bone.ppt

DISEASES OF BONE AND CONNECTIVE TISSUES NOREEN BUKHTIARI

MECHANISM OF BONE FORMATION AND BREAKDOWN
Key words
Osteoblasts : cells that synthesize bone matrix
Osteoid : Unmineralized bone matrix
Osteocytes : mature osteoblasts encased in bone matrix.
Osteoclasts: cells that resorb bone.
Modeling : formation of bone
Remodeling: breakdown and renewal of bone.
Calcidiol : 25 (OH)2 D
Calcitriol : 1, 25 (OH)2 D

OSTEOBLAST
Synthesise and maintain bone matrix
.Present on the surfaces of both cortical and trabecular bones.
Originate from mesenchymal progenitor cells.
Plasma membrane is associated with a very high activity of Alkaline phosphatase.
Osteoblasts express receptors for PTH, Calcitriol, Oestrogen, growth factors and a number of cytokines.
Cytokines and growth factors such as fibroblast growth factor (FGF) and IGF-1 are regulators of formation of these cells.
Mature osteoblasts change into osteocytes embedded in the bone matrix they made.

OSTEOCLASTS
Derived from hematoprogenitor cells that also give rise to monocytes and macrophages.
They are multinucleated, having large number of mitochondria and lysosomes.
Cytokines (interlukin-1, IL-6, IL-11) and tumour necrosis factors (TNF) are responsible for maturation of osteoclasts.
Activated osteoclasts possess a’ ruffled border’ which is delimited by a ‘sealing zone’ at which it is attached to the underlying bone.
Bone resorption occurs as a result of the secretion of protons and proteolytic enzymes into the space between the ruffled border and the bone surface.
Lysosomes dissolves bone crystals and their proteolytic enzymes digest bone matrix.

BONE REMODELING

Components of bone
Calcified matrix (90%),
composed of collagen fibres (type-1),
Glycosaaminoglycan containing ground substance,
Spindle shaped crystals of hydroxyapatite
2. Mineral Element
Crystals of Calcium and Phosphate are arranged either amorphously or as Hydroxyapatite Ca 10 (PO4) 6 (OH) 2 on or within the collagen fibres.
Na, Zn, Mg, Pb, Cu and fluoride.
3. Non Collagenous Components (Proteins):
Osteocalcein: protein produced by the osteoblasts
α2 HS- glycoprotein: produced by the liver and absorbed by the bone matrix
Amino Acids: about one fourth of amino acids present in collagen are proline and hydroxproline.

REMODELING OF BONE
Maintenance of bone mass by replacing pockets of old and / or microdamaged bone.
Quiescent state: bone surface is covered with lining cells.
Resorptive state: excavation of a resorption pit by osteoclasts.
Formation state of new bone matrix followed by mineralization.
Osteoblasts then may turn into bone lining cells or survive as osteocytes in bone lacunae.
Osteoablasts provide much of the control as they receive signals and release soluble mediators (signals) that induce osteoclastic bone resorption.

Formation and resorption are coupled. A critical mechanism by which osteoblasts regulate bone resorption is via a system
‘ RANK/RANKL/OPG’
RANKL: Recetor activator of nuclear factor k-B ligand
OPG: Osteoprotegerin(cytokine), Inhibitor of osteoclastogenesis
RANKL &OPG regulate the development and function of osteoclasts and is expressed on the surface of osteoblasts.
RANK: on the surface of osteoclast precursors
Remodeling can be controlled by systematic and local factors.
During growth bone formation exceeds, whereas In senescence resorption increased due to deficiency of sex hormone, reduced physical activity and various endocrine and inflammatory diseases.
Age related bone loss affects both cortical and trabecular bone.
After menaopause bone loss is from the axial skeleton which has greater proportion of trabecular bone.

RANGE OF PATHOLOGIES THAT IMPACT ON BONE AND CONNECTIVE TISSUES MALIGNANCY HYPERPARATHYROIDISM OSTEOPOROSIS OSTEOMALACIA/RICKETS

MALIGNANT DISEASES WITH OR WITHOUR BONE METASTASIS
NON-METASTATIC
Due to the secretion of PTHRP by some tumours of non endocrine tissues.
PTHRP induce osteoclastic activity and causes hypercalcaemia which is not subject to normal feedback control. It may rise rapidly to dangerously high level.
PO4 will be low relative to urea concentration.
Alk.Phos activity remains high either due to the secondary deposition on bone or its impact on liver or on both.
Bony lesions are not present may be due to early diagnosis/treatment or fatal underlying cause.
METASTATIC
It occur in syndrome with multiple bony metastasis or myelomatosis
Plasma Ca and PO4 conc. Rise in parallel by direct bone breakdown.
Malignant deposits in bone stimulate osteoclastic reaction.
Alk.pos activity rise at early stage, later on it remains normal despite the extensive involvement of bone.
In malignant diseases increase in osteoclastic activity is due to PTHRP, Vit.D in lymphomas, and lymphotoxin in multiple myelomas etc.

HYPERPARATHYROIDISM
PTH: Cal/PO4 homeostasis, Vit.D synthesis and
osteoclastic activity etc..
Its secretion increase with age and in patients with
renal failure.
Inapropriate secretion of PTH
Adenoma, hyperplasia or carcinoma of PT gland.
Ectopic secretion - MEN e.g. pituitary and pancreatic adenoma and carcinomas etc.
Complications
Fluoride parathyroid Bone disease – an uncommon manifestation.
Calcium related skeletal diseases become infrequent due to early diagnosis / treatment.
Mild hyperparathyroidism cause loss of cortical bone – increased risk fracture

Overt Bone disease of P. hyperparathyroidism
In severe hyperparathyroidism:
P. Calcium >3.0 mmol/L and much higher level of PTH.
Larger and growing tumours.
Marked increase in bone resorption.
Vit.D deficiency that occur due to accelerated hepatic metabolism of 25(OH)D or hypercalcaemia
Treatment:
Surgical correction of the cause & antiresorptive therapy to prevent progressive bone loss.
Hungry bone syndrome: After the surgical correction of underlying cause patients may develop severe hypophosphataemia and hypocalcaemia.
Investigation: Inter and post operative PTH level,
S. Cal ,and markers of bone resorption.

Osteitis Fibrosa
Histopatological bone lesion due to the excessive PTH secretion
due to P. hyperparathyroidism or Sec. HPT due to Renal failure.
Marked increase in the rate of bone resorption and formation.
Which result in the increased osteoid surface extent and marrow fibrosis.
Feautures and symptoms similar to Prim and Sec. HPT i.e. generalized bone pain, bone tenderness, proximal myopathy and radiographic subperiosteal erosions of bone.
Condition in P. hyperparathyroidism are not sever because of the surgical removal of the underlying cause but Sec. HPT associated to renal disease are less amiable to treatment.
Cystic lesions ( brown tumours) filled with osteoclasts and marrow fibrosis are a frequent feature of severe P. hyperparathyroidism than ureamic hyperparathyroidism.
Pathological fractures occur mostly at the site of brown tumour.

OSTEOPOROSIS
Reduction in bone mass density to the point that a minor trauma may result in fracture.
Age and gender both reflects importance in its pathogenesis as the incidence of hip and vertebral fracture increases later in life.
The fracture rate at these sites increase in men 10 years later in life.
Osteoporotic bone is normally mineralized but reduced in volume.
Using BMD criteria Osteoporosis is defined as a bone disease when BMD T-score <-2.5. which means a BMD that is more than 2.5 standard deviations below the mean value in the normal young population.
Common osteoporotic fractures of clinical consequence are hip, forearm, vertebral body, humerus, ribs and pelvis.

Primary osteoporosis
Senile osteoporosis:
Ageing – 50 yrs in women and 65-70 in men.
Hormonal alteration (PTH, oestrogen,)
Low synthesis of vit.D, and calcitonin
Nursing home residents
Decreased intestinal absorption of calcium.
Post menopausal: Oestrogen deficiency cause bone resorption
Release of Ca and PO4 in intra cellular spaces that in turn suppress PTH secretion which result in decreased calcitriol synthesis and decreased osteoblastic activity
Idiopathic juvenile osteoporosis:
Recover at puberty, treatment with calcitriol reduce bone fracture.
Present in infants born with low birth weight.

Secondary osteoporosis
Medication:
Glucocorticoids – induce resorption
Corticosteroid – exert inhibitory effect on bone formation
and reduce Ca. and PO4 intestinal absorption
Immunosuppressants , cytotoxic drugs, and Li increase
bone resorption.
TPN:
Long term parenteral alimentation can cause demineralization of bone and osteopenia
Cyclic infusion of TPN solutions contain sulfur containing acidic amino acids. Hypertonic dextrose infusions – hyperinsulinaemia and acidosis.
decrease tubular absorption of calcium.
Main feature: hypercalciuria

Aluminium bone disease
Al. is present in antacids, oral ingestion of aluminium hydroxide as phosphate-binding agent, in dialysis fluids, food and nutritional supplements.
It accumulate in bones, kidneys, brain and parathyroids.
Al. excretion reduced in patients with impaired renal functions.
Its accumulation in bones increases the risk of fracture as it accumulates at the bone-osteoid interface and exerts toxic effects on osteoblasts.
It inhibits bone mineralization at higher concentrations.
MEDICAL CONDITIONS:
Thyrotoxicosis - increase bone resorption
Hypogonadism - less bone mass

DIAGNOSIS
Bone mass densitometry- assessment of bone mass
In clinical context: Renal, liver and bone profiles, Growth hormones, IGF-1, thyroid, PTH and Vit. D.
Plasma and urine cortisol, serum and urine protein electrophoresis, coeliac disease and full blood count.
X-ray and CT to scrutinize malignancy and bone biopsy if required.
Markers of bone (as shown on next slide).

TREATMENT
HRT – increase BMD
Calcium & Vit.D
Biphosphonate – enhance Ca content of bone
Calcitonin – effective for vertebral spinal crush
Life style modification
PTH – increase markers for formation and resorption
Strontium – Antiresorptive and anabolic effects for skeleton

OSTEOMALACIA / RICKETES
Normal amount of osteoid that fail to mineralize.
Rickets: Osteomalacia in children termed as ‘Rickets’.
In infancy
Tetany and seizures
Congenital, or fed on Vit.D deficient mother’s milk or acute infection.
X-Ray : Earliest sign of rickets on wrist and knee.
Rachitic Lung: weak rib cage resulting in secondary defective pulmonary ventilation.
Beyond infancy
Spinal and pelvic deformities: waddling gait, bowed legs and knock knees.
Muscular weakness due to decrease uptake of calcium by myocytes.
Hypotonia in proximal muscles also contribute in waddling gaitprotuberance of abdomen and inefficient lung ventilation

Causes
Inadequate supply of minerals – calciopenic and phosphopenic osteomalacia.
Defective osteoblast function.
CALCIOPENIC RICKETS OSTEOMALACIA
Related with abnormal Vit.D metabolism.
Vitamin D deficiency
Inadequate dietary intake or strict vegetarian diet or milk without Vit.D.
Less exposure to sunlight.
Pigment in dark skin decrease the production of cholecalciferol from 7- dehydrocholesterol
Alteration of Vit.D metabolism in liver and / or kidney.
Low calcitriol leads to hypocalcaemia which stimulate secretion of PTH. Induce osteoclastic activity and mobilize calcium and PO4.
Due to urinary losses of Cal and PO4, the biochemical response will be hypocalcaemia, hypophosphataemia, increased activity of alkaline phosphatase and hyper parathyroid, hyperphosphaturia, aminoadicuria and rachitic bone disease

Vit. D dependent OSteomalacia (Type I and Type II)
Type I: Similar abnormalities as of Vit.D deficient rickets
S. calcidiol will be normal and calcitriol deficient.
Patients heal when physiological doses of calcitriol are administered.
Presumably it is 1 α hydroxylase which is either absent or deficient.
Type II: Normal 25(OH)D3 and 1, 25(OH)D3
Resistant to physiological doses of calcitriol.
It is the end organ resistance to normal physiological dose.
Biochemical response: low Cal, PO4, raised PTH, and 1, 25(OH)D3 and normal 25(OH)D3.
Both types are inherited as an autosomal recessive gene
Calcium deficiency rickets
Features similar to Vit D deficieny osteomalacia as Vit. D
Bowed legs, knock knees, wind swept deformities but no muscular weakness.
Biochemical response: Low S and urine Cal, normal 25(OH)D3, raised alkaline phosphatase, 1, 25(OH)D3 and PTH.

Phosphopenic Osteomalacia
Phosphate deficient
Defect in reabsorption of PO4 in the proximal tubules result in massive hypophastaemia and phosphaturia
Genetic (X- linked ) and / or acquired ( heavy metal or light chain nephropathy)
Low PO4 stimulate the formation of calcitriol, theoretically S. calcitriol should be high but on measurement it is low or low normal this might be due to another defect in the functioning of 1α hydroxylase activity.
Biochemical response:
Very low PO4, low S.Ca, raised or normal PTH and 1, 25(OH)D3.
Treatment : supplements of PO4 and Cholecalciferol.
2. Adult phosphopenic osteomalacia is due to mesenchymal tumours
These tumours secrete FGF23 that induce phosphaturia.
Lab investigation: hypophosphataemia, normal Cal., VitD, and PTH.

3. Osteomalacia secondary to gastrointestinal disease and Hepatic Rickets
Serum 25(OH)D3 is low esp. in patients with hepatobiliary disease
Defective cholecalciferol or ergosterol absorption result in impaired calcidiol production by liver or enhanced calcitriol metabolism
Decrease enterohepatic circulation of 25(OH)D3
due to low 1,25 hydroxylase activity , Vit. D malabsorption
Biochemically there will be low S. 25(OH)D3, and 1, 25(OH)D3
4. Osteomalacia secondary to anticonvulsant medication:
Phenobarbital and phynytoin induce mixed microsomal oxidase enzyme system that convert 25(OH)D3 into polar inactive metabolites consequently calcidiol deficiency.
Anticonvulsants inhibit calcitriol dependant intestinal calcium uptake.
Biochemical response: low Cal, low PO4, hypoclciuria, and elevated alkaline phosphatase and PTH.

PAGETS’ DISEASE
.
Pathogenesis:
Bone lesions on X-ray film and raised alkaline phosphatase
Giant Osteoclast with numerous nuclei, and cytoplasmic inclusion bodies possibly of viral origin.
There is evidence for measles and canine distemper viruses but lab data is still not conclusive.
Primarily a disorder of osteoclasts, causing increased resorption surfaces. Bone formation will increase as well.
At very high rate of bone formation collagen fibers are laid down randomly rather than in usual lamellar pattern. The resulting new bone with abnormal structure known as ‘ woven bone ‘ (mosaic pattern) instead of lamellar bone.
Osteoblasts secrete collagen fibres into the marrow space, causing marrow fibrosis.
Clinical features:
Chronic and persistent bone pain, worse at rest and relieved by movement, sec. osteoarthritis is common as well
very vascular and the high blood flow causes an elevation of skin temperature over the affected bone.

Pagets’ Disease

Biochemical tests:
Alkp and hydroxyproline: monitoring the progress of disease and response to therapy. In monostotic pt. elevation may still be within the ref. range.
All bone turnover markers will increase except osteocalcin.
C- Telopeptides( CTX). α - CTX must be in large proportion than β – CTX
Skin temperature is a useful guide to disease activity affective area can be u to 4°C warmer than unaffected area.
Plasma and Urine calcium
Usually normal but patients with very extensive and progressive pagetic disease may develop hypercalcaemia and hypercalciuria.
Treatment:
No cure, metabolic activity of diseased bone can be inhibited
Biphosphonate can reduce the metabolic activity of bone

Renal Osteodystrophy
Associated with chronic renal failure
Ch. RF Hyperphosphataemia and Hypocalcaemia Secondary Hyperparathyroidism Osteoclastic activity
Less excretion and metabolism of PTH
Low or no alpha-1-hydroxylation
Metabolic acidosis
Release of calcium hydroxyapetite from bone Osteomalacia Osteitis fibrosa

Biochemical implications of Arthritis and gout

KEY WORDS
SYNOVIAL MEMBRANE or SYNOVIUM
One or two cell thick which secrete hyaluronate.
Phagocytose intra articular debris and
Secrete many components of synovial fluid that have immunological properties.
SYNOVIAL FLUID
Ultrafiltrate of plasma with additional components secreted by synovium. Most important is hyaluronate which is important for smooth movement.
Articular surfaces: The bone ends that move against each other.
SYNOVIAL JOINTS
Synovial fluid (90-4ml) to lubricate joint.
Cartilage and synovial fluid together maintain coefficient of friction.

PATHOLOGIES
Over a hundred rheumatic disorders with different underlying causes, different treatments and different outcomes.
CLASSIFICATIONS:
Inflammatory- Rheumatoid arthritis, SLE, and ankylosing spondylitis
Non-inflammatory- Osteoarthritis etc.
OSTEOARTHRITIS:
Causes: Inherited tendency, frequency increase with age, and trauma.
The articular cartilage fissured and gradually weared away.
Joint forms bony outgrowth (osteophytes) in order to heal.
Hip and Knee are affected- Treatment is replacement of joints.
CRYSTALS ARTHRITIS:
The body response to crystals varies. Crystals in joints may provoke a severe inflammatory reaction. Or may just accumulate asymptomatically.
Different crystals tend to favour different sites.
Monosodium urate deposited in cartilage and synovium
CPP in articular fibrocartilage
And basic calcium phosphates in tendons and hyaline cartilage.

Inflammatory Arthritis
The major class of articular diseases is inflammatory arthritis. Group of systemic immunological diseases that focus their attention on the synovium of the joint.
Rheumatoid Arthritis: Archetypical form of inflammatory Arthritis.
The inflammation of synovium, causing pain, tenderness, heat, and stiffness in joint, and systemic reaction causing malaise and fatigue.
Synovial cells are in increased size and number and develop the changes of chronic inflammation with infiltration by macrophages and lymphocytes, and cause alterations in the small blood vessels.
The thickened synovium will spread over the cartilage and erode it and the neighbouring bone. This results is joint damage, deformity and disability.
Ankylosing Spondylitis: mainly affects the small joints of the spine.
The ‘reactive’ arthritis ‘ associated with psoriasis and in response to certain intestinal or genitourinary infections.

Treatment
Day to day basis:
Acute part of inflammatory process can be relieved by anti inflammatory drugs like ibuprofen, celecoxib and diclofenac.
Long term:
Chronic inflammation results in the joint damage and disability. Several drugs can slow down the process eg. methotrexate and sulfasalazine.
The side effects of these drugs are liver damage or bone marrow suppression.
Cytokines such as tumour necrosis factor α (TNF α ) are closely involved in the
rheumatoid process so the recently introduced biological drugs designed to
block the effects of TNFα has revolutionized the RA.
These drugs effect greatly on the synovial thickening and symptoms of RA.

Laboratory Testing in Articular Disease.
Normochronic, normocytic anaemia is frequent.
Anaemia secondary to chronic diseases.
Iron is present in bone marrow but can not be utilized in erythropoiesis.
Hypochromic microcytic anaemia (reduced Hb, MCV and MCH). Anti –inflammatory drugs have a tendency to cause erosions and ulcers in the stomach, duodenum or small bowel resulting in blood loss and iron deficiency.
In RA patients it is often tricky to separate two anaemias, and is made more difficult by the behaviour of ferritin in inflammatory disease.

Ferritin
It is a measure of iron deficiency and an acute phase reactant as well.
In RA patients results should be interpreted with caution.
Usually a conc. <12ug/L is taken as diagnostic of iron deficiency but in RA, rheumatologists take a conc. Of 30µgL to indicate iron deficiency.
Iron deficiency can exist with higher concentration of Ferritin.
Presence of microcytosis favours iron deficiency, but some times examination of bone marrow for iron stores is the only reliable way to differentiate between iron-deficiency anaemia and anaemia of chronic disease.

The Acute Phase Response
ESR: Traditionally used for diagnosis and monitoring the activity
of the disease
CRP: Correlate better with disease activity
In SLE the CRP is often normal. Raised conc. suggest infection rather than disease activity.
Examination of Synovial Fluid
Gram staining will show bacterial infection
Polarizing light microscopy will demonstrate the crystals

Rheumatoid Factors
RF are antibodies directed against the Fc portion of IgG and are present in 75-80% of patients with RA.
In selected population of patients with polyarthritis its positive predictive value is over 80% and a negative predictive value over 95%.
In unselected population its predictive value is low (20%).
Very high value of RF are strong confirmatory evidence of RA but a poor prognostic marker.
Anti-CCP
Antibodies to cyclic citrullinated protein are more specific (96-98%) test for diagnosing RA than RF.

AUTOANTIBODIES
Produced in connective tissue diseases and some cases of vasculitis.
Most autoantibodies occur in several conditions and in normal individuals as well.
Valuable in confirming suspected diagnosis.
Negative tests are useful to rule out diagnoses.
Should not be used for screening purposes or in cases without clinical features suspicious of connective tissue disease.

CONNECTIVE TISSUE DISEASES (CDTs)
In CDTs the person’s ability to recognize their own tissue goes awry and they form antibodies against their own tissues (autoantibodies).
In some cases, these are responsible for the clinical manifestation of the disease.
In others they are a peripheral effect of the underlying disease process.
Systemic Lupus Erythematosus (SLE)
Features:
Mainly affects younger women
Can involve one or more of the bodily systems. Characterized by the formation of autoantibodies against the cell’s nucleus, or part of the nucleus, which are believed to be responsible for many of the manifestations of the disease;
In others they are peripheral effect of the underlying disease.

Joint pains is common, it is unusual to see joint damage such as occurs in RA.
SLE can result in a variety of manifestation in other systems, for example a variety of rashes, haemolytic anaemia, glomerulonephritis leading to renal failure, as well as cerebral, and lung and heart problems. Some of them are life threatening.
Autoantibodies against cell nuclei (anti nuclear factor ANF) are present in almost every case of SLE. However they are also frequently present in other CDTs.
Antibodies to specific components of the nucleus are more diagnostic for example antibodies against double – stranded DNA are strongly suggestive of SLE.
Treatment:
Chloroquine, and / or low doses of prednisone.
Serious cases require high doses of corticosteroids with immunosuppression using clyclophosphamide or azathioprine.

OTHER CTDs
For example:
Sjogren’s syndrome,
Polymyositis,
Scleroderma
Primary biliary cirrhosis
Common Features:
Associated with autoantibody formation
Disease is not believed to be caused by specific antibody-antigen complexes as in SLE.
There is often a cross-over of antibodies in the various diseases and the antibodies are by no means seen in every case.
Concerns over antibody testing:
Low specificity of antibodies triggers inappropriate alarm in patients and increased workload of Rheumatologist and biochemists/immunologists.
These are often positive in normal people, especially low positive e.g. Low titer of TNF is widespread, False positive RF and slightly raised ESR.

GOUT
Gout has prevalence of 3 per 1000 of the general population of which 90 to 95% are men.
Caused by deposition of Monosodium Urate (MSU) crystals in articular tissues (cartilage and synovium).
Hyperuricaemia without attacks of gouty arthritis is common and sometimes plasma UA concentrations are normal during an acute attack of gout.
Uric acid is end product of Purines, they metabolized to UA via hypoxanthine and xanthine.
The final step being catalyzed by xanthine oxidase.
Two – thirds of the urate excreted through kidneys and remainder via the bowel where it is broken down into carbon dioxide and ammonia by bacterial action.

Risk factors:
Hyperuricaemia, obesity, hypertension, age, alcohol consumption, renal insufficiency, and family history (New Zealand Maori).
Several drugs particularly diuretics, low dose aspirin, ciclosporin, and lead poisoning.
conditions with high purine turnover, such as leukaemia and lymphoma and their treatment with cytotoxic drugs, can cause gout by increasing the urate load.
Lesch-Nyhan Syndrome:
A very rare disorder due to inherited abnormality in urate metabolism.
Deficiency of hypoxanthine – guanine phosphoribosyl transferase.

Acute gout
Usually strike on first metatarso-phalangeal joint at night (about 70%). Crystal formation is more likely at colder temperatures and this joint is cooler than more proximal joints.
Joint rapidly become swollen, red and exquisitely tender to touch. There is often a systemic reaction with fever and an acute phase reaction.
Examination of synovial fluid show many MSU crystals. Left to itself acute gout may subside within ten days or so.
Some may never have another attack; there are usually further sporadic attacks.
May become more frequent with involvement of other areas (polyarticular gout ) as the urate load increases.
Chronic Tophaceous Gout
Continuous inflammation of many joints with associated pain, tenderness and immobility
Masses of urate crystals deposit as chalky material called tophi, which some times ulcerate and discharge through the skin. Often seen over joints and bony prominences such as the points of elbows.
Can occur in joints and inside bone causing permanent damage, pain, deformity and disability.
Urate nephropathy and renal calculi of uric acid.

Diagnosis and Treatment
Gout presents in the classic manner. (However infection also presents with painful, swollen, red, hot joints with fever , leukocytes and acute phase reaction.
Reliable diagnosis is by the examination of synovial fluid with Polarizing light microscopy for crystal and Gram staining for bacterial infection.
Only very high UA conc. are convincing, and sometimes helpful in making decision for drug treatment.
Two strands of treatment:
Anti-inflammatory drugs such as diclofenac, indometacin or naproxen. Colchicine can be used when anti-inflammatories are not advisable.
long term to reduce the urate load by allopurinol. Allopurinol is xanthine oxidase inhibitor, which block the conversion of xanthine into urate. Xantine is souble and is excreted renally.
Failure of treatment is seen when there is non-compliance with medication. Often seen in male patients.
Treatment of complicated gout is very difficult e.g. Patients with renal failure and or heart failure often require diuretic which provoke gout.
In transplant patients because of gout inducing anti –rejecting drugs.

Calcium Pyrophosphate Deposition (CPPD)
Common form of crystal arthritis less frequent and less understood.
CPP crystals deposited in articular cartilage and calcification can be seen on X-rays (chondrocalcinosis).
Knee and wrist are most affected.
Symptoms and diagnosis are same as gout. However chronic involvement of several joints can confuse it with other inflammatory articular diseases.
Chondrocalcinosis increase with age, could be triggered by a trauma like surgery.
Familial CPPD is well recognized - a genetic abnormality on the short arm of chromosome 5p has been identified.
Associated with several metabolic diseases e.g. haemochromatosis, hyperparathyroidism, hypomagnesaemia, hypophosphataemia, alkaptonuria and Wilson's disease.
Treatment is with anti-inflammatory drugs and corticosteroid injection of affected joint if required.

Basic Calcium Phosphate Deposition Disease (BCP)
BCP crystals include hydroxyapatite, octacalcium phosphate and tricalcium phosphate.
Often difficult to identify.
Sometimes deposited on soft tissues outside the joint or in tendons.
Tend to occur in young females and affects the shoulder, wrist and even the great toe.
Can cause large effusions and joint resorption in the shoulders of elderly women (Milwaukee shoulder).
Interest in BCP increases as they appear to involve in the process of osteoarthritis.
Injection of corticosteroid often results in dramatic improvement.
Other Crystals:
Crystals of cholesterol, lipids are seen in patients after trauma.
Crystals of oxalic acid are seen in patients of renal failure on dialysis or of primary oxalosis. These can provoke a chronic polyarthritis in the small joints of the hand.

Articular involvement in systemic diseases
Diabetes Mellitus:
Disabling and painful hands and /or shoulders are present in about 30% of diabetics .
Dupuytren’s contracture: thickening of the palmer fascia and increasing contracture of fingers is common is diabetes.
Diabetic cheiroarthropathy or diabetic hand syndrome: thickening of skin and underlying tissues causing limited range of movement of the hands and fingers. Often tendons are affected. Changes are mistaken for rheumatoid arthritis.
Biopsy shows excessive fibrosis and increased deposition of dermal collagen. It is suggested that increases tissue glycation may result in diminished collagen breakdown.
Charcot’s joint or Charcot’s arthritis. Due to the peripheral nerve damage ( a complication of diabetes) usual sensations of joint position and joint movement are lost. Repeated trauma and painless destruction of the joint and bony resorption of large areas of bone may occur in the affected joint.

HAEMOCHROMATOSIS:
Deposition of iron in synovium, loss of joint space and characteristic hook osteophyte formation in these joints. No inflammatory reactions.
ALKAPTONURIA:
Rare autosomal disorder caused by a deficiency of the enzyme homogentisic oxidase.
Result in the build up of homogentisic acid - an intermediate product in the metabolism of phenylalanine and tyrosine.
Excess homogentisic acid oxidized, polymerized and form a blackish pigment “alkapton”, which deposits in cartilage and can be easily seen in the cartilage of ear.
Its deposition in articular cartilage make the joint susceptible to mechanical stress and degeneration. Result in the arthritis of hip, knees and shoulders.
It also deposits in intravertebral discs in the spine, which become calcified.
Diagnosis is made by its characteristic X-ray appearance and estimation of homogentisic acid in urine.

MECHANISMS OF KIDNEY STONE FORMATION AND THEIR INVESTIGATION
Predisposing factors:
Increased concentration of stone constituents due to the excessive production or decreased excretion of stone forming substances.
Changes in urine pH, decreased urine volume, bacterial infection.
Increased urine calcium, urate and oxalate, and decreased Mg, and citrate excretion.
Metabolic Disorders:
Primary hyperparathyroidism,
Renal tubular acidosis type 1
Hereditary hyperoxaluria
Medullary sponge kidney
Cushing’s disease
Milk-alki syndrome

Postulation
Patients with hypercalciuria, hyperoxaluria, and hyperuricosuria do not form stone; conversely may form calculi in the absence of risk factors. It is there fore postulated that:
“ Stone formation occur due to the absence or deficiency in inhibitors of crystal formation in urine”
Inhibitors:
Magnesium, Pyrophosphate, diphosphonate, citrate, Osteopontin, glycosaaminoglycan , and nephrocalcin.
Initiation:
There are many causes for initiatin and propagation of stone
the most determinant is the increased urinary concentration of the stone constituents, such that they exceed their solubility in urine.
Crystals formed spontaneously at supersaturation or a preexisting nuclei can provoke their formation.

Stones and Pathogenesis
Calcium oxalate Calculi:
Majority (70 %) of stones are calcium containing, mostly of calcium oxalate alone or mixed with phosphate.
Calcium containing stones are radio opaque.
Hypercalciura with hypercalcaemia; may be due to primary hyperparathyroidism, sarcoidosis,or neoplastic bony metastases.
Hypercalciuria with normocalcaemia may be idiopathic or due to increased gastro intestinal absorption.
Hypercalciuria in RTA – persistent loss of calcium.
Calcium oxalate and UA Calculi:
As many as 20% calcium oxalate stones are associated with increased uric acid excretion with or without hypercalciuria (hyperuricosuric calcium nephrolithiasis).
The stone formation occurs with nucleation of calcium oxalate by uric acid crystals in the collecting ducts.
Hyperoxaluria can occur in vegetarians and enteric patients due to the over absorption of oxalate by intestine.
Hypocitraturia associated with acidosis and chronic diarrhoea.

Stag horn calculi (Triple stone or Struvite stone 15%)
Composed of MG, NH4 and PO4
Formed largely after infection of urea splitting bacteria (e.g. staphylococcus and proteus). They convert Urea to Ammonia the resultant alkaline urine causes the precipitation of Magnesium ammonium phosphate salts.
Form largest stones as urea excreted in large amount.
Occupy large portion of renal pelvis.
Uric acid Calculi
Uric acid stone are radioluscent and present in 5-10% patients.
Common in patients with hyperuricaemia such as gout and diseases involving rapid cell turnover like leukaemia.
More than half of the patients have neither hyperuricaemia nor increased urinary uric acid excretion.
It’s the tendency of the patients to produce urine with pH lower than 5.5 as uric acid is insoluble at lower acidic pH.
Cystine 1-2%
Genetic defect in the renal reabsorption of amino acids including cystine leading to cystinuria and stone formed at lower urinary pH.

INVESTIGATIONS
Biochemical investigations involve:
Chemical analysis of calculus (if available)
Plasma PTH
Plasma/serum estimation for calcium , albumin, phosphate, bicarbonate and urate.
Urine estimation for
pH (must be very fresh)
qualitative test for cystine
Excretion of calcium, oxalate, urate and citrate in 24 hour urine collection.
Microbiology for the evidence of infection.

bone.ppt

by many87 on Oct 19, 2010

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