain
Ultimately, surgical joint replcmt esp knee, hip
What is rheumatoid arthritis?
Autoimmune problem.
Inflammatory.
Inflam of several joints, w pannus formation in the joints (MCP, PIP), subcutan rheumatoid nodules (fibrinoid necrosis surrounded by palisading histioctes), ulnar deviation, subluxation, baker’s cyst (behind knee).
NO DIP involvement.
Epi/blood work in Rheumatoid arthritis
F>M
Type III HPS rxn
80% of pts are RF+ (so have IgM Ab that is anti-IgG)
Anti-CCP Ab is less sensitive, more specific.
Strong assoc w HLA-DR4
Classic px of Rheumatoid arthritis
morning stiffness lasting >30 min and improves w use
Symmetric joint involvement, system sx (fever, fatigue, pleuritis, pericarditis)
Types of finger joint deformities in Rheumatoid Arthritis
Boutonniere deformity (PIP sticks up) Swan-neck deformoity (PIP is down excessively) Z-thumb deformity (PIP is down excessively)
Arthritis: pain improves w rest vs pain improves w use
Improves w rest = osteoarthritis (mechanical, non-inflam)
Improves w use - rheumatoid arthritis (autoimmune, inflammatory)
Arthritis: morning stiffness vs pain at end of day
Morning stiffness: rheumatoid arthritis (improves w use)
At end of day: osteoarthritis (mechanical, the more you use it the more it hurts.
Gardner’s syndrome
Gardner grows lumps and bumps
Osteoma (benign), often in skull
Lipoma
Colon polyps, which can turn into colorectal carcinoma
Osteosarcoma (osteogenic sarcoma)
Malignant tumor of bone, poor pgx.
(2nd most common malignant tumor of bone, after mult myeloma)
Males 10-20yo
Metaphysis of long bones, often around distal femor or proximal tibia (so around knee)
Predisposing factors: Paget's dz of bone bone infarcts radiation familial retinoblastoma (Rb gene)
On Xray, see Codman’s triangle or sunburst pattern from elevation of periosteum
Ewing’s sarcoma
Anaplastic small blue cell malignant tumor of bone
Most common in boys <15 yo
Extremely aggressive and early metastasis, but very responsive to chemo
Onion skin appearance of bone
In diaphysis of long bones, pelvis, scapula, ribs
Translocation of 11;22
Chondrosarcoma
Malignant cartilaginous tumor
Men 30-60 yo
Usu in pelvis, spine, scapula, humerus, tibia, femur.
Usu of primary origin, but can be from osteochondroma (rare)
Expansile glistening mass w/in medullary cavity
Osteochondroma (exostosis)
Most common benign bone tumor.
Mature bone w cartilaginous cap
Usu males <25yo
Commonly originates from long metaphysis.
Malignant txformation to chondrosarcoma is rare.
Enchondroma
Benign cartilaginous neoplasm found in intramedullary bone.
Usu in distal extremities (vs chondrosarcoma)
Osteoma
Benign bone tumor assoc w Gardner’s syndrome (FAP).
New piece of bone grows on another piece of bone, often in skull.
Osteoid osteoma
Benign bone tumor
Interlacing trabeculae of woven bone surrounded by osteoblasts
<25yo
Giant cell tumor (osteoclastoma)
Benign bone tumor
Occurs mostly at epiphyseal end of long bones
Peak incidence 20-40yo
Locally aggressive (but benign) tumor often around distal femur or proximal tibia (around knee- same place as osteosarcoma).
Dbl-bubble or soap-bubble appearance on xray
Spindle-shaped cells w multinucleated giant cells (so giant cell tumor)
What bone tumors are located in the epiphysis?
Giant cell soap bubble tumor (osteoclastoma) - benign
What bone tumors are located in the Metaphysis?
Benign: osteochondroma (exostosis)
Malignant: Osteosarcoma (see codman’s triangle)
What bone tumors are located in the diaphysis?
Benign: Osteoid osteoma
Malignant: Ewing’s sarcoma
What bone tumors are located in the intramedullary (inside bone)
Benign: Enchondroma (ENside hand/foot bones)
Malignant: chondrosarcoma
Predisposing factors to osteoarthritis
age, obesity, joint deformity
What is osteoarthritis?
Mechanical problem.
Wear/tear on joints leads to destruction of articular cartilage, subchondral cysts, sclerosis, joint space narrowing, osteophytes (bone spurs), eburnation (polished, burnished ivory-like appearance of bone), Heberden’s nodes at DIP, Bouchard’s nodes at PIP, subchondral bone cysts, slight synovial hypertrophy.
Classic px of osteoarthritis
Pain in weight-bearing joints after use (eg pain in knee at the end of the day), improves with rest.
In knees, cartilage loss begins on the medial aspect (“bowlegged”)
Non-inflammatory, and v localized- no systemic sx.
Rx for osteoarthritis
acetominophen
NSAIDs and COX-2 inhibitors
Steroid injections into joint
Hyaluronic acid injections into joint (makes it more slippery)
Opioids for pain
Ultimately, surgical joint replcmt esp knee, hip
What is rheumatoid arthritis?
Autoimmune problem.
Inflammatory.
Inflam of several joints, w pannus formation in the joints (MCP, PIP), subcutan rheumatoid nodules (fibrinoid necrosis surrounded by palisading histioctes), ulnar deviation, subluxation, baker’s cyst (behind knee).
NO DIP involvement.
Epi/blood work in Rheumatoid arthritis
F>M
Type III HPS rxn
80% of pts are RF+ (so have IgM Ab that is anti-IgG)
Anti-CCP Ab is less sensitive, more specific.
Strong assoc w HLA-DR4
Classic px of Rheumatoid arthritis
morning stiffness lasting >30 min and improves w use
Symmetric joint involvement, system sx (fever, fatigue, pleuritis, pericarditis)
Types of finger joint deformities in Rheumatoid Arthritis
Boutonniere deformity (PIP sticks up) Swan-neck deformoity (PIP is down excessively) Z-thumb deformity (PIP is down excessively)
Arthritis: pain improves w rest vs pain improves w use
Improves w rest = osteoarthritis (mechanical, non-inflam)
Improves w use - rheumatoid arthritis (autoimmune, inflammatory)
Arthritis: morning stiffness vs pain at end of day
Morning stiffness: rheumatoid arthritis (improves w use)
At end of day: osteoarthritis (mechanical, the more you use it the more it hurts.
Rx for rheumatoid arthritis
NSAIDS
TNF-a inhibitors: Etanercept, Infliximab, Adalimumab
What are the anti-TNFa drugs used for?
Rheumatoid arthritis
Ankylosing spondylitis
Severe psoriasis
Inflam bowel dz
Sjogren’s syndrome
Triad:
Xerphthalamia (dry eyes, conjuntivits, sand-in-eyes)
Xerostomia (dry mouth, dysphagia)
Arthritis
Also parotid enlargement, increased risk of Bcell lymphoma, and dental carries.
Auto-Ab to ribonucleoprotein Ag: SS-A (anti-Ro) Ab and SS-B (anti-La) Ab. RF can also be elevated.
Usu F 40-60yo
A/w rheumatoid arthritis
Sicca syndrome
Sjorgren’s syndrome but without the arthritis.
Dry eyes, dry mouth, nasal, vag
Chronic bronchitis
Reflux esophagitis
How to Dx gout or pseudogout
Do a joint aspirate and look for crystals
Gout = negatively birefringent, yellow needle-shaped crystals under parallel light (blue under perpendicular)
Pseudogout: weakly positive birefringent; blue rhomboids in parallel light. (yellow in perpendicular)
Findings in gout
Precipitation of monosodium urate crystals into joints d/t hyperuricemia.
90% d/t underexcretion (only 10% d/t overproduction)
Needle-shaped crystals, negatively birefringent (yeLLow under paraLLel light)
More common in males
Gout is caused by hyperuricemia. What can cause hyperuricemia?
Lesch-Nyhan syndrome PRPP excess (meal) Decreased excretion of uric acid (thiazide or loop diruetics cause this) Increased cell turnover von Gierke's dz
von Gierke’s dz
Type I glycogen storage dz d/t deficiency in Glucose-6-Phosphatase (can’t take the P off to turn it into glucose).
Causes severe fasting hypoglycemia, v increased glycogen in liver, increased blood lactate (which can lead to gout) and hepatomegaly.
Lesch-Nyhan syndrome
HGPRT deficiency, which causes a defect in purine salvage.
HGPRT converts hypoxanthine to IMP, and converts guanine to GMP.
If HGPRT is deficient, hypoxanthine and guanine build up and are converted to xanthine, which is converted to uric acid. So, increased uric acid production leads to hyperuricemia and/or gout.
Also causes MR, agressiveness, self-mutilation, chreoathetosis
Rx allopurinol (inhibits xanth oxidase, so cant make xanthine or uric acid)
Sx of Gout
Swollen red painful joint. Asymmetric joint distribution.
Classic manifestation is painful MTP joint of big toe (podagra).
Tophus formation- often on external ear. (also olecranon bursa, achilles tendon)
Acute attack after lg meal and/or alcohol
Why does alcohol precipitate an acute attack of gout?
Alcohol metabolites compete for the same excretion sites in the kidney as uric acid- so there is decreased secretion of uric acid and subsequent buildup in blood.
Rx for gout
NSAIDS (indomethacin, naproxen, ibuprofen, ketorolac)
Colchicine
Probenecid
Allopurinol
T/F Increased uric acid does not predict gout.
True.
Can have increased uric acid but no gout; can have gout w/o increased uric acid.
Pseudogout
Caused by calcium pyrophosphate crystals w/in joint space.
Basophilic, rhomboid crystals- weakly positively birefringent (blue in parallel light)
Usu affects lg joints (esp knee)
>50yo, M=F
Rx: inhibit inflam w NSAIDS and colchicine
Chondrocalcinosis
Calcification of articular cartilage w Calcium pyrophosphate crystals (the crystals of pseudogout).
If crystals are in cartilage (esp knee) it is diagnostic. Esp in bilateral knee menisci.
What are the crystals made of in gout? in pseudogout?
Gout: monosodium urate
Pseudo: calcium pyrophosphate
What drugs are used to treat gout?
Acute: NSAIDs, colchicine
Chronic: Probenecid, Allopurinol, Colchicine, NSAIDs
List the NSAIDs
Ibuprofen
Naproxen
Indomethacin
Ketorolac
How do NSAIDs work?
They reversibly inhibit both COX-1 and COX-2, therefore blocking prostaglandin synthesis.
Prostaglandins keep the afferent arteriole of the kidney open. NSAIDS block this.
Clinical use for NSAIDs
Antipyretic, analgesic, antiinflam
Indomethicin is used to close a PDA
Toxicity of NSAIDs
Renal dmg, fluid retention, aplastic anemia, GI distress, ulcers
How do COX-2 inhibitors work? (celecoxib)
Reversibly inhibit COX-2 specifically.
COX-2 is in inflammatory cells and vascular endothelium, and mediates inflam and pain.
These spare COX-1, so they don’t have the bad GI side effects of COX-1 since they spare the gastric mucosa- less peptic ulcer dz, less gastritis.
What are COX-2 inhibitors used for?
Rheumatoid arthritis
Osteoarthritis
Can also be used for gout, but not 1st choice.
Toxicity of COX-2 inhibitors
Increased risk of thrombosis.
Sulfa allergy (they’re sulfa drugs)
Less toxic to GI than NSAIDs bc no COX-1 effect, so lower incidence of bleeding, ulcers. (BUT: if pt has GI probs, take them off of it- incidence is lower, not absent)
Colchicine
Rx for acute gout
Binds and stabilizes tubulin to inhibit polymerization of MTs, therefore impairs leukocyte chemotaxis and degranulation. (WBCs can’t move to cause inflam)
Has GI side effects (diarrhea), esp if given orally. Indomethicin is less toxic and also used in acute gout.
Probenecid
Used to treat chronic gout (should NOT be used in acute)
Inhibits resorption of uric acid in the PCT, so uric acid is excreted.
Also inhibits secretion of penicillin (used in WWI)
Allopurinol
Drug for chronic gout (should NOT be used in acute), also used in lyphoma/leukemia to prevent tumor-lysis-assoc’d urate nephropathy.
Mech: inhibits xanthine oxidase, so xanthine isn’t converted to uric acid.
Allopurinol increases concentrations of azathioprine (immunosuppressant) and of 6-MP (anti-cancer), since they are both normally metabolized by xanthine oxidase.
Why should you not give salicylates to treat gout?
Salicylates depress uric acid clearance unless the dosage is super high- and even really high doses have only minor uricosuric activity.
What is the normal pathway for uric acid excretion?
Purines (from diet and from nucleic acids) are broken down into hypoxanthine. Xanthine oxidase converts hypoxanthine to xanthine, and then xanthine oxidase again coverts xanthine to plasma uric acid. Kidneys filter and excrete it in urine.
If there is too much uric acid in plasma, urate crystals will deposit in joints- gout.
Diuretics and low-dose salicylates block tubular secretion, so they are bad to use in gout, bc uric acid won’t be secreted.
Probenecid and high dose salicylates will block tubular reabsorption, so more uric acid goes out in the urine- good for gout.
Allopurinol blocks xanthine oxidase at both of its steps.
