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Patofysiologi
Benvävnad/Leder
Per-Åke L 2011
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Factors That Affect Bone Growth
1.
2.
3.
4.
Minerals
Vitamins
Hormones
Exercise
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Factors That Affect Bone Growth
Calcium
Minerals
Makes bone matrix hard
Hypocalcemia: low blood calcium levels.
Hypercalcemia: high blood calcium levels.
Vitamin D
(Calcitriol) Helps build bone by
increasing calcium absorption.
Deficiencies result in “Rickets” in
children
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Factors That Affect Bone Growth
Hormones
Human Growth Hormone
Promotes general growth of all
body tissue and normal growth in
children
Insulin-like Growth Factor Stimulates uptake of amino acids
and protein synthesis
Insulin
Promotes normal bone growth and
maturity
Thyroid Hormones
Promotes normal bone growth and
maturity
Estrogen and
Increases osteogenesis at puberty
Testosterone
and is responsible for gender
differences of skeletons
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Bone fractures are very painful!
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Types of Fractures
• Simple - bone breaks cleanly and does not penetrate the
skin.
• Compound (open) - broken ends of bone protrude
through soft tissues and the skin.
• Comminuted - bone breaks into many fragments.
• Compression - bone is crushed.
• Spiral - ragged break caused by excessive twisting force.
• Greenstick - Bone breaks incompletely.
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Vertebral fractures
Advanced
Osteoporosis
Loss of height
Spine deformity
Often severe
pain,
Loss of mobility
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Subluxation : an incomplete
or partial dislocation of a
joint or organ.
Luxation: a complete
dislocation of
A joint or organ.
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Bone Fracture Repair
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Bone Fracture Repair
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Defining Osteoporosis
• “systemic skeletal disease characterized by
low bone mass and microarchitectural
deterioration of bone tissue, leading to
enhanced bone fragility and a consequent
increase in fracture risk”
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Osteoporosis
• Mechanisms causing osteoporosis
– Imbalance between rate of resorption and
formation
• Types of osteoporosis
– Type I
– Type II
– Secondary
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Osteoporosis - types
• Postmenopausal osteoporosis (type I)
– Caused by lack of estrogen
– Causes PTH to overstimulate osteoclasts
– Excessive loss of trabecular bone
• Age-associated osteoporosis (type II)
– Bone loss due to increased bone turnover
– Malabsorption
– Mineral and vitamin deficiency
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Steroid Induced osteoporosis
Corticosteroids increase the bone resorption rate and depth,
similar to menopause. The steroids block action of
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osteoblasts, so the bone formation
does not increase.
Osteoporosis
• Most common bone disease
• Bones lose mass & become brittle due to loss of
both organic matrix & minerals
– risk of fracture of hip, wrist & vertebral column
– lead to fatal complications such as pneumonia
• Postmenopausal white women at greatest risk
– by age 70, average loss is 30% of bone mass
• ERT (EstrogenReplacementTerapy)slows its
progress, but best treatment is prevention -exercise & calcium intake (1000 mg/day)
between ages 25 and 40
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Spinal Osteoporosis
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Bone Disorders
•Osteomalacia: Loss of bone salts but not collagen
due to poor diet, decreased
absorption of calcium, and vitamin
D deficiency. Calcium is not
deposited in the bones.
•Bones become brittle.
Basically a demineralization of bone
•Example: Rickets in young children Bones become
soft.
•Bowing of the bones,Per-Åke
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other deformities occur. 18
L 2011
Introduction
• Osteomalacia is known as the softening of
bones due to insufficient vitamin D, or
problems with the break down of this vitamin.
• This disease is also known as rickets in
children.Bones with osteomalacia have
sufficient amounts of collagen which gives the
bones their structure, but they lack calcium.
• The softness of the bones is more likely to
cause bow and fractures.
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Causes/Rick Factors
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Vitamin D insufficiency can cause osteomalacia because
vitamin D facilitates calcium absorption and other minerals in the
gastrointestinal tract necessary for bone building. Lack of vitamin
D, calcium and other minerals aren’t absorbed efficiently, so they
are not available for mineralization in the bone building process.
This then result in soft bones.
Insufficient sunlight exposure Sunlight makes vitamin D in your
skin. Therefore osteomalacia can develop in people who spend
little time in the sunlight,
Insufficient vitamin D intake A diet low in vitamin D is the most
common cause seen worldwide.
Certain Surgeries The removal of part or all of your stomach
known as gastrectomy, can lead to this disease because the
stomach breaks down foods to release vitamin D and other
materials, bypassing your small intestine can lead to osteomalacia.
Chronic pancreatitis Pancreatitis is the long-standing
inflammation of your pancreas, an organ that makes digestive
enzymes and hormones
Chronic sprue In this autoimmune disorder, Damaged intestinal
lining doesn’t absorb nutrients, such as vitamin D, as well as a
healthy one would.
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Bone Disorders
Paget’s Disease: Abnormal bone remodeling resulting in
irregular thickening and thinning of
bone through remodeling
Osteomyelitis: Infection of bone most commonly by
Staphylococcus aureus
Osteogenic sarcoma: Bone cancer that affects
osteoblasts at the metaphyses
of long bones. Most common
in teenagers
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Bone pathologies
• Primary bone cancer:
cancer: the cancer started in the bone.
• Metastatic or secondary bone cancer:
cancer: did not start in the
bone but has spread to the bone from other organs. E.g.
when lung cancer spreads to the bones.
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Primary bone cancer
• Osteosarcoma: cancerous tumour of the
bone itself, and it is the most common
primary bone cancer.
• Chondrosarcoma: cancer of cartilage cells
and the second most common primary bone
cancer. After age 20, the risk of developing
chondrosarcoma continues to rise until
reaching about 75 years.
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Secondary bone cancers
• Lymphoma: Non-Hodgkin lymphomas generally
develop in lymph nodes but sometimes start in the
bone. Primary non-Hodgkin lymphoma, multiple
sites in the body are usually involved.
• Multiple myeloma: Although multiple myeloma
almost always starts in bones, do not consider this a
bone cancer because it develops from the plasma
cells of the bone marrow
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Bone Disorders
Arthritis:
Osteoarthritis: “DJD” degenerative joint
disease
Inflammatory Joint Disease:
Rheumatoid arthritis: Initially may be
caused by transient infection that
results in autoimmune attacks against
collagen in the bones at joints.
Gouty Arthritis: Build-up of uric acid in the
joints due to metabolic problems with
handling the amino acid cystine.
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Infection
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Rheumatoid arthritis (RA•
• Systemic disease of joints.
• Inflammatory condition.
• Idiopathic disease that involves immuneimmune-mediated
destruction of joints.
• Acute inflammation: excessive production of synovial
fluid, increased blood flow, neutrophil,
neutrophil, pain, swelling
and joint stiffness.
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RA, Etiology
• Probable background genetic susceptibility (multiple
genes/risk factors involved)
– Concordance rates 15-30% identical twins
– 2.5-3.0 times more prevalent in Women>Men
• Likely environmental triggers in people with genetic
susceptibility
Not seen until late 18th century in EuropeThe exact cause of RA is unknown.
Suspected causes are:
Bacterial Infection
Genetic Marker
Stress
• Viral Infection
• Environmental Triggers
– Tobacco, Caffeine
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How does the immune system play a
role in this disease
• In RA, for some unknown reason, the immune system
considers its own joint tissues foreign.
• White blood cells that normally protect the body,
migrate to the joint cavity.
• Synovium becomes inflammed and fluid, causing
synovitis.
• Lymphocytes, Macrophages, continue to enter the
joint cavity and multiply, differentiate, and release
inflammatory mediators, cytokines, leukotrienes, and
prostaglandins.
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• Within weeks the synovium becomes thickened.
• The mass of synovial tissue that spreads over the top
of cartlidge in a rheumatoid joint is called a pannus,
made of white blood cells: macrophages, B&T Cells,
neutrophils, plasma cells, NK cells, and T Helper cells.
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• These cells produce the Rheumatoid Factor,
prostaglandins, cytokines and other mediators.
• Over time, the chemicals from the cells damage
cartilage, ligaments, tendons, and bone.
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Osteoarthritis
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Gout
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Gout
• Gout is defined as a peripheral arthritis
resulting from the deposition of sodium urate
crystals in one or more joints and soft tissues.
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Pathophysiology
• Primary gout:
• Overproducers: 10%
• Under-excretors: 90%
• Secondary gout:
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Excess nucleoprotein turnover (lymphoma, leukemia)
Increased cell proliferation/death (psoriasis)
Rare genetic disorder Lesch-Nyan Syndrome
pharmaceuticals
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Signs and Symptoms
• Acute attack:
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Over hours frequently nocturnal
Pain
Swelling, redness and tenderness
Podagra: 1st MTP classic presentation
May effect knees, wrist, elbow, and rarely SI and hips.
• Chronic:
• Destructive tophacous
• Much greater chance if untreated
• Rarely presents as a chronic
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Gikt - Definition
• Uric acid is the normal end product of the degradation
of purine compounds.
– Major route of disposal is renal excretion
– Humans lack the enzyme uricase to break down uric
acid into more soluble form.
• Metabolic Disorder underlying gout is hyperuricemia.
• Peak incidence occurs in the fifth decade, but can occur at any
age
• Gout is 5X more common in males than pre-menopausal
females; incidence in women increases after menopause.
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Classification of Hyperuricemia
• Uric acid overproduction
– Accounts for 10% of hyperuricemia
– Defined as 800mg of uric acid excreted
– Acquired disorders
• Excessive cell turnover rates such as Paget’s disease,
hemolytic anemias
– Genetic disorders: derangements in mechanisms that
regulate purine neucleotide synthesis.
• Uric acid underexcretion
– Accounts for >90% of hyperuricemia
– Diminished tubular secretory rate, increased tubular
reabsorption, diminished uric acid filtration
• Drugs, other systemic disease that predispose people to
renal insufficiency
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Pathogenesis of Gouty Inflammation
• Urate crystals stimulate the release of numerous
inflammatory mediators in synovial cells and
phagocytes
• The influx of neutrophils is an important event for
developing acute crystal induced synovitis
• Chronic gouty inflammation associated with cytokine
driven synovial proliferation, cartilage loss and bone
erosion
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Presenting Symptoms
• Systemic: fever rare but patients may have fever, chills and
malaise
• Musculoskeletal: Acute onset of monoarticular joint pain. First
MTP most common. Usually affected in 90% of patients with
gout. Other joints knees, foot and ankles. Less common in
upper extremities
– Postulated that decreased solubility of MSU at lower
temperatures of peripheral structures such as toe and ear
• Skin: warmth, erythema and tenseness of skin overlying joint.
May have pruritus
• Renal colic with renal calculi formation in patients with
hyperuricemia
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Diagnosis
• Definitive diagnosis only
possible by aspirating and
inspecting synovial fluid and
demonstrating crystals
Needle shaped crystals of
monosodium urate
monohydrate
• Polarized microscopy, the
crystals appear as bright
crystals that are yellow
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Systemic Lupus Erythematosis
• Systemic Disorder, involving multiple organs in
multiple ways
• Women:Men = 9:1
• Peak Age of Onset 20’s & 30’s
• Incidence has tripled since 1970’s to
5.56/100,000 population
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SLE= Systemic Lupus Erythematosus
•
Symptoms:
•
fever, weight loss, rash (butterfly rash), hair loss, oral
ulceration, central nervous system involvement (Cognitive
Dysfunction, Lupus Headache, )
Nephritis (Kidney problems), Joint Pain/Arthritis (Arthralgia),
blood disorders, liver problems
•
•
What causes the symptoms?
Most of the symptoms of this disease result from the formation
of immune complexes that deposit within various tissues where
they recruit complement and inflammatory cells to cause
disease
Type III hypersensitivity reaction
•
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What Causes SLE
• Cause is unknown
• What causes SLE is still unknown but it is thought to have a multi-faceted
etiology.
• There are possible genetic and environmental factors
• Genetic factors: Predispose an individual to have this disease
• 10% of individuals who have this disease have a family member who also has
this disease.
• Clear gender and cultural bias for this disease:
women are 10 times more likely than men to get this disease.
• Environmental factors can trigger the disease in genetically predisposed
individuals:
• Most correlated is the presence of female hormone
• ultraviolet light, certain drugs, various infectious agents
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What Happens?
• Loss of self-non-self recognition
• 2 types of autoimmune diseases:
• Organ specific (directed to a target antigen unique to a specific organ or gland)
• Systemic -> has a broad range of antigens and involves many organs and tissues
• Responses in SLE:
widespread inflammation in multiple organs, blood vessels, and other connective
tissues in the body
Inflammation is caused by a profound immune alteration that leads to the
development of T cell and antibody responses
Tissue damage occurs as a result of cell mediated immune responses and direct
damage caused by auto-antibodies or accumulation of immune complexes
• Autoantibodies found in SLE: DNA, , RBCs, platelets, leukocytes, clotting factors
• Autoantibodies specific for RBC’s and platelets can lead to complement-mediated
lysis
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• Hyperactivity of T & B Cells
– Formation of immune complexes
• hypersensitivity reaction. A lot of auto-antibodies being secreted which
react with self antigen
• They bind to form an immune complex
• Complement system is activated to clear these immune complexes
• lead to tissue damage
• Complement activation leads to complement intermediates that mediate
mast-cell degranulation
hemotactically attract neutrophils
Stimulate the release of lytic enzymes from neutrophils trying to phagocytose
the immune complexes
unsuccessful anchored in membranes causes the most damage in SLE
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