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Patofysiologi Benvävnad/Leder Per-Åke L 2011 1 Factors That Affect Bone Growth 1. 2. 3. 4. Minerals Vitamins Hormones Exercise Per-Åke L 2011 2 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 Per-Åke L 2011 3 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 Per-Åke L 2011 4 Bone fractures are very painful! Per-Åke L 2011 5 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. Per-Åke L 2011 6 Vertebral fractures Advanced Osteoporosis Loss of height Spine deformity Often severe pain, Loss of mobility Per-Åke L 2011 7 Subluxation : an incomplete or partial dislocation of a joint or organ. Luxation: a complete dislocation of A joint or organ. Per-Åke L 2011 8 Bone Fracture Repair Per-Åke L 2011 9 Bone Fracture Repair Per-Åke L 2011 10 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” Per-Åke L 2011 11 Osteoporosis • Mechanisms causing osteoporosis – Imbalance between rate of resorption and formation • Types of osteoporosis – Type I – Type II – Secondary Per-Åke L 2011 12 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 Per-Åke L 2011 13 Steroid Induced osteoporosis Corticosteroids increase the bone resorption rate and depth, similar to menopause. The steroids block action of Per-Åke L 2011 14 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 Per-Åke L 2011 15 Spinal Osteoporosis Per-Åke L 2011 16 Per-Åke L 2011 17 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 and 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. Per-Åke L 2011 19 Causes/Rick Factors • • • • • • 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. Per-Åke L 2011 20 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 Per-Åke L 2011 21 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. Per-Åke L 2011 22 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. Per-Åke L 2011 23 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 Per-Åke L 2011 24 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. Per-Åke L 2011 25 Infection Per-Åke L 2011 26 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. Per-Åke L 2011 27 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 Per-Åke L 2011 28 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. Per-Åke L 2011 29 • 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. Per-Åke L 2011 30 • These cells produce the Rheumatoid Factor, prostaglandins, cytokines and other mediators. • Over time, the chemicals from the cells damage cartilage, ligaments, tendons, and bone. Per-Åke L 2011 31 Per-Åke L 2011 32 Osteoarthritis Per-Åke L 2011 33 Gout Per-Åke L 2011 34 Gout • Gout is defined as a peripheral arthritis resulting from the deposition of sodium urate crystals in one or more joints and soft tissues. Per-Åke L 2011 35 Pathophysiology • Primary gout: • Overproducers: 10% • Under-excretors: 90% • Secondary gout: • • • • Excess nucleoprotein turnover (lymphoma, leukemia) Increased cell proliferation/death (psoriasis) Rare genetic disorder Lesch-Nyan Syndrome pharmaceuticals Per-Åke L 2011 36 Signs and Symptoms • Acute attack: • • • • • 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 Per-Åke L 2011 37 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. Per-Åke L 2011 38 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 Per-Åke L 2011 39 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 Per-Åke L 2011 40 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 Per-Åke L 2011 41 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 Per-Åke L 2011 42 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 Per-Åke L 2011 43 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 • Per-Åke L 2011 44 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 Per-Åke L 2011 45 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 Per-Åke L 2011 46 • 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 Per-Åke L 2011 47